MicroRNA-224 Promotes Tumorigenesis through Downregulation of Caspase-9 in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) harbors genetic heterogeneity and generally has more aggressive clinical outcomes. As such, there is urgency in identifying new prognostic targets and developing novel therapeutic strategies. In this study, miR-224 was overexpressed in breast cancer cell lines and TNBC primary cancer samples. Knockdown of miR-224 in MDA-MB-231 cancer cells reduced cell proliferation, migration, and invasion. Through integrating in silico prediction algorithms with KEGG pathway and Gene Ontology analyses, CASP9 was identified to be a potential target of miR-224. miR-224 knockdown significantly increased CASP9 transcript and protein levels. Furthermore, luciferase reporter assays confirmed a direct interaction of miR-224 with CASP9. Our findings have demonstrated that the miR-224/CASP9 axis plays an important role in TNBC progression, providing evidence in support of a promising therapeutic strategy for this disease.

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An orally antitumor chalcone hybrid inhibited HepG2 cells growth and migration as the tubulin binding agent

Summary

Liver cancer is a kind of high mortality cancer due to the difficulty of early diagnosis. It is necessary to develop the anticancer agents to treat liver cancer. Here, a novel chalcone derivative was synthesized and evaluated for anticancer activity in vitro against liver cancer cell lines (HepG2, SNU-423, SMMC7221, and SNU-398). The chalcone hybrid 9 displayed the antiproliferative effect against HepG2, SNU-423, SMMC7221 and SNU-398 cells with IC₅₀ values of 0.9 μM, 2.7 μM, 6.2 μM and 4.6 μM, respectively. Cellular mechanisms showed that derivative 9 could obviously inhibit HepG2 cells growth and colony formation in a concentration-dependent manner. Analogue 9 inhibited the migration by regulating the expression levels of migration-releated markers and transcription factors (Snail and Slug). Tubulin polymerization inhibition assay illustrated that chalcone hybrid 9 might be a potent tubulin polymerization inhibitor. Importantly, compound 9 displayed the antitumor activity against liver cancer HepG2 cells in vivo with the low toxicity toward mice. Therefore, compound 9 as a novel tubulin polymerization inhibitor deserves further investigation to treat liver cancer.

Graphical abstract

Compound 9 displayed the antitumor activity against liver cancer HepG2 cells in vivo and low toxicity toward mice Figure: Orally antitumor chalcone hybrid 9 inhibited HepG2 cells growth and migration as the tubulin binding agent.

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Biliary atresia with an unusual abdominal orientation: A case report.

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Biliary atresia with an unusual abdominal orientation: A case report.

Int J Surg Case Rep. 2019 Jan 30;55:152-155

Authors: Allarakia J, Felemban T, Khayyat W, Alawi A, Mirza A, Alkhazal B, Yousef Y

Abstract
INTRODUCTION: Biliary atresia (BA) is a rare condition where the hepatic or common bile ducts get obliterated by fibrous tissue for unknown causes. It is diagnosed in 5-10 per 100,000 live births worldwide in whom liver injury and death are definite if untreated.
PRESENTATION: We report a case of BA with associated malrotation and situs ambiguous discovered incidentally during Kasai procedure. The small intestine was found to be malrotated with the duodenojejunal junction to the right of the vertebral column. The liver, stomach, and spleen were in the center, right side, and left side of the abdomen respectively. The malrotation was corrected by performing a Ladd's procedure in addition to the Kasai. She had an uneventful postoperative course. At follow-up on the second, sixth and 12th weeks postoperatively, she had normal stool color and liver function.
DISCUSSION: BA patients with associated structural anomalies might have a worse outcome after the Kasai procedure. Several studies demonstrated that the coexistence of malrotation with BA to be in the range of 0.3%-9.4% among BA patients. Also, the presence of situs abnormalities with BA has been reported in some studies to be present in 0.01-0.045% of BA cases. However, the presentation of BA with both situs inversus and intestinal malrotation has seldom been reported.
CONCLUSION: The diagnosis of BA should prompt further investigation for other anatomical abnormalities as the presence of which might affect the management plan.

PMID: 30738370 [PubMed - as supplied by publisher]

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A rare case of nasal septal schwannoma: Case report and literature review.

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A rare case of nasal septal schwannoma: Case report and literature review.

Int J Surg Case Rep. 2019 Jan 30;55:149-151

Authors: Alrasheed W, Almomen A, Alkhatib A

Abstract
INTRODUCTION: Sinonasal schwannoma accounts for only 4% of head and neck nerve sheath tumors. Schwannoma of the nasal septum is still the rarest, with only few cases previously reported.
CASE PRESENTATION: This study presents the case of a 64-year-old Saudi female of the Eastern Province who presented a several-month history of unilateral progressive nasal obstruction and recurrent episodes of epistaxis. The diagnosis of nasal septal schwannoma was made on the basis of a histopathological examination. The case was managed successfully by endoscopic endonasal excision with no postoperative recurrence.
DISCUSSION: Nasal septal schwannoma is rare and has only 32 reported cases. Diagnosis primarily depends on histopathological examination. Endoscopic endonasal excision of the mass is considered the ideal treatment for such pathology.
CONCLUSION: Schwannoma of the nasal septum is rare. However, it should be included as a differential diagnosis in a patient presenting with a unilateral nasal mass.

PMID: 30738369 [PubMed - as supplied by publisher]

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Two cases of debulking surgery for lower limb diffuse plexiform neurofibroma with transcatheter arterial embolisation.

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Two cases of debulking surgery for lower limb diffuse plexiform neurofibroma with transcatheter arterial embolisation.

Int J Surg Case Rep. 2019 Jan 29;55:132-135

Authors: Kitano D, Osaki T, Nakasone M, Nomura T, Hashikawa K, Terashi H

Abstract
INTRODUCTION: Diffuse plexiform neurofibroma (DPN) in patients with neurofibromatosis type 1 (NF1) causes motility dysfunction in severe cases. Transcatheter arterial embolisation (TAE) is an effective haemorrhage control method in vascular tumour surgery.
PRESENTATION OF CASE: We performed debulking surgery for DPN in the buttock and posterior thigh of two NF1 patients. Preoperative TAE with gelatine particles to tumour feeder vessels was conducted in both cases. Operative bleeding volumes were 500 and 4970 mL, respectively. In the latter case, the resection area extended to the upper poles of the buttocks, and the tumour invaded deeply into the surrounding tissues. Massive haemorrhage occurred, and internal iliac arterial balloon was inflated temporarily to further suppress the bleeding. Delayed wound healing due to TAE occurred; debridement and wound closure were required. Motor function improvement was confirmed in both patients.
DISCUSSION: Bleeding volumes varied because of highly developed collateral pathways and tumour invasiveness. As the upper pole of the buttock was perfused by the superior gluteal artery and its numerous collateral vessels, complete haemostasis was difficult despite adequate TAE. Because delineating the tumour border from the normal tissue was impossible due to the high tumour invasiveness, cutting into the hypervascular tumour was inevitable. As gelatine particles were absorbed but remained within the vessels, prolonged wound ischaemia and delayed healing occurred.
CONCLUSION: Although TAE with gelatine particles and balloon occlusion were reliable haemorrhage control methods in debulking surgery for lower limb DPN, optimal haemorrhage control technique, compatible with haemostasis and wound healing, was desired.

PMID: 30738368 [PubMed - as supplied by publisher]

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High Expression of ANXA2 Pseudogene ANXA2P2 Promotes an Aggressive Phenotype in Hepatocellular Carcinoma

Objective. Accumulating evidence suggests that pseudogenes play potential roles in the regulation of their cognate wild-type genes, oncogenes, and tumor suppressor genes. ANXA2P2 (annexin A2 pseudogene 2) is one of three pseudogenes of annexin A2 that have recently been shown to be aberrantly transcribed in hepatocellular carcinoma (HCC) cells. However, its clinical meaning and biological function in HCC have remained unclear. Therefore, the present study was aimed at exploring the prognostic value of a high expression of ANXA2P2 in HCC tissue and at identifying whether it can affect the efficacy of targeted drugs (sorafenib, regorafenib, and lenvatinib). Methods. We obtained ANXA2P2 mRNA expression levels from The Cancer Genome Atlas (TCGA) RNA sequence database. The expression levels of ANXA2P2 in 49 pairs of intratumoral and peritumoral liver tissues were examined by RT-PCR. Wound healing and transwell assays were performed to confirm the tumor-promoting properties of ANXA2P2 in HCC cells. CCK8 assay was conducted to identify whether ANXA2P2 can affect the growth of HCC cells when administered with targeted drugs (sorafenib, regorafenib, and lenvatinib). Results. The expression of ANXA2P2 in HCC tissues was significantly higher than that in adjacent cancerous tissues from TCGA database and validation group. Additionally, patients with high ANXA2P2 expression in HCC tissue had a shorter overall survival, whereas no statistically significant correlation was found between ANXA2P2 expression and disease-free survival () as well as other clinical parameters, such as age, gender, histological grade, T classification, stage, albumin level, alpha-fetoprotein, and vascular invasion (, 0.8807, 0.5762, 0.8515, 0.7113, 0.242, 1.0000, and 0.7685, respectively). Furthermore, in vitro experiments showed that knockdown of ANXA2P2 inhibited migration and invasion of HCC cells but did not have an influence on the HCC cell proliferation when treated with targeted drugs (sorafenib, regorafenib, and lenvatinib). Conclusion. Our study confirmed elevated ANXA2P2 expression levels in HCC tissue compared with adjacent noncancerous tissue and a worse prognosis of patients with high ANXA2P2 levels in the HCC tissue. The newly found properties of promoting migration and invasion of ANXA2P2 in HCC help to explain this phenomenon. ANXA2P2 could be a novel and suitable predicative biomarker for the risk assessment of recurrence or metastasis of HCC patients but may not be effective to predict the efficacy of targeted drugs.

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Metformin Use and Lung Cancer Risk in Diabetic Patients: A Systematic Review and Meta-Analysis

Background. Antidiabetic medications (ADMs) can alter the risk of different types of cancer, but the relationship between lung cancer incidence and metformin remains controversial. Our aim was to quantitatively estimate the relationship between incidences of lung cancer and metformin in patients with diabetes in this meta-analysis. Methods. We performed a search in PubMed, Embase, ISI Web of Science, and Cochrane Library until September 20, 2017. The odds ratio (OR), relative risk (RR) or hazard ratio (HR), and 95% confidence interval (95% CI) were estimated using the random-effect model. The Newcastle-Ottawa Scale (NOS) was used to assess the study quality. Results. A total of 13 studies (10 cohort studies and 3 case-control studies) were included in the meta-analysis. Compared to nonmetformin users, metformin probably decreased lung cancer incidence in diabetic patients (; 95% CI, 0.83-0.96; ) with significant heterogeneity (,%, ). Subgroup analysis showed that cohort studies (; 95% CI, 0.85-0.98; ), location in Europe (; 95% CI, 0.86-0.94; ), the control drug of the sulfonylurea group (; 95% CI, 0.86-0.96; ), and adjusting for smoking (; 95% CI, 0.75-1.00; ) may be related to lower lung cancer risk. No significant publication bias was detected using a funnel plot. Conclusion. Metformin use was related to a lower lung cancer risk in diabetic patients compared to nonusers, but this result was retrieved from observational studies and our findings need more well-designed RCTs to confirm the association.

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An efficient new dual fluorescent pyrene based chemosensor for the detection of bismuth (III) and aluminium (III) ions and its applications in bio-imaging

Publication date: 1 June 2019

Source: Talanta, Volume 198

Author(s): Arjunan Saravanan, Selvaraj Shyamsivappan, Thangaraj Suresh, Gopalan Subashini, Krishna Kadirvelu, Nanjan Bhuvanesh, Raju Nandhakumar, Palathurai Subramaniam Mohan

Abstract

A new simple pyrene based schiff base chemosensor 1 (nicotinic acid pyren-1-ylmethylene-hydrazide) has been constructed and is prepared from 1-pyrenecarboxaldehyde and nicotinic hydrazide. Notably, the chemosensor 1 exhibited remarkable colour changes while in the presence of trivalent metal ions like Bi³⁺ & Al³⁺ ion in DMSO-H₂O, (1:1 v/v, HEPES = 50 mM, pH = 7.4). The UV–Vis spectral investigation of chemosensor 1 showed that the maximum absorption peak appeared at 378 nm. In emission studies, chemosensor 1 develops weak fluorescence, while upon the addition of Bi³⁺ and Al³⁺ ions, it exhibits an enhancement of fluorescence intensity. Nevertheless, rest of metal ions have no changes in the emission spectra. The association constant of chemosensor 1 for binding to Bi³⁺ & Al³⁺ system had a value of 1.27 × 10⁴ M⁻¹ and 1.53 × 10⁴ M⁻¹. The detection limits were 0.12 µM for Bi³⁺ and 0.17 µM for Al³⁺ respectively. The overall results reveal that chemosensor 1 can act as a dual-channel, highly selective, and sensitive probe for Bi³⁺ and Al³⁺ ions. Moreover, the fluorescence imaging of chemosensor 1 was applied in RAW 264.7 cell line and cytotoxicity assay prove that this chemosensor 1 is non-toxic as well as highly biocompatible.

Graphical abstract

A new pyrene based schiff base derivative (chemosensor 1) was designed and synthesized for the detection of dual metal ions Bi³⁺ and Al³⁺ ions with live cell imaging.

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T2 mapping with 3.0 T MRI of the temporomandibular joint disc of patients with disc dislocation

Publication date: Available online 10 February 2019

Source: Magnetic Resonance Imaging

Author(s): Margit Bristela, Astrid Skolka, Jaryna Eder, Pavol Szomolanyi, Michael Weber, Eva Piehslinger, Martina Schmid-Schwap, Siegfried Trattnig

Abstract

Introduction

T2 mapping, as a quantitative biochemical MRI-technique that provides information on water and collagen fiber content and composition, was shown to be clinically feasible for the evaluation of healthy temporomandibular joints.

Objectives

The aim of our study was to compare the T2 values of whole discs in patients with and without disc dislocation, to evaluate the possible influence of morphological findings on T2 values and to assess the interrater agreement.

Methods

Sixty-six patients were included in the study. Three experienced examiners assessed the perceptibility of the morphological parameters and the position of the articular disc on the morphological MR images. On the T2 maps, the T2 values of the region-of-interest (ROI) were assessed.

Results

The ICC (Intraclass Correlation Coefficient) for the reproducibility of the T2 values was 0.717. The assessment of the morphologic parameters was excellent or good in most of the discs. There was no significant difference in the T2 values based on disc position or signal intensity. But, a statistically significant moderation effect (p = .014) could be identified, indicating that the effect of disc position differs for different signal intensities. Condyle position, effusion, and degenerative changes showed pronounced moderation effects on the T2 values.

Conclusion

Due to the high sensitivity to effusion, T2 mapping currently seems to be unsuitable as a diagnostic tool for routine use in the temporomandibular joint. The moderation effect clearly shows the influence of factors such as signal intensity, effusion, arthrosis, and condyle position. Perhaps a solution for these problems could be the development of dedicated TMJ coils for higher field strengths at 7.0 T.

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Stereotactic radiosurgery with concurrent lapatinib is associated with improved local control for HER2-positive breast cancer brain metastases.

Stereotactic radiosurgery with concurrent lapatinib is associated with improved local control for HER2-positive breast cancer brain metastases.

J Neurosurg. 2019 Feb 08;:1-9

Authors: Parsai S, Miller JA, Juloori A, Chao ST, Kotecha R, Mohammadi AM, Ahluwalia MS, Murphy ES, Barnett GH, Vogelbaum MA, Angelov L, Peereboom DM, Suh JH

Abstract
OBJECTIVEWith increasing survival for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer in the trastuzumab era, there is an increased risk of brain metastasis. Therefore, there is interest in optimizing intracranial disease control. Lapatinib is a small-molecule dual HER2/epidermal growth factor receptor inhibitor that has demonstrated intracranial activity against HER2+ breast cancer brain metastases. The objective of this study was to investigate the impact of lapatinib combined with stereotactic radiosurgery (SRS) on local control of brain metastases.METHODSPatients with HER2+ breast cancer brain metastases who underwent SRS from 1997-2015 were included. The primary outcome was the cumulative incidence of local failure following SRS. Secondary outcomes included the cumulative incidence of radiation necrosis and overall survival.RESULTSOne hundred twenty-six patients with HER2+ breast cancer who underwent SRS to 479 brain metastases (median 5 lesions per patient) were included. Among these, 75 patients had luminal B subtype (hormone receptor-positive, HER2+) and 51 patients had HER2-enriched histology (hormone receptor-negative, HER2+). Forty-seven patients received lapatinib during the course of their disease, of whom 24 received concurrent lapatinib with SRS. The median radiographic follow-up among all patients was 17.1 months. Concurrent lapatinib was associated with reduction in local failure at 12 months (5.7% vs 15.1%, p < 0.01). For lesions in the ≤ 75th percentile by volume, concurrent lapatinib significantly decreased local failure. However, for lesions in the > 75th percentile (> 1.10 cm3), concurrent lapatinib did not significantly improve local failure. Any use of lapatinib after development of brain metastasis improved median survival compared to SRS without lapatinib (27.3 vs 19.5 months, p = 0.03). The 12-month risk of radiation necrosis was consistently lower in the lapatinib cohort compared to the SRS-alone cohort (1.3% vs 6.3%, p < 0.01), despite extended survival.CONCLUSIONSFor patients with HER2+ breast cancer brain metastases, the use of lapatinib concurrently with SRS improved local control of brain metastases, without an increased rate of radiation necrosis. Concurrent lapatinib best augments the efficacy of SRS for lesions ≤ 1.10 cm3 in volume. In patients who underwent SRS for HER2+ breast cancer brain metastases, the use of lapatinib at any time point in the therapy course was associated with a survival benefit. The use of lapatinib combined with radiosurgery warrants further prospective evaluation.

PMID: 30738402 [PubMed - as supplied by publisher]

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Comparison of the efficacy of trastuzumab emtansine between patients with metastatic human epidermal growth factor receptor 2-positive breast cancers previously treated with combination trastuzumab and pertuzumab and with trastuzumab only in Japanese population.

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Comparison of the efficacy of trastuzumab emtansine between patients with metastatic human epidermal growth factor receptor 2-positive breast cancers previously treated with combination trastuzumab and pertuzumab and with trastuzumab only in Japanese population.

Breast Cancer. 2019 Feb 08;:

Authors: Noda-Narita S, Shimomura A, Kawachi A, Sumiyoshi-Okuma H, Sudo K, Shimoi T, Noguchi E, Yonemori K, Shimizu C, Fujiwara Y, Tamura K

Abstract
BACKGROUND: Trastuzumab emtansine (T-DM1) has been approved since 2013 for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who had received trastuzumab (Tmab) and taxane. However, no clinical trial has evaluated the efficacy of T-DM1 in those who have previously received pertuzumab (Pmab). This study aimed to compare the efficacy of T-DM1 between patients who had received Tmab and Pmab and those who had received Tmab only in Japanese population.
METHODS: We identified all patients with HER2-positive MBC who received T-DM1 between April 1, 2014 and February 28, 2017 in our institution. The patients were divided into the Tmab group (i.e., those who received only Tmab before T-DM1 treatment) and the Tmab/Pmab group (i.e., those who received Tmab and Pmab before T-DM1 treatment), and progression-free survival (PFS) and best response were compared between the two groups.
RESULTS: A total of 42 patients were enrolled for outcome analysis. The median follow-up period was 4.8 months, and the median number of prior chemotherapy regimens for metastatic disease before T-DM1 was 1 (range 1-2) in the Tmab/Pmab group and 2 (range 0-6) in the Tmab group. The median PFS was 2.8 months in the Tmab/Pmab group (95% confidence interval [CI] 1.7-4.8 months) and 7.8 months in the Tmab group (95% CI 5.5-15.9 months) (p = 0.0030). The best response was lower in the Tmab/Pmab group (11.1% vs. 25.0%).
CONCLUSIONS: Patients with HER2-positive MBC who received Tmab and Pmab treatment before T-DM1 have fewer benefits from T-DM1.

PMID: 30737616 [PubMed - as supplied by publisher]

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Transcriptomic and ChIP-sequence interrogation of EGFR signaling in HER2+ breast cancer cells reveals a dynamic chromatin landscape and S100 genes as targets.

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Transcriptomic and ChIP-sequence interrogation of EGFR signaling in HER2+ breast cancer cells reveals a dynamic chromatin landscape and S100 genes as targets.

BMC Med Genomics. 2019 Feb 08;12(1):32

Authors: Nava M, Dutta P, Zemke NR, Farias-Eisner R, Vadgama JV, Wu Y

Abstract
BACKGROUND: The Human Epidermal Growth Factor Receptor (EGFR/HER1) can be activated by several ligands including Transforming Growth Factor alpha (TGF-α) and Epidermal Growth Factor (EGF). Following ligand binding, EGFR heterodimerizes with other HER family members, such as HER2 (human epidermal growth factor receptor-2). Previously, we showed that the EGFR is upregulated in trastuzumab resistant HER2 positive (HER2+) breast cancer cells. This study is aimed to determine the downstream effects on transcription following EGFR upregulation in HER2+ breast cancer cells.
METHODS: RNA-sequence and ChIP-sequence for H3K18ac and H3K27ac (Histone H3 lysine K18 and K27 acetylation) were conducted following an Epidermal Growth Factor (EGF) treatment time course in HER2+ breast cancer cells, SKBR3. The levels of several proteins of interest were confirmed by western blot analysis. The cellular localization of proteins of interest was examined using biochemically fractionated lysates followed by western blot analysis.
RESULTS: Over the course of 24 h, EGFR stimulation resulted in the modulation of over 4000 transcripts. Moreover, our data demonstrates that EGFR/HER2 signaling regulates the epigenome, with global H3K18ac and H3K27ac oscillating as a function of time following EGF treatment. RNA-sequence data demonstrates the activation of immediate early genes (IEGs) and delayed early genes (DEGs) within 1 h of EGF treatment. More importantly, we have identified members of the S100 (S100 Calcium Binding Protein) gene family as likely direct targets of EGFR signaling as H3K18ac, H3K27ac and pol2 (RNA polymerase II) increase near the transcription start sites of some of these genes.
CONCLUSIONS: Our data suggests that S100 proteins, which act as Ca2+ sensors, could play a role in EGF induced tumor cell growth and metastasis, contribute to trastuzumab resistance and cell migration and that they are likely drug targets in HER2+ breast cancer.

PMID: 30736768 [PubMed - in process]

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Hereditary Pancreatic Cancer: A Retrospective Single-Center Study of 5143 Italian Families with History of BRCA-Related Malignancies.

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Hereditary Pancreatic Cancer: A Retrospective Single-Center Study of 5143 Italian Families with History of BRCA-Related Malignancies.

Cancers (Basel). 2019 Feb 07;11(2):

Authors: Toss A, Venturelli M, Molinaro E, Pipitone S, Barbieri E, Marchi I, Tenedini E, Artuso L, Castellano S, Marino M, Tagliafico E, Razzaboni E, De Matteis E, Cascinu S, Cortesi L

Abstract
The identification of BRCA mutations plays a crucial role in the management of hereditary cancer prevention and treatment. Nonetheless, BRCA-testing in pancreatic cancer (PC) patients is not universally introduced in clinical practice. A retrospective analysis was conducted, firstly, to evaluate the rate of BRCA-positive families among those presenting a family history of PC besides breast and/or ovarian cancer. Secondly, the relationship between BRCA pathogenic variants and PC risk was evaluated. Finally, the characteristics of PC developed in BRCA families were described. Among 5143 family trees reporting breast and/or ovarian cancer cases, 392 showed a family history of PC. A total of 35 families (24.5% selected by the Modena Criteria and 21.3% by the NCCN Criteria) were positive to BRCA testing. Among the BRCA1 mutations, 36.8% were found within a region defined by c.3239⁻c.3917, whilst 43.7% of BRCA2 mutations were located within c.7180⁻c.8248. This study confirmed that an increase in the rate of positive tests in families with PC when associated to breast and/or ovarian tumors. Moreover, this analysis indicated two possible Pancreatic Cancer Cluster Regions that should be verified in future research. Finally, PC in families with breast and/or ovarian cancer history, particularly in BRCA families, were diagnosed at younger age and showed better one-year overall survival.

PMID: 30736435 [PubMed]

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Medical Management of Gastroenteropancreatic Neuroendocrine Tumors: Current Strategies and Future Advances.

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Medical Management of Gastroenteropancreatic Neuroendocrine Tumors: Current Strategies and Future Advances.

J Nucl Med. 2019 Feb 08;:

Authors: Mohamed A, Strosberg JR

Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare neoplasms, characterized by a propensity to secrete hormones which cause distinct clinical syndromes. During the past decade, the systemic treatment landscape has improved significantly: new options include everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), sunitinib, an angiogenesis inhibitor, and cytotoxic regimens such as capecitabine and temozolomide. Moreover, the recent approval of the radiolabeled somatostatin analog 177Lutetium(Lu)-dotatate has had a significant impact on management of neuroendocrine malignancies. In this review, we discuss advances in the medical management of GEP-NETs within the context of the larger multidisciplinary approach to these diseases.

PMID: 30737297 [PubMed - as supplied by publisher]

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Comprehensive genetic characterization of human thyroid cancer cell lines: a validated panel for preclinical studies.

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Comprehensive genetic characterization of human thyroid cancer cell lines: a validated panel for preclinical studies.

Clin Cancer Res. 2019 Feb 08;:

Authors: Landa-Lopez I, Pozdeyev N, Korch C, Marlow LA, Smallridge RC, Copland JA, Henderson YC, Lai SY, Clayman GL, Onoda N, Tan AC, Garcia-Rendueles MER, Knauf JA, Haugen BR, Fagin JA, Schweppe RE

Abstract
PURPOSE: Thyroid cancer cell lines are valuable models but have been neglected in pan-cancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers.
EXPERIMENTAL DESIGN: We performed next-generation sequencing and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers.
RESULTS: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell cycle checkpoint, histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced vs. differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAFV600E vs. RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization.
CONCLUSIONS: This cell line resource will help inform future pre-clinical studies exploring tumor-specific dependencies.

PMID: 30737244 [PubMed - as supplied by publisher]

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Comprehensive, integrated, and phased whole-genome analysis of the primary ENCODE cell line K562.

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Comprehensive, integrated, and phased whole-genome analysis of the primary ENCODE cell line K562.

Genome Res. 2019 Feb 08;:

Authors: Zhou B, Ho SS, Greer SU, Zhu X, Bell JM, Arthur JG, Spies N, Zhang X, Byeon S, Pattni R, Ben-Efraim N, Haney MS, Haraksingh RR, Song G, Ji HP, Perrin D, Wong WH, Abyzov A, Urban AE

Abstract
K562 is widely used in biomedical research. It is one of three tier-one cell lines of ENCODE and also most commonly used for large-scale CRISPR/Cas9 screens. Although its functional genomic and epigenomic characteristics have been extensively studied, its genome sequence and genomic structural features have never been comprehensively analyzed. Such information is essential for the correct interpretation and understanding of the vast troves of existing functional genomics and epigenomics data for K562. We performed and integrated deep-coverage whole-genome (short-insert), mate-pair, and linked-read sequencing as well as karyotyping and array CGH analysis to identify a wide spectrum of genome characteristics in K562: copy numbers (CN) of aneuploid chromosome segments at high-resolution, SNVs and indels (both corrected for CN in aneuploid regions), loss of heterozygosity, megabase-scale phased haplotypes often spanning entire chromosome arms, structural variants (SVs), including small and large-scale complex SVs and nonreference retrotransposon insertions. Many SVs were phased, assembled, and experimentally validated. We identified multiple allele-specific deletions and duplications within the tumor suppressor gene FHIT Taking aneuploidy into account, we reanalyzed K562 RNA-seq and whole-genome bisulfite sequencing data for allele-specific expression and allele-specific DNA methylation. We also show examples of how deeper insights into regulatory complexity are gained by integrating genomic variant information and structural context with functional genomics and epigenomics data. Furthermore, using K562 haplotype information, we produced an allele-specific CRISPR targeting map. This comprehensive whole-genome analysis serves as a resource for future studies that utilize K562 as well as a framework for the analysis of other cancer genomes.

PMID: 30737237 [PubMed - as supplied by publisher]

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A GBM-like V-ATPase signature directs cell-cell tumor signaling and reprogramming via large oncosomes.

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A GBM-like V-ATPase signature directs cell-cell tumor signaling and reprogramming via large oncosomes.

EBioMedicine. 2019 Feb 05;:

Authors: Bertolini I, Terrasi A, Martelli C, Gaudioso G, Di Cristofori A, Storaci AM, Formica M, Braidotti P, Todoerti K, Ferrero S, Caroli M, Ottobrini L, Vaccari T, Vaira V

Abstract
BACKGROUND: The V-ATPase proton pump controls acidification of intra and extra-cellular milieu in both physiological and pathological conditions. We previously showed that some V-ATPase subunits are enriched in glioma stem cells and in patients with poor survival. In this study, we investigated how expression of a GBM-like V-ATPase pump influences the non-neoplastic brain microenvironment.
METHODS: Large oncosome (LO) vesicles were isolated from primary glioblastoma (GBM) neurospheres, or from patient sera, and co-cultured with primary neoplastic or non-neoplastic brain cells. LO transcript and protein contents were analyzed by qPCR, immunoblotting and immunogold staining. Activation of pathways in recipient cells was determined at gene and protein expression levels. V-ATPase activity was impaired by Bafilomycin A1 or gene silencing.
FINDINGS: GBM neurospheres influence their non-neoplastic microenvironment by delivering the V-ATPase subunit V1G1 and the homeobox genes HOXA7, HOXA10, and POU3F2 to recipient cells via LO. LOs reprogram recipient cells to proliferate, grow as spheres and to migrate. Moreover, LOs are particularly abundant in the circulation of GBM patients with short survival time. Finally, impairment of V-ATPase reduces LOs activity.
INTERPRETATION: We identified a novel mechanism adopted by glioma stem cells to promote disease progression via LO-mediated reprogramming of their microenvironment. Our data provide preliminary evidence for future development of LO-based liquid biopsies and suggest a novel potential strategy to contrast glioma progression. FUND: This work was supported by Fondazione Cariplo (2014-1148 to VV) and by the Italian Minister of Health-Ricerca Corrente program 2017 (to SF).

PMID: 30737083 [PubMed - as supplied by publisher]

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The Developing Story of Predictive Biomarkers in Colorectal Cancer.

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The Developing Story of Predictive Biomarkers in Colorectal Cancer.

J Pers Med. 2019 Feb 07;9(1):

Authors: Boussios S, Ozturk MA, Moschetta M, Karathanasi A, Zakynthinakis-Kyriakou N, Katsanos KH, Christodoulou DK, Pavlidis N

Abstract
Colorectal cancer (CRC) is the third most common malignancy worldwide. Surgery remains the most important treatment for non-metastatic CRC, and the administration of adjuvant chemotherapy depends mainly on the disease stage, which is still the strongest prognostic factor. A refined understanding of the genomics of CRC has recently been achieved thanks to the widespread use of next generation sequencing with potential future therapeutic implications. Microsatellite instability (MSI) has been suggested as a predictive marker for response to anti-programmed-cell-death protein 1 (PD-1) therapy in solid tumors, including CRC. It should be noted that not all cancers with MSI phenotype respond to anti-PD-1 immunotherapy, highlighting the urgent need for even better predictive biomarkers. Mitogen-Activated Protein Kinase (MAPK) pathway genes KRAS, NRAS, and BRAF represent important molecular targets and could serve as independent prognostic biomarkers in CRC, and identify those who potentially benefit from anti-epidermal growth factor receptor (EGFR) treatment. Emerging evidence has attributed a significant role to inflammatory markers including blood cell ratios in the prognosis and survival of CRC patients; these biomarkers can be easily assessed in routine blood exams and be used to identify high-risk patients or those more likely to benefit from chemotherapy, targeted therapies and potentially immunotherapy. Analysis of cell-free DNA (cfDNA), circulating tumor cells (CTC) and/or micro RNAs (miRNAs) could provide useful information for the early diagnosis of CRC, the identification of minimal residual disease and, the evaluation of the risk of recurrence in early CRC patients. Even the selection of patients suitable for the new targeted therapy is becoming possible with the use of predictive miRNA biomarkers. Finally, the development of treatment resistance with the emergence of chemo-resistance clones after treatment remains the most important challenge in the clinical practice. In this context it is crucial to identify potential biomarkers and therapeutic targets which could lead to development of new and more effective treatments.

PMID: 30736475 [PubMed]

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A Novel Heterozygous Mutation of the COL4A3 Gene Causes a Peculiar Phenotype without Hematuria and Renal Function Impairment in a Chinese Family

Mutations in the COL4A3 gene are frequently reported to be associated with various types of hereditary nephropathy. COL4A3 encodes the α3 chain of type IV collagen, which is the main structural protein in the basement membrane. Mutations in this gene are always related to kidney performance, and deafness and ocular lesion have also been reported. In this study, using next-generation sequencing, we investigated the DNA of a family visiting a clinic for hearing loss. A new missense mutation was found in COL4A3 of 5 patients, c.3227C>T (p.P1076L). Based on these results, we predict that the mutation is pathogenic and leads to abnormal collagen IV. Here, we report for the first time on this autosomal dominant syndrome, characterized by hearing loss and eye abnormalities, but without renal damage, in all carriers. Since the oldest patient in the trial was less than 50 years old, however, we recommend that renal examination be reviewed regularly. Our results reveal expansion in the mutation spectrum of the COL4A3 gene and phenotypic spectrum of collagen IV disease. Our study suggests that next-generation sequencing is an economical and effective method and may help in the accurate diagnosis and treatment of these patients.

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Sign of Life is Associated with Return of Spontaneous Circulation After Resuscitative Thoracotomy: Single Trauma Center Experience of Republic of Korea.

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Sign of Life is Associated with Return of Spontaneous Circulation After Resuscitative Thoracotomy: Single Trauma Center Experience of Republic of Korea.

World J Surg. 2019 Feb 08;:

Authors: Kang BH, Choi D, Huh Y, Kwon J, Jung K, Lee JC, Moon J

Abstract
BACKGROUND: Resuscitative thoracotomy (RT) can be a lifesaving treatment, but it has not yet been performed in Korea. In this study, we review our experience of RT after a regional trauma center was constructed.
METHODS: This is a retrospective study of RT conducted at a single Korean trauma center from May 2014 to March 2018. The primary outcome was survival, and the secondary outcome was return of spontaneous circulation (ROSC). The clinical characteristics of the patients were compared between the ROSC and non-ROSC groups. Survivors were also reviewed.
RESULTS: A total of 62 patients were reviewed, and 60 patients had experienced blunt injury. Thirty-nine patients had ROSC. The ROSC group had short cardiopulmonary resuscitation (CPR) time (6 [2-10] min vs 11 [8-12] min, p < 0.001), the presence of sign of life at the trauma bay [32 (86.5%) vs 7 (28.0%), p < 0.001], and a low Injury Severity Score [26 (25-39) vs 37 (30-75), p = 0.038] compared to the non-ROSC group. On multivariate analysis, only the presence of sign of life was significantly associated with ROSC [11.297 (1.496-85.309) OR (95% CI), p = 0.019]. The 24-h survival rate was 8.1%, and the successful discharge rate was 4.8%.
CONCLUSION: The outcome of RT in a Korean trauma center was favorable. ROSC after RT was strongly associated with the presence of sign of life, and RT may be performed in the presence of sign of life regardless of prehospital CPR time.

PMID: 30737554 [PubMed - as supplied by publisher]

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Letter to Editor: Can Mainstreaming Surgery Advocacy into NCD Advocacy Help Us Overcome the NCD Epidemic?

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Letter to Editor: Can Mainstreaming Surgery Advocacy into NCD Advocacy Help Us Overcome the NCD Epidemic?

World J Surg. 2019 Feb 08;:

Authors: Pigeolet M, Marks I, Bentounsi Z, Wanjau W

Abstract

PMID: 30737553 [PubMed - as supplied by publisher]

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Autofluorescence in Parathyroidectomy: Signal Intensity Correlates with Serum Calcium and Parathyroid Hormone but Routine Clinical Use is Not Justified.

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Autofluorescence in Parathyroidectomy: Signal Intensity Correlates with Serum Calcium and Parathyroid Hormone but Routine Clinical Use is Not Justified.

World J Surg. 2019 Feb 08;:

Authors: DiMarco A, Chotalia R, Bloxham R, McIntyre C, Tolley N, Palazzo FF

Abstract
BACKGROUND: The inability to identify the pathological gland at surgery results in failure to cure hyperparathyroidism in 2-5%. The poorly understood characteristic of parathyroid tissue to manifest autofluorescence (AF) under near-infrared (NIR) light has been promoted as an intraoperative adjunct in parathyroid surgery. This study sought to explore potential clinical correlates for AF and assess the clinical utility of AF in parathyroid surgery.
METHODS: Consecutive patients undergoing parathyroid surgery for primary and renal disease were included. NIR imaging was used intraoperatively and the degree of AF of parathyroid glands graded by the operating surgeon. Variables assessed for correlation with AF were: pre-operative serum calcium and PTH, SestaMIBI positivity, gland weight and histological composition.
RESULTS: Ninety-six patients underwent parathyroidectomy over an 8-month period: 49 bilateral explorations, 41 unilateral and 6 focussed lateral approaches: 284 potentially 'visualisable' glands in total. Two hundred and fifty-seven glands (90.5%) were visualised with NIR. Correlation was found between the degree of fluorescence and pre-operative serum calcium and PTH, but not between gland weight and SestaMIBI positivity. In those with renal hyperparathyroidism, a predominance of oxyphil cells correlated with increased AF.
CONCLUSION: Autofluorescence intensity correlates with serum calcium, PTH and gland composition. Further refinements would be required for this information to be of value in a clinical setting. Improvements allowing NIR to visualise the additional 9.5% of parathyroids and overcome the variation in signal intensity due to depth of access are required for the routine adoption of this technology. At present, its routine use in a clinical setting cannot be justified.

PMID: 30737552 [PubMed - as supplied by publisher]

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Proposal of a Scoring Scale to Estimate Risk of the Discontinuation of S-1 Adjuvant Monotherapy in Patients with Stage II to III Gastric Cancer: A Multi-Institutional Dataset Analysis.

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Proposal of a Scoring Scale to Estimate Risk of the Discontinuation of S-1 Adjuvant Monotherapy in Patients with Stage II to III Gastric Cancer: A Multi-Institutional Dataset Analysis.

World J Surg. 2019 Feb 08;:

Authors: Iizuka A, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y

Abstract
BACKGROUND: Discontinuation of postoperative S-1 adjuvant monotherapy is a frequent problem in the management of patients with gastric cancer.
METHODS: A total of 355 stage II/III gastric cancer patients who underwent gastrectomy and adjuvant S-1 were retrospectively analyzed using a multicenter dataset. We randomly assigned patients into either discovery or validation cohort in a 2:1 ratio. In the discovery cohort, 29 parameters were assessed as candidate factors to predict discontinuation of S-1 adjuvant within 6 months. A scoring system was designed using independent risk factors identified by the multivariate analysis. Reproducibility was tested in the validation cohort.
RESULTS: Overall, 92 patients (25.9%) discontinued the treatment within 6 months because of adverse effects. Age, preoperative urea nitrogen (UN) and the preoperative albumin-to-bilirubin index (ALBI) showed the highest area under the curve (AUC) for the discontinuation of S-1 adjuvant within 6 months in each category: body status, blood tests and indices. In the multivariate analysis, age ≥ 64 years, preoperative UN ≥ 15.2 mg/dl and preoperative ALBI ≥ -0.265 were identified as independent risk factors. A scoring scale consisting of these three factors was developed for the prediction of drug discontinuation and demonstrated a greater AUC (0.728) than that of each of the three constituents. The time to treatment discontinuation decreased incrementally as the risk score increased. The reproducible findings were confirmed in the validation cohort.
CONCLUSIONS: We identified risk factors and developed a scoring scale to predict S-1 adjuvant monotherapy discontinuation in patients with stage II/III gastric cancer.

PMID: 30737551 [PubMed - as supplied by publisher]

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Bradycardia During Laparoscopic Surgeries: A Retrospective Cohort Study.

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Bradycardia During Laparoscopic Surgeries: A Retrospective Cohort Study.

World J Surg. 2019 Feb 08;:

Authors: Dabush-Elisha I, Goren O, Herscovici A, Matot I

Abstract
BACKGROUND: A recent analysis found bradycardia during laparoscopy as a potential early warning sign of cardiac arrest. Knowledge regarding bradycardia frequency and its consequences during laparoscopy is limited.
METHODS: Using the computerized record database, files of 9915 patients undergoing laparoscopic surgery, between June 2008 and August 2013 at a tertiary, academic medical center, were screened for intraoperative bradycardia (heart rate <50 beats/min for at least three consecutive measures).
RESULTS: Intraoperative bradycardia occurred in 1540 (15.5%) patients, in the majority (945, 61.3%) heart rate decreased to <45 beats/min. Mean (SD) duration of bradycardia was 14.8 (16.8) min. Bradycardia was more prevalent in males, older patients, smokers, patients with comorbidities and those treated with β, α and calcium channel blockers. The majority of events were related to CO2 insufflation and bolus opioid administration. In 1343 (87%), noteworthy decreases in blood pressure were recorded; the average (SD) drop in systolic blood pressure was 35 (21) mmHg. Pharmacological intervention to alleviate bradycardia was used in up to 23% of episodes. Bradycardia did not result in intraoperative cardiac arrest, neither did it increase the frequency of intensive care unit admission or mortality rate.
CONCLUSION: Bradycardia is common during laparoscopy. Despite being more prevalent in older and sicker patients, bradycardia did not significantly affect outcome, suggesting that routine preventive measures do not need to be implemented. Rather, intraoperative bradycardia events should be wisely followed with prompt response, when hemodynamic perturbations occur, the threshold of which is yet to be defined.

PMID: 30737550 [PubMed - as supplied by publisher]

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Development of a validated method for the qualitative and quantitative analysis of cannabinoids in plant biomass and medicinal cannabis resin extracts obtained by super-critical fluid extraction.

Development of a validated method for the qualitative and quantitative analysis of cannabinoids in plant biomass and medicinal cannabis resin extracts obtained by super-critical fluid extraction.

J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Jan 30;1109:76-83

Authors: Elkins AC, Deseo MA, Rochfort S, Ezernieks V, Spangenberg G

Abstract
The social push for the therapeutic use of cannabis extracts has increased significantly over recent years. Cannabis is being used for treatment for conditions such as epilepsy, cancer and pain management. There are a range of medicinal cannabis products available, but the use of cannabis resin obtained by super critical fluid extraction, often diluted in oil, is becoming increasingly more prominent. Much of the research on cannabis has focused on plant biomass or the final therapeutic product with a concerning lack of information on the intermediate resin. This study aims to bridge the gap between current methods of analysis for biomass and the final therapeutic product by describing a fully developed and validated ultra-high-performance-liquid-chromatography method with diode array detection (UHPLC-DAD) for the qualification and quantification of the cannabinoids CBDA, CBD, CBN, THC, CBC and THCA, in medicinal cannabis biomass and resin obtained by super-critical fluid extraction (SFE). The method was validated for specificity, linearity, limit of detection (LOD), limit of quantitation (LOQ), precision, accuracy, robustness, spike recovery and stability in accordance with the Validation of Analytical Procedures: Text and Methodology Q2 to meet the requirements of the International Council for Harmonisation (ICH), Therapeutic Goods Authority (TGA) and the Food and Drug Administration (FDA) test method validation regulations.

PMID: 30738340 [PubMed - as supplied by publisher]

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Epilepsy surgery in low- and middle-income countries: A scoping review.

Epilepsy surgery in low- and middle-income countries: A scoping review.

Epilepsy Behav. 2019 Feb 06;92:311-326

Authors: Watila MM, Xiao F, Keezer MR, Miserocchi A, Winkler AS, McEvoy AW, Sander JW

Abstract
BACKGROUND: Epilepsy surgery is an important treatment option for people with drug-resistant epilepsy. Surgical procedures for epilepsy are underutilized worldwide, but it is far worse in low- and middle-income countries (LMIC), and it is less clear as to what extent people with drug-resistant epilepsy receive such treatment at all. Here, we review the existing evidence for the availability and outcome of epilepsy surgery in LMIC and discuss some challenges and priority.
METHODS: We used an accepted six-stage methodological framework for scoping reviews as a guide. We searched PubMed, Embase, Global Health Archives, Index Medicus for South East Asia Region (IMSEAR), Index Medicus for Eastern Mediterranean Region (IMEMR), Latin American & Caribbean Health Sciences Literature (LILACS), African Journal Online (AJOL), and African Index Medicus (AIM) to identify the relevant literature.
RESULTS: We retrieved 148 articles on epilepsy surgery from 31 countries representing 22% of the 143 LMIC. Epilepsy surgery appears established in some of these centers in Asia and Latin America while some are in their embryonic stage reporting procedures in a small cohort performed mostly by motivated neurosurgeons. The commonest surgical procedure reported was temporal lobectomies. The postoperative seizure-free rates and quality of life (QOL) are comparable with those in the high-income countries (HIC). Some models have shown that epilepsy surgery can be performed within a resource-limited setting through collaboration with international partners and through the use of information and communications technology (ICT). The cost of surgery is a fraction of what is available in HIC.
CONCLUSION: This review has demonstrated the availability of epilepsy surgery in a few LMIC. The information available is inadequate to make any reasonable conclusion of its existence as routine practice. Collaborations with international partners can provide an opportunity to bring high-quality academic training and technological transfer directly to surgeons working in these regions and should be encouraged.

PMID: 30738248 [PubMed - as supplied by publisher]

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Agomelatine alleviates neuronal loss through BDNF signaling in the post-status epilepticus model induced by kainic acid in rat.

Agomelatine alleviates neuronal loss through BDNF signaling in the post-status epilepticus model induced by kainic acid in rat.

Brain Res Bull. 2019 Feb 06;:

Authors: Tchekalarov J, Atanasova D, Kortenska L, Lazarov N, Shishmanova-Doseva M, Galchev T, Marinov P

Abstract
Recently, we have reported that while agomelatine (Ago) is unable to prevent development of epilepsy it exerts a strong neuroprotective and anti-inflammatory response in the KA post-status epilepticus (SE) rat model. In the present study, we aimed to explore whether the brain-derived neurotrophic factor (BDNF) in the hippocampus is involved in the neuroprotective effect of Ago against the KA-induced SE and epileptiform activity four months later in rats. Lacosamide (LCM) was used as a positive control. The EEG-recorded seizure activity was also evaluated in two treatment protocols. In Experiment#1, Ago given repeatedly at a dose of 40 mg/kg during the course of SE was unable neither to modify EEG-recorded epileptiform activity nor the video- and EEG-recorded spontaneous seizures four months later compared to LCM (50 mg/kg). However, both Ago and LCM inhibited the expression of BDNF in the mossy fibers and also prevented neuronal loss in the dorsal hippocampal and the piriform cortex after SE. In Experiment#2, acute injection of Ago and LCM on epileptic rats, characterized by high seizure rates, did not prevent EEG-recorded paroxysmal events while only LCM decreased either absolute or relative powers of gamma (28-60 Hz) and high (HI) (60-120 Hz) frequency bands to baseline in the frontal and parietal cortex, respectively. Our results suggest that the protection against neuronal loss in specific limbic regions and overexpressed BDNF in the mossy fibers resulting from the repeated treatment with Ago and LCM, respectively, during SE is not a prerequisite for alleviation of epileptogenesis and development of epilepsy. In addition, a reduction of gamma and HI bands in the frontal and parietal cortex is not associated with EEG-recorded paroxysmal events after acute injection of LCM.

PMID: 30738136 [PubMed - as supplied by publisher]

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Treatment of migraine in a patient with epilepsy.

Treatment of migraine in a patient with epilepsy.

Wiad Lek. 2018;71(9):1793-1802

Authors: Czapińska-Ciepiela E

Abstract
Epilepsy and migraine often occur concomitantly in the same patient. The cause may be found in the similar genetic and pathophysiological background of the two diseases that is manifested by an excessive tendency towards neuronal hyperexcitation. Migraine concomitant with epilepsy increases the risk of the patient developing drug-resistant epilepsy, depression and anxiety disorders, as well as significantly decreases his quality of life. Therefore, in such patients, it is important to introduce effective and safe antimigraine treatment. In prophylactic migraine therapy such agents are recommended as certain anti-epileptic medications, calcium channel blockers, β-blockers, antidepressants and antihypertensives, while in interim treatment, triptans, analgesics and non-steroidal anti-inflammatory medications are employed. The therapy should be individualized to meet the patient's needs and also be based on the analysis of drug interactions, profile of adverse effects of the medications and concomitant diseases.

PMID: 30737943 [PubMed - in process]

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Impact of epilepsy duration, seizure control and EEG abnormalities on cognitive impairment in drug-resistant epilepsy patients.

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Impact of epilepsy duration, seizure control and EEG abnormalities on cognitive impairment in drug-resistant epilepsy patients.

Acta Neurol Belg. 2019 Feb 08;:

Authors: Gavrilovic A, Toncev G, Boskovic Matic T, Vesic K, Ilic Zivojinovic J, Gavrilovic J

Abstract
Cognitive impairment frequently occurs in epilepsy patients. Patients with drug-resistant epilepsy (DRE) have poor drug responsivity and higher seizure frequency which consequently lead to brain damage and may have implications on cognitive status. In the present study, we assessed a frequency and degree of cognitive impairment in 52 patients with drug-sensitive epilepsy (DSE) and 103 DRE patients at three time points (baseline, after 12 and 18 months). Degree of cognitive decline was assessed with Montreal Cognitive Assessment (MoCA) scale. We examined the possible correlation between demographic and clinical characteristics and cognitive deterioration in epilepsy patients. Patients in the DRE group had significantly lower MoCA score than patients in the DSE group at baseline (28.83 ± 2.05 vs. 29.69 ± 0.61, p = 0.003), after 12 months (27.36 ± 2.40 vs. 29.58 ± 1.22, p = 0.000) and 18 months (26.86 ± 2.73 vs. 29.33 ± 1.47, p = 0.000). Patients with DRF epilepsy had significantly lower MoCA score than patients with DSF epilepsy at three time points (28.71 ± 2.48 vs. 29.86 ± 0.35, p = 0.015; 27.22 ± 2.72 vs. 29.52 ± 1.37, p = 0.000; 26.80 ± 2.99 vs. 29.31 ± 1.56, p = 0.000). After 12 and 18 months of follow-up, patients with DRG epilepsy had significantly lower MoCA score than patients with DSG epilepsy (27.52 ± 2.01 vs. 29.65 ± 1.02, p = 0.000; 26.94 ± 2.43 vs. 29.35 ± 1.40, p = 0.000). Illness duration negatively correlated with cognitive status (p = 0.005); seizure control and EEG findings positively correlated with MoCA score (p = 0.000). Illness duration, seizure control, drug responsivity, and EEG findings are significant predictors of MoCA score (p < 0.05). Clinicians have to pay attention to patients with drug-resistant epilepsy and concepts of aggressive treatment to minimize the adverse effects of epilepsy on cognition.

PMID: 30737651 [PubMed - as supplied by publisher]

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Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of Androgen Independent Prostate tumors.

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Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of Androgen Independent Prostate tumors.

Int J Cancer. 2019 Feb 09;:

Authors: Singh V, Jaiswal PK, Ghosh I, Koul HK, Yu X, De Benedetti A

Abstract
Standard therapy for advanced Prostate Cancer (PCa) consists of anti-androgens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, establishing the existence of a ADT>TLK1>NEK1>ATR>Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen-independent (AI) colonies of LNCaP and TRAMP-C2 cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several PCa cells in vitro (including AI lines). Administration of THD or bicalutamide was not effective at inhibiting long-term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth via bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1-T141A mutant were durably suppressed with bicalutamide. Collectively, these results suggest that targeting the TLK1/NEK1 axis might be a novel therapy for PCa in combination with standard of care (ADT). This article is protected by copyright. All rights reserved.

PMID: 30737777 [PubMed - as supplied by publisher]

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The p300/YY1/miR-500a-5p/HDAC2 signalling axis regulates cell proliferation in human colorectal cancer.

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The p300/YY1/miR-500a-5p/HDAC2 signalling axis regulates cell proliferation in human colorectal cancer.

Nat Commun. 2019 Feb 08;10(1):663

Authors: Tang W, Zhou W, Xiang L, Wu X, Zhang P, Wang J, Liu G, Zhang W, Peng Y, Huang X, Cai J, Bai Y, Bai L, Zhu W, Gu H, Xiong J, Ye C, Li A, Liu S, Wang J

Abstract
The biological role of miR-500a-5p has not yet been reported in the context of colorectal cancer (CRC). Here, we show that miR-500a-5p expression is decreased in CRC tissues compared with adjacent normal tissues. Low miR-500a-5p expression is associated with malignant progression. Moreover, transfection of CRC cells with miR-500a-5p induces G0/G1 cell cycle arrest and inhibits their growth and migration. Mechanistically, miR-500a-5p directly targets HDAC2 and inhibits HDAC2-mediated proliferation in CRC in nude mice. Furthermore, YY1 binds to the promoter of miR-500a-5p and negatively regulates its transcription. Restoration of miR-500a-5p expression is up-regulated via the p300/YY1/HDAC2 complex. Besides, therapeutic delivery of miR-500a-5p significantly suppresses tumour development in a xenograft tumour model and a HDAC2 inhibitor FK228-treated CRC model. Our studies demonstrate that miR-500a-5p functions as a tumour suppressor in CRC by targeting the p300/YY1/HDAC2 axis, which contributes to the development of and provides new potential candidates for CRC therapy.

PMID: 30737378 [PubMed - in process]

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Overexpression of miR-1258 inhibits cell proliferation by targeting AKT3 in osteosarcoma.

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Overexpression of miR-1258 inhibits cell proliferation by targeting AKT3 in osteosarcoma.

Biochem Biophys Res Commun. 2019 Feb 05;:

Authors: Liu W, Zhou Z, Zhang Q, Rong Y, Li L, Luo Y, Wang J, Yin G, Lv C, Cai W

Abstract
Osteosarcoma (OS) has emerged as the most common primary musculoskeletal malignant tumor which affects children and adolescents. A growing number of relevant studies have shown that many microRNAs (miRNAs) play a vital regulatory role in the etiology of various types of cancer. miR-1258 has been widely studied in various cancers, but there have been few studies of its role in OS. In this present study, miR-1258 expression was dramatically decreased in OS tissues as well as OS cell lines. In addition, decreased expression of miR-1258 was significantly associated with malignant clinical manifestations and poor clinical prognosis of patients with OS. Moreover, upregulation of miR-1258 significantly inhibited cell proliferation as well as promoting cell cycle arrest at G0/G1. AKT3 was identified as a direct target of miR-1258 by binding to its 3'-UTR, and miR-1258 was negatively correlated with AKT3 expression in clinical OS tissues. AKT3 was evidently upregulated in OS tissues and cells and upregulation of AKT3 accelerated the progression of OS. Moreover, through a series of rescue experiments, we demonstrated that AKT3 can abolish the role of miR-1258 in suppressing proliferation as well as regulating the cell cycle in OS cells. In conclusion, our results suggest that the miR-1258-AKT3 axis may be a promising prognostic marker and therapeutic target for human OS.

PMID: 30737029 [PubMed - as supplied by publisher]

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Novel Targeted Anti-Tumor Nanoparticles Developed from Folic Acid-Modified 2-Deoxyglucose.

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Novel Targeted Anti-Tumor Nanoparticles Developed from Folic Acid-Modified 2-Deoxyglucose.

Int J Mol Sci. 2019 Feb 06;20(3):

Authors: Jin S, Du Z, Guo H, Zhang H, Ren F, Wang P

Abstract
The glucose analog, 2-deoxyglucose (2-DG), specifically inhibits glycolysis of cancer cells and interferes with the growth of cancer cells. However, the excellent water solubility of 2-DG makes it difficult to be concentrated in tumor cells. In this study, a targeted nano-pharmacosome was developed with folic acid-modified 2-DG (FA-2-DG) by using amino ethanol as a cleavable linker. FA-2-DG was able to self-assemble, forming nano-particles with diameters of 10⁻30 nm. The biological effects were evaluated with cell viability assays and flow cytometry analysis. Compared with a physical mixture of folic acid and 2-DG, FA-2-DG clearly reduced cell viability and resulted in cell cycle arrest. A computational study involving docking simulation suggested that FA-2-DG can dock into the same receptor as folic acid, thus confirming that the structural modification did not affect the targeting performance. The results indicated that the nano-pharmacosome consisting of FA-2-DG can be used for targeting in a nano-drug delivery system.

PMID: 30736291 [PubMed - in process]

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Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival.

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Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival.

Cancers (Basel). 2019 Feb 06;11(2):

Authors: Jacobsen NL, Pontifex TK, Langlais PR, Burt JM

Abstract
Differential phosphorylation of the carboxyl-terminus of connexin 37 (Cx37-CT) regulates phenotypic switching between cell growth phenotypes (cell death, cell cycle arrest, proliferation). The specific phosphorylation events in the Cx37-CT that are necessary for these growth regulatory effects are currently unknown. Through the combined use of deletion and site specific (de)phospho-mimetic Cx37-CT mutants, our data suggest a phosphorylation-dependent interaction between the mid-tail (aa 273⁻317) and end-tail (aa 318⁻333) portions of the Cx37-CT that regulates cell survival. As detected by mass spectrometry, Cx37 was phosphorylated at serines 275, 321, and 328; phosphomimetic mutations of these sites resulted in cell death when expressed in rat insulinoma cells. Alanine substitution at S328, but not at S275 or S321, also triggered cell death. Cx37-S275D uniquely induced the death of only low density, non-contact forming cells, but neither hemichannel open probability nor channel conductance distinguished death-inducing mutants. As channel function is necessary for cell death, together the data suggest that the phosphorylation state of the Cx37-CT controls an intra-domain interaction within the CT that modifies channel function and induces cell death.

PMID: 30736283 [PubMed]

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Bronchiolitis Obliterans After Cefuroxime-Induced Stevens-Johnson Syndrome.

Related Articles

Bronchiolitis Obliterans After Cefuroxime-Induced Stevens-Johnson Syndrome.

Am J Case Rep. 2019 Feb 09;20:171-174

Authors: Shabrawishi M, Qanash SA

Abstract
BACKGROUND Bronchiolitis obliterans is the term used to describe a clinical syndrome of irreversible airflow obstruction. Among the etiologies linked to this entity is the rarely reported association with Stevens-Johnson syndrome, which has had a poor outcome in most of the previously published cases. The optimum management of bronchiolitis obliterans as a complication of Stevens-Johnson syndrome is not well defined. CASE REPORT A 41-year-old woman developed significant shortness of breath 3 months after recovering from Stevens-Johnson syndrome precipitated by a second-generation cephalosporin. She was found to have severe irreversible airway obstruction on physiology studies, and computed tomography scans of the inspiratory and expiratory phases of respiration showed air trapping that was more prominent on expiratory films. The patient was diagnosed with bronchiolitis obliterans, for which bronchodilators and long-term macrolide therapy were administered. Although she did not recover completely, her follow-up physiology studies showed that the bronchiolitis obliterans was stable. CONCLUSIONS Bronchiolitis obliterans secondary to Stevens-Johnson syndrome is a rare entity that is progressive and can lead to functional impairment. Identifying the disease at an early stage might stabilize or slow its progression. Herein, we describe a case of bronchiolitis obliterans as a complication of Stevens-Johnson syndrome and review the literature to raise awareness of this condition, highlight its course, and discuss the available treatments.

PMID: 30737366 [PubMed - in process]

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Juvenile nasopharyngeal angiofibroma: A retrospective study of 27 cases in the ent Department of ipo‐Porto

Abstract

Juvenile nasopharyngeal angiofibroma (JNA) is a benign, rare and highly vascular tumour, occurring in adolescent males.

Clinical records of 27 patients who underwent surgical resection, performed between 1989 and 2017, were reviewed.

Three patients were submitted to paralatero‐nasal rhinotomy, 23 patients (85%), to the sublabial transnasomaxillary approach (Rouge Denker approach), complemented in 19 (70.0%) with transpalatine approach (Wilson technique). Endoscopic resection was performed only at one patient stage IB.

There were no cases of death, major significant complications or significant morbidity. Persistence rate was 18.5% and recurrence rate 14.8%.

Patients with tumour extension to infratemporal fossa and no massive cavernous sinus invasion may be treated effectively without previous embolization and facial scars, with sublabial transnasomaxillary approach (Rouge Denker approach), complemented with transpalatine approach (Wilson technique).

This article is protected by copyright. All rights reserved.

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Early versus late MCI: Improved MCI staging using a neuropsychological approach.

Related Articles

Early versus late MCI: Improved MCI staging using a neuropsychological approach.

Alzheimers Dement. 2019 Feb 05;:

Authors: Edmonds EC, McDonald CR, Marshall A, Thomas KR, Eppig J, Weigand AJ, Delano-Wood L, Galasko DR, Salmon DP, Bondi MW, Alzheimer's Disease Neuroimaging Initiative

Abstract
INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) separates "early" and "late" mild cognitive impairment (MCI) based on a single memory test. We compared ADNI's MCI classifications to our neuropsychological approach, which more broadly assesses cognitive abilities.
METHODS: Three hundred thirty-six ADNI-2 participants were classified as "early" or "late" MCI. Cluster analysis was performed on neuropsychological test data, and participants were reclassified based on cluster results. These two staging approaches were compared on progression rates, cerebrospinal fluid biomarkers, and cortical thickness profiles.
RESULTS: There was little correspondence between the two staging methods. ADNI's early MCI group included a large proportion of false-positive diagnostic errors. The reclassified neuropsychological MCI groups showed steeper survival curves and more abnormal biomarkers.
CONCLUSIONS: Our novel neuropsychological approach improved the staging of MCI by (1) capturing individuals at an early symptomatic stage, (2) minimizing false-positive cases, and (3) identifying a late MCI group further along the disease trajectory.

PMID: 30737119 [PubMed - as supplied by publisher]

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Perturbation-driven paradoxical facilitation of visuo-spatial function: Revisiting the ‘Sprague effect’

Publication date: Available online 10 February 2019

Source: Cortex

Author(s): Antoni Valero-Cabre, Monica N. Toba, Claus C. Hilgetag, R. Jarrett Rushmore

Abstract

The 'Sprague Effect' described in the seminal paper of James Sprague (Science 153:1544–1547, 1966a) is an unexpected paradoxical effect in which a second brain lesion reversed functional deficits induced by an earlier lesion. It was observed initially in the cat where severe and permanent contralateral visually guided attentional deficits generated by the ablation of large areas of the visual cortex were reversed by the subsequent removal of the superior colliculus (SC) opposite to the cortical lesion or by the splitting of the collicular commissure. Physiologically, this effect has been explained in several ways - most notably by the reduction of the functional inhibition of the ipsilateral SC by the contralateral SC, and the restoration of normal interactions between cortical and midbrain structures after ablation. In the present review, we aim at reappraising the 'Sprague Effect' by critically analyzing studies that have been conducted in the feline and human brain. Moreover, we assess applications of the 'Sprague Effect' in the rehabilitation of visually guided attentional impairments by using non-invasive therapeutic approaches such as transcranial magnetic stimulation (TMS) and transcranial direct-current stimulation (tDCS). We also review theoretical models of the effect that emphasize the inhibition and balancing between the two hemispheres and show implications for lesion inference approaches. Last, we critically review whether the resulting inter-hemispheric rivalry theories lead toward an efficient rehabilitation of stroke in humans. We conclude by emphasizing key challenges in the field of 'Sprague Effect' applications in order to design better therapies for brain-damaged patients.

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Punishment-related memory-guided attention: Neural dynamics of perceptual modulation

Publication date: Available online 10 February 2019

Source: Cortex

Author(s): Samuel Suárez-Suárez, Socorro Rodríguez Holguín, Fernando Cadaveira, Anna Christina Nobre, Sonia Doallo

Abstract

Remembering the outcomes of past experiences allows us to generate future expectations and shape selection in the long-term. A growing number of studies has shown that learned positive reward values impact spatial memory-based attentional biases on perception. However, whether memory-driven attentional biases extend to punishment-related values has received comparatively less attention. Here, we manipulated whether recent spatial contextual memories became associated with successful avoidance of punishment (potential monetary loss). Behavioural and electrophysiological measures were collected from 27 participants during a subsequent memory-based attention task, in which we tested for the effect of punishment avoidance associations. Punishment avoidance significantly amplified effects of spatial contextual memories on visual search processes within natural scenes. Compared to non-associated scenes, contextual memories paired with punishment avoidance lead to faster responses to targets presented at remembered locations. Event-related potentials elicited by target stimuli revealed that acquired motivational value of specific spatial locations, by virtue of their association with past avoidance of punishment, dynamically affected neural signatures of early visual processing (indexed by larger P1 and earlier N1 potentials) and target selection (as indicated by reduced N2pc potentials). The present results extend our understanding of how memory, attention, and punishment-related mechanisms interact to optimize perceptual decision in real world environments.

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The effect of sunlight and UV lamps on EPR signal in nails

Abstract

The effects of illumination of nail clippings by direct sunlight, UV lamps and fluorescent bulbs on native and radiation-induced electron paramagnetic resonance (EPR) signals in nails are presented. It is shown that a few minutes of exposure of the nail clippings to light including a UV component (sunlight and UV lamps) generates a strong EPR signal similar to the other EPR signals observable in nails: native background (BKG), mechanically induced (MIS) or radiation-induced (RIS). This effect was observed in clippings exposed and unexposed to ionizing radiation prior to the light illuminations. An exposure of the clippings to fluorescent light without a UV component generated, within the examined range of the light fluences (up to 240 kJ/m²), an EPR signal with considerably lower yield than UV light. The light-induced signal (LIS) decayed after 10 min of water treatment of the samples. In contrast, it was still observable 3 months after illumination in samples stored in air at room temperature, and 3 weeks in frozen samples, respectively. It is concluded that the LIS can considerably affect assessment of the dosimetric RIS components in irradiated nails, and of the background signals in unirradiated nails, thus contributing to errors in EPR dosimetry in nails.

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Accuracy of Dynamic Virtual Articulation: Trueness and Precision

Abstract

Purpose

To study the effects of altering condylar settings and pin openings on the trueness and precision of virtual articulators vs. mechanical articulators.

Materials and Methods

Maxillary and mandibular typodonts with fiducial markers were mounted on a mechanical Artex‐CR articulator, and the mandibular teeth were prepared to allow guidance solely by the posterior determinants of the articulator and the incisal table. The relationship of the mounted typodonts was preserved digitally by scanning using manufacturer transfer plate adaptors. On the mechanical articulator, pattern resin was allowed to set between the maxillary and mandibular occlusal surfaces (area #25‐30) at the endpoints of dynamic movements at 3 condylar inclinations (SCI): 10°, 30°, and 45°, n = 12/inclination, or at 3 incisal pin openings (2, 5, and 10 mm, n = 12/opening). All other articulator settings were kept constant. Resin specimens attached to the typodonts were scanned within 5 minutes of setting, then removed and the articulated typodonts rescanned. Fixed dental prostheses (FDPs) #25‐30 were designed on the virtual articulator using identical parameters to the mechanical articulator. Dynamic virtual movements were used to sculpt the design, and a file of the design was saved. The files of both types of samples were aligned and overlaid. Interocclusal separation was measured in triplicate at the indentation created by the mesiolabioincisal point angle on the incisal edge of #8 and the mesiobucco‐occlusal point angle of #3. Trueness and precision of both types of articulators were calculated and compared using one‐way ANOVA, followed by the Tukey HSD test (α = 0.05).

Results

There was no statistically significant difference at altered pin openings in either trueness (F = 0.202, p = 0.37) or precision (F = 3.134, p = 0.09) for the majority of measurements. The only significant difference was in the precision between the 2 types of articulators at 5 mm incisal opening, and only at the anterior measurement point (F = 15.134, p = 0.0008); however, these differences were less than 100 μm. When the SCI was altered, there was no statistically significant difference (F = 3.624, p > 0.05) between the virtual and mechanical articulators in trueness for 5 of the 6 measurements obtained (F = 3.624, p = 0.07) or for all of the precision measurements (F = 3.529, p = 0.07). The one trueness measurement that was significantly different (F = 9.237, p = 0.006) occurs at SCI of 10°, and it was less than 100 μm.

Conclusions

Dynamic movements on the virtual articulator were shown to be as true and precise as to the mechanical articulator. When there were deviations, these deviations were less than 100 μm and thus, these deviations may not be clinically relevant.

This article is protected by copyright. All rights reserved

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An overview of heat stress relief with global warming in perspective

Abstract

Global warming seems more probable, whether as gradual warming or increased frequency of warmer episodes. The productivity of cattle in temperate countries will decline unless counteracting steps are adopted. The probability of pre-emptive breeding for maintaining temperate breed performance coupled with heat stress tolerance is too low to be adopted for counteracting warming. The expected warming will mostly involve temperature increases. These will indirectly affect radiant heat gain in animals owing to reduced radiant heat dissipation from the body by convective heat loss, which results in an increased sensitivity to incoming radiant heat at higher air temperatures. These necessitate an emphasis on increasing convective heat loss by structure design and forced air flow by fans. Convective heat loss diminishes with increasing air temperatures. Evaporative heat loss remains the alternative. Evaporative cooling of the ambient requires partial enclosing of the space surrounding the animals and is limited by the humidity in ambient air. An alternative was developed of coupling forced ventilation with wetting of animal surface. The exchange of ambient air flowing on animal surface makes the evaporation practically independent of air humidity and the loss of heat from animal surface practically independent of the surface to air temperature gradient. The coupling of forced ventilation with wetting combination may be attained in various parts of the dairy farm, the holding area of the milking parlour, the feeding trip and the resting area. Each of these requires differing structural and technological adaptations. Climate and farming systems vary between locations which require specific solutions.

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The predictability of heat-related mortality in Prague, Czech Republic, during summer 2015—a comparison of selected thermal indices

Abstract

We compared selected thermal indices in their ability to predict heat-related mortality in Prague, Czech Republic, during the extraordinary summer 2015. Relatively, novel thermal indices—Universal Thermal Climate Index and Excess Heat Factor (EHF)—were compared with more traditional ones (apparent temperature, simplified wet-bulb globe temperature (WBGT), and physiologically equivalent temperature). The relationships between thermal indices and all-cause relative mortality deviations from the baseline (excess mortality) were estimated by generalized additive models for the extended summer season (May–September) during 1994–2014. The resulting models were applied to predict excess mortality in 2015 based on observed meteorology, and the mortality estimates by different indices were compared. Although all predictors showed a clear association between thermal conditions and excess mortality, we found important variability in their performance. The EHF formula performed best in estimating the intensity of heat waves and magnitude of heat-impacts on excess mortality on the most extreme days. Afternoon WBGT, on the other hand, was most precise in the selection of heat-alert days during the extended summer season, mainly due to a relatively small number of "false alerts" compared to other predictors. Since the main purpose of heat warning systems is identification of days with an increased risk of heat-related death rather than prediction of exact magnitude of the excess mortality, WBGT seemed to be a slightly favorable predictor for such a system.

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Spring- and fall-flowering species show diverging phenological responses to climate in the Southeast USA

Abstract

Plant phenological shifts (e.g., earlier flowering dates) are known consequences of climate change that may alter ecosystem functioning, productivity, and ecological interactions across trophic levels. Temperate, subalpine, and alpine regions have largely experienced advancement of spring phenology with climate warming, but the effects of climate change in warm, humid regions and on autumn phenology are less well understood. In this study, nearly 10,000 digitized herbarium specimen records were used to examine the phenological sensitivities of fall- and spring-flowering asteraceous plants to temperature and precipitation in the US Southeastern Coastal Plain. Climate data reveal warming trends in this already warm climate, and spring- and fall-flowering species responded differently to this change. Spring-flowering species flowered earlier at a rate of 1.8–2.3 days per 1 °C increase in spring temperature, showing remarkable congruence with studies of northern temperate species. Fall-flowering species flowered slightly earlier with warmer spring temperatures, but flowering was significantly later with warmer summer temperatures at a rate of 0.8–1.2 days per 1 °C. Spring-flowering species exhibited slightly later flowering times with increased spring precipitation. Fall phenology was less clearly influenced by precipitation. These results suggest that even warm, humid regions may experience phenological shifts and thus be susceptible to potentially detrimental effects such as plant-pollinator asynchrony.

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Evidence for the therapeutic effect of the organic content in Szigetvár thermal water on osteoarthritis: a double-blind, randomized, controlled clinical trial

Abstract

The therapeutic effects of mineral waters have been attributed to the inorganic components alone; however, biologically active organic components are also present. We aimed to investigate whether the healing effect of Szigetvár thermal mineral water could relate to the organic matter in patients suffering from osteoarthritis of the hips and the knees. XAD macroreticular resins were used to prepare the organic fraction. Patients received a 30-min thermal water (34 °C) treatment in a bath tub, five times a week for 3 weeks. After randomization, patients were divided into three groups: tap water, mineral water, and organic fraction group. Primary outcomes were range of movement (ROM), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and visual analog scale (VAS) for pain severity, and the Short Form 36 (SF-36) questionnaire was used. These scores and indices were measured at baseline, after the last treatment, and at the end of the 3-month follow-up period. Seventy-four patients (age 67.3 ± 4.48 years) were enrolled: tap water n = 24, mineral water n = 26, and organic fraction n = 24. Treatment with the redissolved organic fraction significantly improved ROM, WOMAC, and SF-36 scores compared to the tap water. Our clinical trial provided evidence for the beneficial health effects of the organic fraction of Szigetvár medicinal water.

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Climatic determinants impacting the distribution of greenness in China: regional differentiation and spatial variability

Abstract

This study investigated climatic determinants for regional greenness in China and spatially variable correlations between climatic determinants and vegetation in specific regions using the geographical detector and geographically weighted regression (GWR) methodologies. The analyses were based on normalized difference vegetation index (NDVI) and interpolations of climatic determinants from 652 Chinese meteorological stations. The study period (1982–2013) was divided into two stages (T1–T2) before and after the inflection year identified by the accumulative anomaly of NDVI. Three typical regions (R1–R3) were then selected according to the same NDVI variation trend as China in the two periods. Precipitation was the dominant climatic factor of NDVI in China, and the effect of temperature on greenness increased with warming from T1 to T2. In a relatively arid region (R1), the effect of precipitation in T2 was further strengthened compared to T1. Meanwhile, the effect of minimum temperature in T2 also increased compared with T1 in a relatively humid region (R2), becoming the major climatic determinant. In addition to the regional differentiation, spatial variability was investigated by comparing normalized coefficients of GWR for climatic determinants; this showed significant spatial heterogeneity within each region. Temperature impact areas also existed within precipitation-dominated regions (R1 and R3), where areas of precipitation impact expanded from T1 to T2. Furthermore, regression coefficients between NDVI dynamics and climate variability revealed relationships between regional differentiation and spatial variability. For example, the increasing precipitation rate could mediate the adverse impacts on greenness caused by the higher warming rate in relatively arid regions (R1).

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Effects of deciduous shade trees on surface temperature and pedestrian thermal stress during summer and autumn

Abstract

In a context of urban warming, the effects of trees on outdoor thermal stress are important even during the increasingly hot autumn season. This study examines the effects of a deciduous tree species (Tilia x europaea L) on surface temperature over different ground materials and in turn on human thermal comfort, with a particular focus on tree shade variation due to leaf fall. Grass, asphalt, and gravel-covered ground surfaces, both sun-exposed and under the Tilia, were monitored in Florence, Italy, during the summer (2014) and autumn (2017) seasons. The Index of Thermal Stress (ITS) was used to gauge the micrometeorological effects of the changing tree canopy, with tree defoliation quantified by the Plant Area Index. On clear summer days, thermal discomfort was especially pronounced over exposed asphalt, and even more intense above exposed gravel due to its higher reflectivity—while shaded surfaces showed large reductions in thermal stress. Even though incoming solar radiation decreases over the course of the fall season, the direct radiation under the gradually defoliating tree canopy actually increases. Due to this diminished shading effect, the differences in surface temperature between exposed and shaded asphalt shrink dramatically from about 20 to 3 °C. However, since ambient conditions become milder as the season progresses, the Tilia demonstrated a double benefit in terms of ITS: providing thermal comfort under its full canopy at the beginning of autumn and maintaining comfort even as its canopy thins out. At the same time, tree species with earlier defoliation may be unable to replicate such benefits.

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Activity modification in heat: critical assessment of guidelines across athletic, occupational, and military settings in the USA

Abstract

Exertional heat illness (EHI) risk is a serious concern among athletes, laborers, and warfighters. US Governing organizations have established various activity modification guidelines (AMGs) and other risk mitigation plans to help ensure the health and safety of their workers. The extent of metabolic heat production and heat gain that ensue from their work are the core reasons for EHI in the aforementioned population. Therefore, the major focus of AMGs in all settings is to modulate the work intensity and duration with additional modification in adjustable extrinsic risk factors (e.g., clothing, equipment) and intrinsic risk factors (e.g., heat acclimatization, fitness, hydration status). Future studies should continue to integrate more physiological (e.g., valid body fluid balance, internal body temperature) and biometeorological factors (e.g., cumulative heat stress) to the existing heat risk assessment models to reduce the assumptions and limitations in them. Future interagency collaboration to advance heat mitigation plans among physically active population is desired to maximize the existing resources and data to facilitate advancement in AMGs for environmental heat.

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Short-term heat shock proteins 70 and 90 mRNA expression profile and its relation to thermo-physiological parameters in goats exposed to heat stress

Abstract

To follow the inheritance potential for heat tolerance after a crossing program in goats, 24 kids from four groups of goat kids (6 kids in each) from Aradi (A) and Damascus (D), their crossbred first-generation F₁ (½D½A) and second-generation F₂ (¾D¼A), were exposed to acute elevated environmental temperature in controlled climatic chambers. Rectal temperature (RT), respiratory rate (RR), heat tolerance coefficient (HTC), adaptability coefficient (AC), and mRNA expression of heat shock proteins 70 and 90 ((HSP70 and HASP90, respectively), using real-time PCR were estimated. Results showed that Aradi breed goats had the highest level of expression for heat shock proteins 70 and 90, followed by F₁, F₂, and Damascus (P ≤ 0.01). Crossbreeds and Damascus showed the highest RT, while Aradi breed showed the lowest value (P ≤ 0.01). Aradi and crossbreeds showed the highest RR, while Damascus showed the lowest RR (P ≤ 0.05). Aradi and F₁ showed the highest HTC (P ≤ 0.05), while there was no significant difference between pure breeds and crossbreeds in AC. A significant positive phenotypic correlation (0.81) was observed between HSP70 and HSP90. In addition, RR showed moderate positive correlation with both HSP70 and HSP90. It could be concluded that Aradi breed had putative heat tolerance in comparison to its crossbred progeny from the Damascus breed. The crossbreeding may result in some loss of heat tolerance potential, but the crossbreeds still better adapted to high environmental temperature than the Damascus breed.

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Changes in agro-climatic indices related to temperature in Central Chile

Abstract

Climate change has profound environmental and socio-economic implications. To analyze climate change in relation to crops, a wide variety of agro-climatic indices has been proposed by the scientific community. In this study, changes in a set of 12 agro-climatic indices related to temperature were investigated in Central Chile over a 56-year period (1961–2016). The indices were computed based on data referring to daily maximum and minimum temperatures (TX and TN). They were organized in two categories: (1) cold- and (2) heat-related indices. Cold-related indices consisted of first frost day (FFD), last frost day (LFD), frost period (FP), number of frost days (FD), accumulated frost (AF), and number of days when TN is below − 2 °C (FD-2). Heat-related indices included the growing degree day (GDD) index, calculated based on four thresholds which measure the available heat resources for a wide variety of plants with different thermal requirements, and two heat stress indices which quantify the number of days with TX above 25 °C (plant heat stress (PHS)) and above 30 °C (plant high heat stress (PHHS)). Changes in agro-climatic indices were investigated using the Mann–Kendall test and the Sen's slope estimator. The main results revealed that the FFD occurred later, while LFD occurred earlier, thus determining a shortening of the FP in the northern half of the studied area. Trends in FD, AF, and FD-2 indices generally indicated warmer conditions in terms of TN during the cold period of the year. Agro-climatic indices related to heat showed important changes in Central Chile. Thus, statistically, the majority of trends become significant and indicated enhanced condition for crops in respect of GDD indices. However, from the heat stress perspective, the analyzed indices showed that conditions become worse in most of the studied locations for crops sensible to temperatures higher than 25 and 30 °C.

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