Bibliometric Analysis of Worldwide Publications on Antimalarial Drug Resistance (2006–2015)

Background. In response to international efforts to control and eradicate malaria, we designed this study to give a bibliometric overview of research productivity in antimalarial drug resistance (AMDR). Methods. Keywords related to AMDR were used to retrieve relevant literature using Scopus database. Results. A total of 976 publications with an h-index of 63 were retrieved. The number of publications showed a noticeable increase starting in the early 1990s. The USA was the most productive country with 337 publications equivalent to one-third of worldwide publications in this field. More than two-thirds of publications by the USA (236, 70.03%) were made by international collaboration. Of the top ten productive countries, two countries were from Mekong subregion, particularly Thailand and Cambodia. The Malaria Journal was the most productive journal (136, 13.93%) in this field. Mahidol University (80, 8.20%) in Thailand was the most productive institution. Seven articles in the top-ten list were about artemisinin resistance in Plasmodium falciparum, one was about chloroquine resistance, one was about sulfadoxine-pyrimethamine resistance, and the remaining one was about general multidrug resistance. Conclusion. Eradication and control of AMDR require continuing research activity to help international health organizations identify spots that require an immediate action to implement appropriate measures.

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Upper airway surgery for obstructive sleep apnea reduces blood pressure

Objectives/Hypothesis

To evaluate if upper airway surgery reduces blood pressure in patients with obstructive sleep apnea (OSA).

Study Design

Prospective series.

Methods

A prospective series of 112 consecutive OSA patients with hypertension (HTN). All patients were > 18 years old, respiratory disturbance index >5, all levels of apnea-hypopnea index (AHI), with a history of HTN treated with medication for at least 6 months. Surgical procedures included septoplasty, turbinate reduction, palate surgery, and tongue base reduction.

Results

There were 92 men and 20 women, with a mean age of 48.6 years, mean body mass index (BMI) was 27.5 (range, 19.7–34.7). Mean follow-up was 16.1 months. The mean preoperative AHI was 32.6 (range, 1.2–104), with the mean lowest oxygen saturation (LSAT) of 79.9% (range, 52%–93%). The mean adjusted preoperative and postoperative systolic blood pressure (SBP) was reduced from 146 ± 15.3 mm Hg to 122 ± 12.5 mm Hg (P < .001), and diastolic blood pressure (DBP) was reduced from 91 ± 10.2 mm Hg to 76 ± 7.8 mm Hg (P < .001). There was a decrease in overall BMI from 27.5 ± 3.6 to 25.5 ± 3.0 (P < .001); however, based on multivariate analysis, the reduction in SBP and DBP was not affected by this BMI reduction. Fifty-eight patients (51.8%) did not require their antihypertensive after surgery. There was poor correlation noted between HTN with AHI, LSAT, and oxygen duration <90%.

Conclusions

Upper airway surgery does reduce SBP and DBP in patients with OSA.

Level of Evidence

4. Laryngoscope, 2017

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Resistance training does not alter same-day sleep architecture in institutionalized older adults

Summary

Sleep disturbance is a common symptom in institutionalized older adults that reduces their quality of life and may contribute to progression of cognitive impairment. While we found that a 7-week combination of resistance training, walking and social activity significantly improved sleep in institutionalized older adults compared with a usual care control group, no one to our knowledge has determined the acute effects of resistance training on same-day sleep in this population. Given the effort required to promote exercise adherence in institutionalized older adults and to obtain a positive training effect, understanding of the acute effects of resistance training on same-day sleep architecture should be elucidated, especially with respect to unintended consequences. This secondary data analysis assessed if resistance training altered the same-day sleep architecture in institutionalized older adults. Forty-three participants (age 81.5 ± 8.1 years, male = 17, female = 26) had two attended overnight polysomnography tests in their rooms for sleep architecture analysis; one polysomnography with same-day resistance training, one without any resistance training. Resistance training consisted of chest and leg press exercises (three sets, eight repetitions, 80% predicted one-repetition maximum). There were no significant changes in sleep architecture between either polysomnography nights; sleep efficiency (P = 0.71), time in non-rapid eye movement stages (P = 0.50), time in rapid eye movement stages (P = 0.14), time awake (P = 0.56), time until sleep onset (P = 0.47), total sleep stage shifts (P = 0.65) or rapid eye movement sleep stage latency (P = 0.57). Our results show no acute same-day effects of resistance training on sleep architecture in institutionalized older adults.

Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00888706.

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Beyond Genomics - Targeting the Epigenome in Diffuse Large B-Cell Lymphoma

Publication date: Available online 9 August 2017
Source:Cancer Treatment Reviews
Author(s): Andrea Kühnl, David Cunningham, Ian Chau
After decades of intense research on genetic alterations in cancer and successful implementation of genetically-based targeted therapies, the field of cancer epigenetics is only beginning to be fully recognized. The discovery of frequent mutations in genes modifying the epigenome in diffuse large B-cell lymphoma (DLBCL) has highlighted the outstanding role of epigenetic deregulation in this disease. Identification of epigenetically-driven DLBCL subgroups and development of novel epigenetic drugs have rapidly advanced. However, further insights are needed into the biological consequences of epigenetic alterations and the possibility of restoring the aberrant epigenome with specific therapies to bring this treatment concept further into clinical practice. This review will summarize the main epigenetic changes found in DLBCL and their potential for precision medicine approaches.



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New blood test could help save patients with hard-to-spot type of head and neck cancer, Chinese University says - South China Morning Post

Bloomberg

New blood test could help save patients with hard-to-spot type of head and neck cancer, Chinese University says South China Morning Post A breakthrough blood test by Hong Kong scientists could lead to discovery of a hard-to-detect type of head and neck cancer at a significantly earlier stage, potentially saving lives, the Chinese University announced on Thursday. Researchers, in a study ... Silicon Valley Startup Grail Sees Hope for Cancer Blood TestBloomberg Study Boosts Hope of 'Liquid Biopsies' for Cancer ScreeningU.S. News & World Report Low-cost Liquid Biopsy for Epstein-Barr Virus Detects Nasopharyngeal CarcinomaCancer Therapy Advisor all 15 news articles »

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A combination of anti-PD-L1 mAb plus Lm-LLO-E6 vaccine efficiently suppresses tumor growth and metastasis in HPV-infected cancers

Abstract

PD-1/PD-L1 immunotherapy is viewed as having clinical benefits in advanced cancers but is effective in only a few patients, suggesting that an efficient combination approach is needed to improve efficacy. Immunohistochemistry analysis indicated that PD-L1 expression was correlated with the E6 expression in tumors from 122 lung cancer patients. The poorest survival occurred in PD-L1-positive/E6-positive tumor. PD-L1 expression was increased by the expression of E6, but not the E7, oncoprotein in lung and cervical cancer cells. PD-L1 expression was responsible for E6-mediated colony formation and soft agar growth. Therefore, PD-L1 secreted from tumor cells may directly promote tumor progression, particularly in E6-positive tumors. Immune deficiency nude mice were used to test the possibility that combining anti-PD-L1 mAb with Lm-LLO-E6 vaccine could have a higher antitumor activity compared with anti-PD-L1 mAb or Lm-LLO-E6 vaccine alone. A greater antitumor activity was obtained with anti-PD-L1 mAb + Lm-LLO-E6 vaccine than with anti-PD-L1 mAb or Lm-LLO-E6 alone in subcutaneous and metastatic tumors induced by TL-1 and SiHa cells. The longest survival time for nude mice was observed in the anti-PD-L1 mAb + Lm-LLO-E6 vaccine group. In conclusion, an anti-PD-L1 mAb + Lm-LLO-E6 vaccine may be an efficient treatment for suppression of tumor growth and metastasis induced by HPV-infected cells.

We have provided evidence that an anti-PD-L1 mAb + Lm-LLO-E6 vaccine combination is an efficient therapeutic approach against HPV-infected NSCLC. In addition, the anti-PD-L1 mAb + Lm-LLO-E6 vaccine combination also efficiently suppresses SiHa cell-induced tumors in nude mice. Therefore, we suggest that anti-PD-L1 mAb + Lm-LLO-E6 vaccine combination therapy may have a greater clinical benefit than anti-PD-L1 or HPV DNA vaccine immunotherapy in cancer patients with HPV-infected tumors.

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Dissipation kinetics, pre-harvest residue limits, and hazard quotient assessments of pesticides flubendiamide and fluopicolide in Korean melon ( Cucumis melo L. var. makuwa ) grown under regulated conditions in plastic greenhouses

Abstract

The dissipation kinetics, pre-harvest residue limits, and hazard quotient (HQ) assessments of the pesticides flubendiamide and fluopicolide were conducted for Korean melon (Cucumis melo L. var. makuwa) cultivated at two different sites. A single extraction and cleanup procedure was carried out using acetone (partitioned with dichloromethane) and amino solid-phase extraction cartridges, respectively. Residue analysis was performed by HPLC with ultraviolet detection. Both pesticides showed excellent linearity with correlation coefficients of 0.9999 and 0.9996 for flubendiamide and fluopicolide, respectively. The accuracy (expressed as recovery %) at three spiking levels was 92.0–103.6 and 82.8–105.3%, and the precision (expressed as relative standard deviation) was 1.7–3.4 and 2.7–5.3% for flubendiamide and fluopicolide, respectively. The initial residues of flubendiamide/fluopicolide were 0.326/0.376 and 0.206/0.298 mg/kg at sites 1 and 2, respectively. These amounts were substantially lower than the maximum residue limits (MRLs = 1 and 0.5 mg/kg for flubendiamide and fluopicolide, respectively) established by the Korean Ministry of Food and Drug Safety. The half-lives of flubendiamide were 5.8 and 6.5 days, and those of fluopicolide were 6.7 and 9.1 days at sites 1 and 2, respectively. The shorter half-lives were attributed to seasonal variations (higher temperatures) and enzymatic and metabolic profiling. The risk assessment HQs of flubendiamide were 0.217/0.249 on day 0, which decreased to 0.102/0.168 on day 5, and to 0.065/0.88 on day 10; the HQ values for fluopicolide were 0.029/0.042, 0.022/0.025, and 0.010/0.019 on day 0, day 5, and day 10, for sites 1/2, respectively. From this data, we concluded that the fruits could be consumed safely.

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Community based saving groups: an innovative approach to overcome the financial and social barriers in health care seeking by the women in the rural remote communities of Pakistan

In remote rural areas of Pakistan, access to the maternal, newborn and child health (MNCH) care provided by a skilled health provider is quite difficult. There are many reasons such as women's restricted socia...

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Angiographic classification of patterns of restenosis following femoropopliteal artery intervention: A proposed scoring system

Abstract

Objectives

To propose a classification system for characterizing angiographic femoropopliteal artery restenosis patterns associated with common endovascular modalities.

Background

Peripheral artery disease is a worldwide issue affecting millions of people. Despite a myriad of endovascular technologies available to treat peripheral artery disease of the femoropopliteal arteries, restenosis remains a common failure mode. Characterizing common patterns of restenosis is important to discern the potential impact of baseline patient, lesion, and procedural characteristics, as well as treatment modalities on either the primary success or the failure patterns associated with restenosis.

Methods

Studies included in the analysis were from previous core laboratory-adjudicated femoropopliteal artery disease trials and registries reflecting a wide array of treatment modalities.

Results

From the subjects enrolled and analyzed, there were 403 total angiograms for analysis and adjudication. Target lesion revascularization images of the 32 validation cases were evaluated for index treated length, diameter stenosis, and lesion morphology characteristics. The following lesion types are proposed: Type 1 "Focal" pattern, which may be "Edge Proximal" or "Edge Distal" depending on location; a Type 2 "Multifocal" pattern which may also exhibit edge restenosis, but may also be "Edge Bilateral"; a Type 3 "Moderate" pattern and a Type 4 "Diffuse" pattern; and finally, a Type 5 "Occlusion".

Conclusions

A classification system that enables healthcare professionals to anticipate and describe failures following the index procedure, thereby impacting the choice of options for retreatment, may facilitate consistency and standardization within the heterogeneous field of endovascular device treatments for the femoropopliteal artery.

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Robotic technology in interventional cardiology: Current status and future perspectives

Abstract

Robotic technology has been utilized in cardiovascular medicine for over a decade, and over that period, its use has been expanded to percutaneous coronary and peripheral vascular interventions. The safety and feasibility of robotically assisted percutaneous cardiovascular interventions has been demonstrated in studies including simple to complex coronary lesions, and both iliac and femoropopliteal lesions. These reports have shown that robotically assisted PCI significantly reduces operator exposure to harmful ionizing radiation without a detrimental effect on procedural success or clinical efficacy. Additionally, the use of robotics has the intuitive benefit of alleviating the risk of orthopedic injuries faced by interventional operators. In addition to the interventional operator benefits, robotically assisted intervention has the potential for patient level benefit by allowing more accurate lesion length measurement, precise stent placement, and lower patient radiation exposure. However, further investigation is required to fully elucidate these potential benefits.

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Coronary dominance and prognosis in patients with chronic total occlusion treated with percutaneous coronary intervention

Abstract

Aim

The prognostic value of coronary artery dominance pattern in patients with chronic total occlusions (CTO) is unknown. The aim of this study was to assess the influence of coronary vessel dominance on short and long-term outcomes in patients undergoing percutaneous coronary intervention (PCI) for CTO.

Methods and results

Our study population consisted of 2002 consecutive patients (17% females, mean age 65.2 ± 10.7 years) who underwent PCI of at least one coronary CTO lesion at our center between 01/2005 and 12/2013. Based on the origin of the posterior descending coronary artery, coronary circulation was categorised into left, right, and balanced coronary dominance. Right coronary dominance (RD) was present in 88% (n = 1759), left coronary dominance (LD) in 7% (n = 136), and balanced coronary dominance (BD) in 5% (n = 107) of the study population. After a median follow-up duration of 2.6 years [interquartile range 1.1–3.1 years] all-cause mortality was significantly higher in patients with LD as compared with RD and BD (log rank = 0.001). Accordingly, the presence of a LD system was identified as a significant predictor for all-cause mortality (adjusted HR 1.7, 95% CI: 1.2-2.6, P = .007) and major adverse cardiac events (MACE) (adjusted HR 1.4, 95% CI: 1.1-1.8, P = 0.02).

Conclusion

Our data suggest that LD is an independent predictor of increased all-cause death and MACE in patients with CTO. Therefore, assessment of coronary vessel dominance by angiography may contribute to risk stratification in these patients.

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Utility of the guideliner catheter for percutaneous coronary interventions in patients with prior transcatheter aortic valve replacement

Abstract

The safety and utility of GuideLiner catheters in complex percutaneous coronary interventions (PCI) has been well established. Patients with prior trans-catheter aortic valve replacement especially with CoreValve, who present for PCI, pose a unique set of challenges. Not only does the operator often encounter difficulty with selective engagement of coronary ostia through the struts of the CoreValve, but also the complex nature of the underlying CAD in this high-risk population. We present a case series to illustrate the use of GuideLiner catheter as an adjunctive tool for PCI in this patient population.

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Hospital teaching status and trascatheter aortic valve replacement outcomes in the United States: Analysis of the national inpatient sample

Abstract

Background

Evidence suggests that medical service offerings vary by hospital teaching status. However, little is known about how these translate to patient outcomes. We therefore sought to evaluate this gap in knowledge in patients undergoing Transcatheter aortic valve replacement (TAVR) in the United States.

Methods

This study was conducted using the National Inpatient Sample (NIS) in the United States from 2011 to 2014. Teaching status was classified, as teaching vs. nonteaching and endpoints were clinical outcomes, length of stay and cost. Procedure-related complications were identified via ICD-9 coding and analysis was performed via mixed effect model.

Results

An estimated 33,790 TAVR procedures were performed in the U.S between 2011 and 2014, out of which 89.3% were in teaching hospitals. Mean (SD) age was 81.4 (8.5) and 47% were females. There was no significant difference between teaching versus nonteaching hospitals in regards to the primary outcome of in-hospital mortality and secondary outcomes of several cardiovascular and other end points except for a high rates of acute kidney injury (AKI) (OR: 1.34 [95% CI, 1.04–1.72]) and lower rate for use of mechanical circulatory support devices in teaching vs. nonteaching centers. The mean length of stay was significantly higher in teaching hospitals (7.7 days) vs. nonteaching hospitals (6.8 days) (P = 0.002) and so was the median cost of hospitalization (USD 50,814 vs. USD 48, 787, P = 0.02) for teaching vs. nonteaching centers.

Conclusion

Most TAVR related short-term outcomes including all cause in-hospital mortality are about the same in teaching and nonteaching hospitals. However, AKI, length of hospital stay and TAVR related cost were significantly higher in teaching than nonteaching hospitals. There was more use of mechanical circulatory support in nonteaching than teaching hospitals.

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What's the Link Between Alcohol and Colon Cancer? - U.S. News & World Report

U.S. News & World Report

What's the Link Between Alcohol and Colon Cancer? U.S. News & World Report Dr. Mark Pochapin, professor and director of the division of gastroenterology at NYU Langone Medical Center, says we have good data from a meta-analysis that shows the more you drink, the higher your risk for colorectal cancer. "Alcohol is literally a ...

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First Japanese case report of atypical Spitz tumor with an ALK rearrangement

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A novel method for sex estimation using 3D computed tomography models of tooth roots: A volumetric analysis

Publication date: November 2017
Source:Archives of Oral Biology, Volume 83
Author(s): Seyedeh M. Kazzazi, Elena F. Kranioti
Advances in technologies such as computed tomography (CT) scanning have allowed for further examination of dental sexual dimorphism in modern and archaeological populations.



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Issue Information - Contents

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Cover Image

The cover image, by Jacqui Allen et al., is based on the Original Article Assessment of videofluoroscopic swallow study findings before and after cricopharyngeal myotomy, DOI: 10.1002/hed.24846.

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Issue Information - Contents

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Cover Image

The cover image, by Jacqui Allen et al., is based on the Original Article Assessment of videofluoroscopic swallow study findings before and after cricopharyngeal myotomy, DOI: 10.1002/hed.24846.

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Identification of the SOX2 interactome by BioID reveals EP300 as a mediator of SOX2-dependent squamous differentiation and lung squamous cell carcinoma growth [Research]

Lung cancer is the leading cause of cancer mortality worldwide, with squamous cell carcinoma (SQCC) being the second most common form. SQCCs are thought to originate in bronchial basal cells through an injury response to smoking, which results in this stem cell population committing to hyperplastic squamous rather than mucinous and ciliated fates. Copy number gains in SOX2 in the region of 3q26-28 occur in 94% of SQCCs, and appear to act both early and late in disease progression by stabilizing the initial squamous injury response in stem cells and promoting growth of invasive carcinoma. Thus, anti-SOX2 targeting strategies could help treat early and/or advanced disease. Since SOX2 itself is not readily druggable, we sought to characterize SOX2 binding partners, with the hope of identifying new strategies to indirectly interfere with SOX2 activity. We now report the first use of proximity-dependent biotin labeling (BioID) to characterize the SOX2 interactome in vivo. We identified 82 high confidence SOX2-interacting partners. An interaction with the coactivator EP300 was subsequently validated in both basal cells and SQCCs, and we demonstrate that EP300 is necessary for SOX2 activity in basal cells, including for induction of the squamous fate. We also report that EP300 copy number gains are common in SQCCs and that growth of lung cancer cell lines with 3q gains, including SQCC cells, is dependent on EP300. Finally, we show that EP300 inhibitors can be combined with other targeted therapeutics to achieve more effective growth suppression. Our work supports the use of BioID to identify interacting protein partners of non-druggable oncoproteins such as SOX2, as an effective strategy to discover biologically relevant, druggable targets.

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Flow induced adherens junction remodeling driven by cytoskeletal forces

Publication date: Available online 10 August 2017
Source:Experimental Cell Research
Author(s): Deepika Verma, Vivek Bajpai, Nannan Ye, Mohammad M. Maneshi, Deekshitha Jetta, Stelios T. Andreadis, Frederick Sachs, Susan Z. Hua
Adherens junctions (AJs) are a key structural component for tissue organization and function. Under fluid shear stress, AJs exhibit dynamic assembly/disassembly, but how shear stress couples to AJs is unclear. In MDCK cells we measured simultaneously the forces in cytoskeletal α-actinin and the density and length of AJs using a genetically coded optical force sensor, actinin-sstFRET, and fluorescently labeled E-cadherin (E-cad). We found that shear stress of 0.74dyn/cm² for 3hours significantly enhanced E-cad expression at cell-cell contacts and this phenomenon has two phases. The initial formation of segregated AJ plaques coincided with a decrease in cytoskeletal tension, but an increase in tension was necessary for expansion of the plaques and the formation of continuous AJs in the later phase. The changes in cytoskeletal tension and reorganization appear to be an upstream process in response to flow since it occurred in both wild type and dominant negative E-cad cells. Disruption of F-actin with a Rho-ROCK inhibitor eliminated AJ growth under flow. These results delineate the shear stress transduction paths in cultured cells, which helps to understand pathology of a range of diseases that involve dysfunction of E-cadherin.



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Improved therapeutic efficacy of mammalian expressed-recombinant interferon gamma against ovarian cancer cells

Publication date: Available online 10 August 2017
Source:Experimental Cell Research
Author(s): Ali Razaghi, Carina Villacrés, Vincent Jung, Narges Mashkour, Michael Butler, Leigh Owens, Kirsten Heimann
Human interferon gamma (hIFNγ) affects tumour cells and modulates immune responses, showing promise as an anti-cancer biotherapeutic. This study investigated the effect of glycosylation and expression system of recombinant hIFNγ in ovarian carcinoma cell lines, PEO1 and SKOV3. The efficacy of E. coli- and mammalian-expressed hIFNγ (hIFNγ-CHO and HEK293, glycosylated/de-glycosylated) on cytostasis, cell death (MTT, and Guava-ViaCount^® flow-cytometry) and apoptotic signalling (Western blot of Cdk2, histone H3, procaspase-3, FADD, cleaved PARP, and caspase-3) was examined. Hydrophilic Interaction Liquid Chromatography determined the structure of N-linked glycans present in HEK293-expressed hIFNγ (hIFNγ-HEK). PEO1 was more sensitive to hIFNγ than SKOV3, but responses were dose-dependent and expression platform/glycosylation status-independent, whereas SKOV3 responded to mammalian-expressed hIFNγ in a dose-independent manner, only. Complex-type oligosaccharides dominated the N-glycosylation pattern of hIFNγ-HEK with some terminal sialylation and core fucosylation. Cleaved PARP and cleaved caspase-3 were not detected in either cell line, but FADD was expressed in SKOV3 with levels increased following treatment. In conclusion, hIFNγ did not induce apoptosis in either cell line. Mammalian- expressed hIFNγ increased cell death in the drug-resistant SKOV3. The presence of FADD in SKOV3, which may inhibit apoptosis through activation of NF-κB, could serve as a novel therapeutic target.

Graphical abstract

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A novel RIPK1 inhibitor that prevents retinal degeneration in a rat glaucoma model

Publication date: Available online 9 August 2017
Source:Experimental Cell Research
Author(s): Yun-Ju Do, Jee-Won Sul, Ki-Hong Jang, Nam Sook Kang, Young-Hoon Kim, Young-Gwan Kim, Eunhee Kim
In glaucoma, retinal ganglion cells (RGCs) are exposed to ischemic stress with elevation of the intraocular pressure and are subsequently lost. Necroptosis, a type of regulated necrosis, is known to play a pivotal role in this loss. We observed that receptor-interacting protein kinase 1 (RIPK1), the key player of necroptosis, was activated by diverse ischemic stresses, including TCZ, chemical hypoxia (CH), and oxygen glucose deprivation (OGD). In this study, we introduce a RIPK1-inhibitory compound (RIC) with a novel scaffold. RIC inhibited downstream events following RIPK1 activation, including necrosome formation and mitochondrial dysfunction in RGC5 cells. Moreover, RIC protected RGCs against ischemic injury in the rat glaucoma model, which was induced by acute high intraocular pressure. However, RIC displayed biochemical characteristics that are distinct from those of previous RIPK1 inhibitors (necrostatin-1; Nec-1 and Compound 27; Cpd27). RIC protected RGCs against OGD insult, while Nec-1 and Cpd27 did not. Conversely, Nec-1 and Cpd27 protected RGCs from TNF-stimulated death, while RIC failed to inhibit the death of RGCs. This implies that RIPK1 activates alternative pathways depending on the context of the ischemic insults.



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PPARGC1A is Upregulated and Facilitates Lung Cancer Metastasis

Publication date: Available online 10 August 2017
Source:Experimental Cell Research
Author(s): Jin-dong Li, Qing-chuan Feng, Yu Qi, Guanghui Cui, Song Zhao
Lung cancer remains a leading cause of cancer-related mortality, with metastatic progression remaining the single largest cause of lung cancer mortality. Hence it is imperative to determine reliable biomarkers for lung cancer prognosis. We performed quantitative real-time PCR (qRT-PCR) analysis to explore epithelial-mesenchymal transition (EMT) inducers that regulate EMT process in three patients with advanced lung cancer disease. Peroxisome proliferator-activated receptor gamma (PPARGC1A) was uniformly the topmost overexpressed gene in all three human non-small cell lung cancer (NSCLC) patient samples. Further evaluation in human normal lung and metastatic lung cancer cell lines revealed that the expression of PPARGC1A was upregulated in metastatic lung cancer cell lines. Metagenomic analysis revealed direct correlation among PPARGC1A, zinc-finger transcription factor snail homolog 1 (SNAI1), and metastatic lung disease. Upregulation of PPARGC1A transcript expression was independent of a differential upregulation of the upstream AMP-dependent protein kinase (AMPK) activation or steady state expression of the silent mating type information regulation 2 homolog 1 (SIRT1). Xenograft tail vein colonization assays proved that the high expression of PPARGC1A was a prerequisite for metastatic progression of lung cancer to brain. Our results indicate that PPARGC1A might be a potential biomarker for lung cancer prognosis.



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High-glucose induces tau hyperphosphorylation through activation of TLR9-P38MAPK pathway

Publication date: Available online 10 August 2017
Source:Experimental Cell Research
Author(s): Yue Sun, Qian Xiao, Cheng Luo, Yuxing Zhao, Die Pu, Kexiang Zhao, Jinliang Chen, Meili Wang, Zhiyin Liao
Diabetic encephalopathy (DE) is one of the most common complications of diabetes. The major pathological variations include neurofibrillary tangles (NFTs), which are caused by tau hyperphosphorylation, and senile plaques (SPs) consisting of amyloid β- protein(Aβ) deposits. In recent years, DE research studies have focused on exploring the activation of the inflammatory signaling pathway in immune cells. Toll-like receptor 9 (TLR9) is well known to regulate the inflammatory reactions in immune processes. During the tau hyperphosphorylation process, TLR9 in microglia plays bidirectional roles. However, no studies have clearly demonstrated the relationship between TLR9 and tau hyperphosphorylation in neurons. Based on our experiments, we found significant increase in TLR9 expression in neurons and an increase in tau hyperphosphorylation in high-glucose media. However, these alterations can be reversed by TLR9 inhibitor. Furthermore, we specifically inhibited the activation of P38mitogenactivated protein kinase(P38MAPK) and found an effective decrease in tau hyperphosphorylation. This effect is likely related to Unc93b1. Meanwhile, High glucose levels can induce neuronal apoptosis via the TLR9 signaling pathway.Our studies are the first to reveal that high glucose can regulate tau hyperphosphorylation and neuronal apoptosis via TLR9-P38MAPK signaling pathway. These findings provide a new method for studying the mechanism underlying DE.



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Beyond Genomics - Targeting the Epigenome in Diffuse Large B-Cell Lymphoma

Approximately one third of patients with diffuse large B-cell lymphoma (DLBCL) relapse after first-line therapy. Outcome of relapsed/refractory DLBCL remains poor and there is an unmet need for novel agents to improve treatment of this patient population. Remarkable progress has recently been made in the development of "epigenetic drugs" and in our understanding of the epigenetic basis of DLBCL. Epigenetics define mechanisms of regulating cellular functions without changing the genetic code. Key elements of the epigenome are chromatin modifications in form of DNA methylation as well as post-translational modifications of histones.

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The value of intraoperative EABRs in auditory brainstem implantation

To compare the intraoperative electrically evoked auditory brainstem response (EABR) morphologies between neurofibromatosis II (NF2) adult auditory brainstem implant (ABI) recipients who had auditory percepts post-operatively and those who did not and between NF2 adult ABI recipients and non-NF2 pediatric ABI recipients.

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The value of intraoperative EABRs in auditory brainstem implantation

To compare the intraoperative electrically evoked auditory brainstem response (EABR) morphologies between neurofibromatosis II (NF2) adult auditory brainstem implant (ABI) recipients who had auditory percepts post-operatively and those who did not and between NF2 adult ABI recipients and non-NF2 pediatric ABI recipients.

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Beyond Genomics - Targeting the Epigenome in Diffuse Large B-Cell Lymphoma

Approximately one third of patients with diffuse large B-cell lymphoma (DLBCL) relapse after first-line therapy. Outcome of relapsed/refractory DLBCL remains poor and there is an unmet need for novel agents to improve treatment of this patient population. Remarkable progress has recently been made in the development of "epigenetic drugs" and in our understanding of the epigenetic basis of DLBCL. Epigenetics define mechanisms of regulating cellular functions without changing the genetic code. Key elements of the epigenome are chromatin modifications in form of DNA methylation as well as post-translational modifications of histones.

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Radiation-induced gliomas: a report of four cases and analysis of molecular biomarkers

Abstract

Radiation-induced glioma (RIG) is a rare secondary glioma. The tumors morphologically resemble their sporadically arising counterparts. Recently, the WHO classification of tumors of the central nervous system was revised to incorporate molecular biomarkers together with classic histological features. The status of molecular biomarkers in RIG, however, remains unclear. The objective of this study was to investigate if commonly accepted glioma-specific biomarkers are relevant in RIGs. Among 269 gliomas diagnosed as WHO grade 2, 3 and 4 in our institution, four were diagnosed as RIGs. Immunohistochemical (IHC) staining for isocitrate dehydrogenase 1 (IDH1), p53, alpha thalassemia/mental retardation syndrome X-linked (ATRX), and H3K27M, and direct DNA sequencing of IDH1/2, telomerase reverse transcriptase (TERT) promoter, Histone H3.3 (H3F3A) and B-Raf (BRAF) genes was performed. All tumor specimens were IDH1-, p53- and H3K27M-negative. The nuclei of tumor cells in all cases exhibited positive staining for ATRX. In direct DNA sequencing analysis, no IDH1, IDH2, TERT promoter, H3F3A or BRAF mutations were found in any of the cases. Our findings suggest that these characteristic glioma-associated molecular mutations may be rare events in RIGs. More RIGs need to be tested for analysis of molecular biomarkers to clarify the clinical and histopathological spectra of this tumor.

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Variations in the labyrinthine segment of facial nerve canal revealed by high-resolution computed tomography

To study variations in the labyrinthine segment of fallopian canal and the associated middle and inner ear malformations.

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Reliability and Validity of Speech Evaluation in Adductor Spasmodic Dysphonia

The aim of this study was to evaluate speech in patients with adductor spasmodic dysphonia (ADSD) by perceptual evaluations and acoustic measures, and to examine the reliability and validity of these measures.

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Auditory-Perceptual Evaluation of Dysphonia: A Comparison Between Narrow and Broad Terminology Systems

In auditory-perceptual voice analysis, a multiparameter approach and a more reductionist approach may be compared with narrow and broad phonetic transcription and used interchangeably, depending on the purpose. The aim of this study was to investigate the perspectives of a translation of the terminology used in the multiparameter Danish Dysphonia Assessment (DDA) approach into the five-parameter GRBAS system.

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Blood test can screen for rare sinus cancer, study finds - UPI.com

UPI.com

Blood test can screen for rare sinus cancer, study finds UPI.com WEDNESDAY, Aug. 9, 2017 -- A new DNA blood test can catch a rare but deadly form of cancer that occurs in the sinuses, researchers report. The test, which looks for DNA evidence of Epstein-Barr virus in blood samples, was 97 percent accurate at ... and more »

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Dr. Weiss on Developments in the Treatment of Head and Neck Cancer - OncLive

Dr. Weiss on Developments in the Treatment of Head and Neck Cancer OncLive Jared Weiss, MD, assistant professor, UNC Lineberger Comprehensive Cancer Center, discusses developments of immunotherapy trials for patients with head and neck cancer. There is a trial of pembrolizumab (Keytruda) in combination with radiation, which ...

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Long-term employment outcomes following rehabilitation for significant neurological impairment in UK military personnel: a 3-year study

Background

Returning to employment is a major modifiable factor affecting long-term health in brain injury which neurological and vocational rehabilitation attempts to address. In military patients, little is known about long-term employability, whether employment is sustained and how they fare in civilian roles.

Methods

A telephone review was undertaken of every military patient having undergone inpatient neurorehabilitation between 2012 and 2014. This was compared to their employment outcomes one to three years post discharge. We further evaluated whether this employment was sustained over successive years in the same patients. Finally, we identify those rehabilitation interventions deemed most influential in improving employment outcomes in brain injury.

Results

During this period, an average of 57 (51–61) such patients were discharged each year. A review conducted by telephone successfully contacted 46% (43%–49% across cohorts) of all possible patients; 71.4% (64–81) returned to work increasing to 80.7% (76–85) including those training/actively seeking-work. Overall, 31.7% (24–40) returned to full-time military—in those leaving, 89.6% (85.4–90.9) were discharged for medical reasons. Severity of brain injury was unrelated to successful employment; 63.6%/78.6% had the same vocational outcome over two consecutive years while 36.3%/21.4% showed improved outcomes.

Discussion

Despite significant brain/neurological injury (graded by severity/Mayo Portland Adaptability Inventory 4), 80.7% (76–85) were working/training 2/3 years postdischarge from neurorehabilitation with 31.7% returning to full-time military role. Inability to continue within the military was not synonymous with inability to work. Return to work was independent of severity of brain/neurological injury and follow-up over consecutive years demonstrated sustained employment. The argument against inpatient neurorehabilitation has always been cost> This 3-year analysis reinforces that patients can and most likely will return to employment with all the benefits this brings to person/family/society. Vocational rehabilitation is therefore recommended for all brain/neurological injury.

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The future of resuscitative endovascular balloon occlusion in combat operations

Damage control resuscitation and early thoracotomy have been used to increase survival after severe injury in combat. There has been a renewed interest in resuscitative endovascular balloon occlusion of the aorta (REBOA) in both civilian and military medical practices. REBOA may result in visceral and limb ischaemia that could be harmful if use of REBOA is premature or prolonged. The purpose of this paper is to align our experience of combat injuries with the known capability of REBOA to suggest an implementation strategy for the use of REBOA in combat care. It may replace the resuscitative effect of thoracotomy; can provide haemostasis of non-compressible torso injuries such as the junctional and pelvic haemorrhage caused by improvised explosive devices. However, prehospital use of REBOA must be in the context of an overall surgical plan and should be restricted to deployment in the distal aorta. Although REBOA is technically easier than a thoracotomy, it requires operator training and skill to add to the beneficial effect of damage control resuscitation and surgery.

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Achieving and maintaining lung volume in the preterm infant: from the first breath to the NICU

Abstract

Please check if statements under Abstract section are presented correctly.

The main goal for the neonatologist is to facilitate the adaptation to extra-uterine life during initial transition, while minimizing lung injury opening and protecting the premature lung from the first breath onwards. An appropriate management from birth should lead to the achievement of an early functional residual capacity (FRC), and the following steps should aim at maintaining an adequate lung volume. To date, different strategies are available to optimize fetal-neonatal transition and promote lung recruitment. New ventilation approaches, such as sustained lung inflation (SLI) and "open lung strategy", well-established ventilation techniques with a more tailored application and less invasive modalities to administer surfactant have been recently introduced in clinical practice with promising results.

Conclusions: given the current status of neonatal care, it seems that lung injury and BPD could be reduced with multiple strategies starting early in the delivery room. Literature underlines the importance of a respiratory tailored management of preterm infants from birth and during the whole NICU stay.

What is Known: • Experimental and clinical studies have shown that the transition from fetal to adult type cardiorespiratory circulation needs an adequate lung ventilation. An appropriate management in the delivery room should lead to the achievement of an early FRC, and through the following steps, the neonatologist should aim at maintaining an adequate lung volume. • Literature underlines the importance of a respiratory tailored management of preterm infants during the whole NICU stay to maintain the benefits of a successful postnatal adaption.

What is New: • Herewith, we describe the most relevant and recent interventions which can be performed from the delivery room to the NICU stay to guarantee an adequate tradition to postnatal life and an effective cardiorespiratory stability.

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A competent catalytic active site is necessary for substrate induced dimer assembly in triosephosphate isomerase

Publication date: Available online 9 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Pedro Jimenez-Sandoval, Jose Luis Vique-Sanchez, Marisol López Hidalgo, Gilberto Velazquez-Juarez, Corina Diaz-Quezada, Luis Fernando Arroyo-Navarro, Gabriela Montero Moran, Juliana Fattori, A. Jessica Diaz-Salazar, Enrique Rudiño-Pinera, Rogerio Sotelo-Mundo, Ana Carolina Migliorini Figueira, Samuel Lara-Gonzalez, Claudia G. Benítez-Cardoza, Luis G. Brieba
The protozoan parasite Trichomonas vaginalis contains two nearly identical triosephosphate isomerases (TvTIMs) that dissociate into stable monomers and dimerize upon substrate binding. Herein, we compare the role of the "ball and socket" and loop 3 interactions in substrate assisted dimer assembly in both TvTIMs. We found that point mutants at the "ball" are only 39 and 29-fold less catalytically active than their corresponding wild-type counterparts, whereas loop 3 deletions are 1502 and 9400-fold less active. Point and deletion mutants dissociate into stable monomers. However, point mutants assemble as catalytic competent dimers upon binding of the transition state substrate analog PGH, whereas loop 3 deletions remain monomeric. A comparison between crystal structures of point and loop 3 deletion monomeric mutants illustrates that the catalytic residues in point mutants and wild-type TvTIMs are maintained in the same orientation, whereas the catalytic residues in deletion mutants show an increase in thermal mobility and present structural disorder that may hamper their catalytic role. The high enzymatic activity present in monomeric point mutants correlates with the formation of dimeric TvTIMs upon substrate binding. In contrast, the low activity and lack of dimer assembly in deletion mutants suggests a role of loop 3 in promoting the formation of the active site as well as dimer assembly. Our results suggest that in TvTIMs the active site is assembled during dimerization and that the integrity of loop 3 and ball and socket residues is crucial to stabilize the dimer.

Graphical abstract

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Maternal Western diet age-specifically alters female offspring voluntary physical activity and dopamine- and leptin-related gene expression [Research]

Prenatal overnutrition affects development into adulthood and influences risk of obesity. We assessed the transgenerational effect of maternal Western diet (WD) consumption on offspring physical activity. Voluntary wheel running was increased in juvenile (4–7 wk of age), but decreased in adult (16–19 wk of age), F₁ female WD offspring. In contrast, no wheel-running differences in F₁ male offspring were observed. Increased wheel running in juvenile female WD offspring was associated with up-regulated dopamine receptor (DRD)-1 and -2 in the nucleus accumbens (NAc) and with down-regulated Lepr in the ventral tegmental area (VTA). Conversely, decreased wheel running by adult female WD offspring was associated with down-regulated DRD1 in the NAc and with up-regulated Lepr in the VTA. Body fat, leptin, and insulin were increased in male, but not in female, F₁ WD offspring. Recombinant virus (rAAV) leptin antagonism in the VTA decreased wheel running in standard diet but not in WD F₁ female offspring. Analysis of F₂ offspring found no differences in wheel running or adiposity in male or female offspring, suggesting that changes in the F₁ generation were related to in utero somatic reprogramming. Our findings indicate prenatal WD exposure leads to age-specific changes in voluntary physical activity in female offspring that are differentially influenced by VTA leptin antagonism.—Ruegsegger, G. N., Grigsby, K. B., Kelty, T. J., Zidon, T. M., Childs, T. E., Vieira-Potter, V. J., Klinkebiel, D. L., Matheny, M., Scarpace, P. J., Booth, F. W. Maternal Western diet age-specifically alters female offspring voluntary physical activity and dopamine- and leptin-related gene expression.

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Glucose potentiates {beta}-cell function by inducing Tph1 expression in rat islets [Research]

Impaired pancreatic β-cell function is the primary defect in type 2 diabetes. Glucose is an important regulator of β-cell growth and function; however, the mechanisms that are involved in the chronic adaptation of β-cells to hyperglycemia remain largely unknown. In the present study, global gene expression patterns revealed that tryptophan hydroxylase 1 (Tph1) was the most profound of genes that are up-regulated in rat islets exposed to high glucose. Calcium and cAMP signals synergistically mediated glucose-stimulated Tph1 transcription in β-cells by activating cAMP-responsive element–binding protein and promoting its binding with a Tph1 promoter. Similar to in vitro results, in vivo infusion of high glucose also strongly induced Tph1 expression and serotonin production in rat islets, along with enhanced islet function. Inhibition or knockdown of Tph1 markedly decreased glucose-potentiated insulin secretion. In contrast, overexpression of Tph1 augmented glucose-stimulated insulin secretion in rat islets by up-regulating the expression of genes that are related to islet function. In addition, the long-acting glucagon-like peptide 1 receptor agonist, exendin-4, stimulated Tph1 expression in a glucose-dependent manner. Knockdown of Tph1 inhibited exendin-4–potentiated insulin secretion in rat islets. These findings suggest that Tph1 mediates the compensation of islet function induced by glucose, and that promoting Tph1 expression in pancreatic β-cells will provide a new strategy for the treatment of type 2 diabetes mellitus.—Zhang,Y., Deng, R., Yang, X., Xu, W., Liu, Y., Li, F., Zhang, J., Tang, H., Ji, X., Bi, Y., Wang, X., Zhou, L., Ning, G. Glucose potentiates β-cell function by inducing Tph1 expression in rat islets.

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Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells [Research]

Tumor cell metastasis to the brain involves cell migration through biochemically and physically complex microenvironments at the blood–brain barrier (BBB). The current understanding of tumor cell migration across the BBB is limited. We hypothesize that an interplay between biochemical cues and physical cues at the BBB affects the mechanisms of brain metastasis. We found that astrocyte conditioned medium (ACM) applied directly to tumor cells increased tumor cell velocity, induced elongation, and promoted actin stress fiber organization. Notably, treatment of the extracellular matrix with ACM led to even more significant increases in tumor cell velocity in comparison with ACM treatment of cells directly. Furthermore, inhibiting matrix metalloproteinases in ACM reversed ACM's effect on tumor cells. The effects of ACM on tumor cell morphology and migration also depended on astrocytes' activation state. Finally, using a microfluidic device, we found that the effects of ACM were abrogated in confinement. Overall, our work demonstrates that astrocyte-secreted factors alter migration and morphology of metastatic breast tumor cells, and this effect depends on the cells' mechanical microenvironment.—Shumakovich, M. A., Mencio, C. P., Siglin, J. S., Moriarty, R. A., Geller, H. M., Stroka, K. M. Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells.

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Towards a natural classification of Annulatascaceae -like taxa: introducing Atractosporales ord. nov. and six new families

Abstract

Species with relatively small, membraneous, black ascomata, with or without long necks, unitunicate, cylindrical asci with apical rings and fusiform, hyaline ascospores with or without mucilaginous sheaths are common in freshwater habitats in tropical and temperate regions. Many of these taxa have originally been recorded as Annulatascaceae-like taxa. Twenty genera have been included in the family Annulatascaceae, mostly based on morphological characters, while molecular work and phylogenetic analyses are lacking for many genera. In this study, nine new Annulatascaceae-like taxa collected from Thailand were morphologically examined. Pure cultures obtained from single ascospores were used in molecular studies. The nine new strains and several other strains of Annulatascaceae-like Sordariomycetes species were used to establish phylogenetic and evolution relationships among the taxa, based on combined LSU, SSU, ITS and RPB2 sequence data. Phylogenetic analyses provide evidence to introduce one new order and six new families, to accommodate taxa excluded from Annulatascaceae sensu stricto. A new order Atractosporales is established based on the molecular study, including three new introduced families Conlariaceae, Pseudoproboscisporaceae and Atractosporaceae. Conlariaceae is introduced for the genus Conlarium which comprises two species, Conlarium duplumascosporun and a new Hyphomycetous asexual morph taxon Conlarium aquaticum which has subglobose or irregular, brown, clathrate, muriform conidia. Pseudoproboscisporaceae includes Pseudoproboscispora and Diluviicola, while Atractosporaceae includes the genera Rubellisphaeria and Atractospora. Barbatosphaeria, Xylomelasma and Ceratostomella form a distinct stable lineage which is introduced as a new family Barbatosphaeriaceae in Diaporthomycetidae families incertae sedis. A new family Lentomitellaceae is introduced in Diaporthomycetidae families incertae sedis, to accommodate the genus Lentomitella. Woswasiaceae is introduced to accommodate Woswasia, Xylochrysis and Cyanoannulus in Diaporthomycetidae families incertae sedis. Three new species of Fluminicola viz. F. saprophytica, F. thailandensis and F. aquatica are introduced. A new sexual morph, Dictyosporella thailandensis, is reported and Dictyosporella is excluded from Annulatascaceae and placed in Diaporthomycetidae genera incertae sedis. The first sexual morph of Sporidesmium, S. thailandense is also described. The new species Atractospora thailandensis, Diluviicola aquatica and Pseudoproboscispora thailandensis are also introduced. Platytrachelon is added to Papulosaceae based on phylogenetic analysis and morphological characters. Aquaticola, Fusoidispora and Pseudoannulatascus are excluded from Annulatascaceae and placed in Diaporthomycetidae genera incertae sedis. Mirannulata is accommodated in Sordariomycetes, genera incertae sedis.

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Temporal Subtraction of Serial CT Images with Large Deformation Diffeomorphic Metric Mapping in the Identification ... - UroToday

Temporal Subtraction of Serial CT Images with Large Deformation Diffeomorphic Metric Mapping in the Identification ... UroToday From the Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan (R.S., M.Y., K.F., T.K., T.A., K.T.); Advanced Information & Real-world Technology ...

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A small molecule activator of SIRT3 promotes deacetylation and activation of manganese superoxide dismutase

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Jiaqi Lu, Hua Zhang, Xian Chen, Yong Zou, Jiasong Li, Li Wang, Minhao Wu, Jianye Zang, Yang Yu, Wei Zhuang, Qing Xia, Jiangyun Wang
The modulation of protein acetylation network is a promising strategy for life span extension and disease treatment (Sabari et al., 2016; Giblin et al., 2014) [1,2]. A variety of small molecules have been developed to target deacetylases, but extremely few of these molecules are capable of activating the mitochondrial NAD-dependent deacetylase sirtuin-3 (SIRT3) (Gertz and Steegborn, 2016; Scholz et al., 2015) [3,4]. Manganese superoxide dismutase (MnSOD) is the major superoxide scavenger in mitochondria, whose activity is regulated by SIRT3-mediated deacetylation, particularly at the Lys68 site (Chen et al., 2011) [5]. To investigate the influence of Lys68 acetylation on MnSOD activity, we produced a mutant MnSOD protein-bearing N-acetyllysine (AcK) at its Lys68 position through the genetic code expansion approach. We solved the crystal structure of this acetylated MnSOD (MnSODK68AcK), thus revealing the structural and electrostatic basis for the significant activity decrease upon Lys68 acetylation. On the basis of an assay we developed for the SIRT3-mediated deacetylation of MnSODK68AcK, we identified a novel SIRT3 activator, 7-hydroxy-3-(4′-methoxyphenyl) coumarin (C12), which binds to SIRT3 with high affinity and can promote the deacetylation and activation of MnSOD. C12 adds to the current repertoire of extremely few SIRT3 activators, which are potentially valuable for treating a wide array of diseases via modulating the cellular acetylome.

Graphical abstract

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Fructose induced neurogenic hypertension mediated by overactivation of p38 MAPK to impair insulin signaling transduction caused central insulin resistance

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Pei-Wen Cheng, Yu-Te Lin, Wen-Yu Ho, Pei-Jung Lu, Hsin-Hung Chen, Chi-Cheng Lai, Gwo-Ching Sun, Tung-Chen Yeh, Michael Hsiao, Ching-Jiunn Tseng, Chun-Peng Liu
Type 2 diabetes are at a high risk of complications related to hypertension, and reports have indicated that insulin levels may be associated with blood pressure (BP). Fructose intake has recently been reported to promote insulin resistance and superoxide formation. The aim of this study is to investigate whether fructose intake can enhance superoxide generation and impair insulin signaling in the NTS and subsequently elevate BP in rats with fructose-induced hypertension. Treatment with fructose for 4 weeks increased the BP, serum fasting insulin, glucose, homeostatic model assessment-insulin resistance, and triglyceride levels and reduced the serum direct high-density lipoprotein level in the fructose group. The Tempol treatment recovered the fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that fructose increased the p38- and fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1^S307) and suppressed Akt^S473 and neuronal nitric oxide synthase phosphorylation. Similarly, fructose was able to impair insulin sensitivity and increase insulin levels in the NTS. Fructose intake also increased the production of superoxide in the NTS. The results of this study suggest that fructose might induce central insulin resistance and elevate BP by enhancing superoxide production and activating p38 phosphorylation in the NTS.

Graphical abstract

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p63{alpha} protein upregulates heat shock protein 70 expression via E2F1 transcription factor 1, promoting Wasf3/Wave3/MMP9 signaling and bladder cancer invasion [Gene Regulation]

Bladder cancer (BC) is the sixth most common cancer in the United States and is the number one cause of death among patients with urinary system malignancies. This makes the identification of invasive regulator(s)/effector(s) as the potential therapeutic targets for managing BC a high priority. p63 is a member of the p53 family of tumor suppressor genes/proteins, plays a role in the differentiation of epithelial tissues, and is believed to function as a tumor suppressor. However, whether and how p63 functions in BC cell invasion after tumorigenesis remains unclear. Here, we show that p63α protein levels were much higher in mouse high-invasive BC tissues than in normal tissues. Our results also revealed that p63α is crucial for heat shock protein 70 (Hsp70) expression and subsequently increases the ability of BC invasion. Mechanistic experiments demonstrated that p63α can transcriptionally up-regulate Hsp70 expression, thereby promoting BC cell invasion via the Hsp70/Wasf3/Wave3/MMP-9 axis. We further show that E2F transcription factor 1 (E2F1) mediates p63α overexpression-induced Hsp70 transcription. We also found that p63α overexpression activates E2F1 transcription, which appears to be stimulated by p63α together with E2F1. Collectively, our results demonstrate that p63α is a positive regulator of BC cell invasion after tumorigenesis, providing significant insights into the biological function of p63α in BC and supporting the notion that p63α might be a potential target for invasive BC therapy.

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Intracellular rebinding of transition-state analogues provides extended in vivo inhibition lifetimes on human purine nucleoside phosphorylase [Enzymology]

Purine nucleoside phosphorylase (PNP) is part of the human purine salvage pathway. Its deficiency triggers apoptosis of activated T-cells, making it a target for T-cell proliferative disorders. Transition-state analogues of PNP bind with picomolar (pM) dissociation constants. Tight-binding PNP inhibitors show exceptionally long lifetimes on the target enzyme. We solve the mechanism of the target residence time by comparing functional off-rates in vitro and in vivo. We report in vitro PNP-inhibitor dissociation rates (t1/2) from 3 to 31 min for seven Immucillins with dissociation constants of 115 to 6 pM. Treatment of human erythrocytes with DADMe-Immucillin-H (DADMe-ImmH, 22 pM) causes complete inhibition of PNP. Loss of [14C]DADMeImmH from erythrocytes during multiple washes is slow and biphasic, resulting from inhibitor release and rebinding to PNP catalytic sites. The slow phase gave a t1/2 of 84 hr. Loss of [14C]DADMe-ImmH from erythrocytes in the presence of excess unlabeled DADMe-ImmH increased to a t1/2 of 1.6 hr, by preventing rebinding. Thus, in human erythrocytes, rebinding of DADMeImmH is 50-fold more likely than diffusional loss of the inhibitor from the erythrocyte. Humans treated with a single oral dose of DADMe-ImmH in phase 1 clinical trials exhibit regain of PNP activity with a t1/2 of 59 days, corresponding to the erythropoiesis rate in humans. Thus, the PNP catalytic site recapture of DADMe-ImmH is highly favored in vivo. We conclude that transition-state analogues with picomolar dissociation constants exhibit long lifetimes on their targets in vivo because the probability of the target enzyme recapturing inhibitor molecules is greater than diffusional loss to the extracellular space.

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In vitro reconstitution of the yeast spore wall dityrosine layer to disclose the mechanism of its assembly [Cell Biology]

In response to nutrient starvation, diploid cells of the budding yeast Saccharomyces cerevisiae differentiate into a dormant form of haploid cell termed a spore. The dityrosine layer forms the outermost layer of the wall of S. cerevisiae spores and endows them with resistance to environmental stresses. LL-bisformyl dityrosine is the main constituent of the dityrosine layer but the mechanism of its assembly remains elusive. Here, we found that LL-bisformyl dityrosine, but not LL-dityrosine, stably associated in vitro with dit1Δ spores, which lack the dityrosine layer. No other soluble cytosolic materials were required for this incorporation. In several aspects, the dityrosine incorporated in trans resembled the dityrosine layer. For example, dityrosine incorporation obscured access of the dye calcofluor white to the underlying chitosan layer, and LL-bisformyl dityrosine molecules bound to dit1Δ spores were partly isomerized to the DL- form. Mutational analyses revealed several spore wall components required for this binding. One was the chitosan layer located immediately below the dityrosine layer in the spore wall. However, LL-bisformyl dityrosine did not stably bind to chitosan particles, indicating that chitosan is not sufficient for this association. Several lines of evidence demonstrated that proteins resident to the spore are involved in the incorporation, including the Lds proteins which are localized to lipid droplets attached to the developing spore wall. In conclusion, our results provide insight into the mechanism of dityrosine layer formation, and the in vitro assay described here may be used to investigate additional mechanisms in spore wall assembly.

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microRNA-125b is a key epigenetic regulatory factor that promotes nuclear transfer reprogramming [Cell Biology]

Somatic cell nuclear transfer (SCNT)-mediated reprogramming is a rapid, efficient, and sophisticated process that reprograms differentiated somatic cells to a pluripotent state. However, many factors in this elaborate reprogramming process remain largely unknown. Here, we report that the microRNA (miR) miR-125b is an important component of SCNT-mediated reprogramming. Luciferase reporter assay, quantitative PCR and Western blotting demonstrated that miR-125b directly binds the 3'-untranslated region of SUV39H1, encoding the histone-lysine N-methyltransferase SUV39H1, to downregulate histone H3 lysine-9 tri-methylation (H3K9me3) in SCNT embryos. Furthermore, the miR-125b/SUV39H1 interaction induced loss of SUV39H1-mediated H3K9me3, caused heterochromatin relaxation, and promoted the development of SCNT embryos. Transcriptome analyses of SCNT blastomeres indicated that HNF1 homeobox B (HNF1B), a gene encoding a transcription factor downstream of and controlled by the miR-125b/SUV39H1 axis, is important for conferring developmental competence on preimplantation embryos. We conclude that miR-125b promotes SCNT-mediated nuclear reprogramming by targeting SUV39H1 to decrease the deposition of repressive H3K9me3 modifications.

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Both brown adipose tissue and skeletal muscle thermogenesis processes are activated during mild to severe cold adaptation in mice [Bioenergetics]

Thermogenesis is an important homeostatic mechanism, essential for survival and normal physiological functions in mammals. Both brown adipose tissue (BAT) (i.e. uncoupling protein 1 [UCP1]-based) and skeletal muscle (i.e. sarcolipin [SLN]-based) thermogenesis processes play important roles in temperature homeostasis, but their relative contributions differ from small to large mammals. In this study, we investigated the functional interplay between skeletal muscle and BAT-based thermogenesis under mild versus severe cold adaptation employing UCP1-/- and SLN-/- mice. Interestingly, adaptation of SLN-/- mice to mild cold conditions (16 C) significantly increased UCP1 expression, suggesting an increased reliance on BAT-based thermogenesis. This was also evident from structural alterations in BAT morphology, including mitochondrial architecture, increased expression of electron transport chain proteins, and depletion of fat droplets. Similarly, UCP1-/- mice adapted to mild cold upregulated muscle-based thermogenesis, indicated by increases in muscle succinate dehydrogenase activity, SLN expression, mitochondrial content, and neovascularization as compared with WT mice. These results further confirmed that SLN-based thermogenesis is a key player in muscle non-shivering thermogenesis (NST) and can compensate for loss of BAT activity. We also present evidence that the increased reliance on BAT-based NST depends on increased autonomic input as indicated by abundant levels of tyrosine hydroxylase and neuropeptide Y. Our findings demonstrate that both BAT and muscle-based NST are equally recruited during mild and severe cold adaptation, and loss of heat production from one thermogenic pathway leads to increased recruitment of the other, indicating a functional interplay between these two thermogenic processes.

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Niemeier Lattices in the Free Fermionic Heterotic–String Formulation

The spinor–vector duality was discovered in free fermionic constructions of the heterotic string in four dimensions. It played a key role in the construction of heterotic–string models with an anomaly-free extra symmetry that may remain unbroken down to low energy scales. A generic signature of the low scale string derived model is via diphoton excess that may be within reach of the LHC. A fascinating possibility is that the spinor–vector duality symmetry is rooted in the structure of the heterotic–string compactifications to two dimensions. The two-dimensional heterotic–string theories are in turn related to the so-called moonshine symmetries that underlie the two-dimensional compactifications. In this paper, we embark on exploration of this connection by the free fermionic formulation to classify the symmetries of the two-dimensional heterotic–string theories. We use two complementary approaches in our classification. The first utilises a construction which is akin to the one used in the spinor–vector duality. Underlying this method is the triality property of representations. In the second approach, we use the free fermionic tools to classify the twenty-four-dimensional Niemeier lattices.

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Clinical analysis of 48-h emergency department visit post outpatient extracorporeal shock wave lithotripsy for urolithiasis

Patients suffering from renal or ureteral stones can undergo significant discomfort, even when timely diagnosed and treated. The aim of this study was to assess the risk factors and safety of outpatient Extracorporeal Shock Wave Lithotripsy (ESWL) in the management of patients with renal or ureteral stones.

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Ultrasound versus magnetic resonance imaging of the temporomandibular joint in juvenile idiopathic arthritis: a systematic review

A systematic review of published articles on ultrasound (US) and magnetic resonance imaging (MRI) of the temporomandibular joint (TMJ) in juvenile idiopathic arthritis (JIA) was performed to answer the question "What is the sensitivity and specificity of US as compared to MRI in diagnosing acute and chronic joint changes in patients with JIA?" The most recent evidence was sought in published articles via a search of the PubMed, Ovid, and Embase databases. Article appraisal was performed by two reviewers.

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Clinical application of autogenous partially demineralized dentin matrix prepared immediately after extraction for alveolar bone regeneration in implant dentistry: a pilot study

The aim of this study was to examine the efficacy and safety of autogenous partially demineralized dentin matrix (APDDM) prepared onsite, for clinical application in bone regeneration procedures related to implant dentistry, including socket preservation, alveolar ridge augmentation, and maxillary sinus floor augmentation. In this study, 16 patients underwent dental implant placement using APDDM transplantation. There were no systemic or local complications (including surgical site infection) in any of the cases, and oral rehabilitation using dental implants was successful in all cases for at least 2 years after attachment of the suprastructure.

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Association between elevated central venous pressure and outcomes in critically ill patients

Some prior studies have shown that elevated mean central venous pressure in certain patient populations and disease processes may lead to poor prognosis. However, these studies failed to generalize the concept...

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Highly Efficient Flexible Quantum Dot Solar Cells with Improved Electron Extraction Using MgZnO Nanocrystals

ACS Nano

DOI: 10.1021/acsnano.7b04332

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Hsa_circ_0045714 regulates chondrocyte proliferation, apoptosis and extracellular matrix synthesis by promoting the expression of miR-193b target gene IGF1R

Abstract

In recent years, some studies have been made on the effects of circular RNA (circRNA) in osteoarthritis (OA) and so on; however, its mechanisms remain to be further explored. Studies have shown that tumor necrosis factor-alpha can inhibit hsa_circ_0045714 expression in chondrocytes so as to upregulate miR-193b expression. Dual-luciferase reporter assay showed that insulin-like growth factor 1 receptor (IGF1R) is a key target gene of miR-193b. Hsa_circ_0045714 over-expression does not influence miR-193b expression, but can inhibit its transcriptional activity, thereby upregulating IGF1R expression. Hsa_circ_0045714 can promote the expression of type II collagen and aggrecan, and upregulate chondrocyte proliferation, while its linear sequences cannot. IGF1R has similar function, while miR-193b can inhibit the expression of type II collagen and aggrecan, and downregulate chondrocyte proliferation but enhance their apoptosis. IGF1R overexpression can reverse the effect of miR-193b, while miR-193b mimics or IGF1R siRNA can inhibit the function of hsa_circ_0045714. Therefore, hsa_circ_0045714 can regulate extracellular matrix synthesis as well as proliferation and apoptosis of chondrocytes by promoting the expression of miR-193b target gene IGF1R. The findings will provide new proofs for studies on the applications of circRNA in OA and other orthopedic diseases.

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DMKN contributes to the epithelial-mesenchymal transition through increased activation of STAT3 in pancreatic cancer

Summary

DMKN was first identified in relation to skin lesion healing and skin carcinoma. Recently, its expression has been associated with pancreatic cancer tumorigenesis, although its involvement remains poorly understood. Herein, we show that DMKN loss of function in Patu-8988 and PANC-1 pancreatic cancer cell lines results in reduced phosphorylation of signal transducer and activator of transcription-3 (STAT3), and increased activation of extracellular signal-regulated kinase (ERK1/2) and AKT serine/threonine kinase. This decreases the proliferation ability of pancreatic ductal adenocarcinoma (PDAC) cells. In addition, DMKN knockdown decreased the invasion and migration of PDAC cells, partially reversed the epithelial-mesenchymal transition, retarded tumor growth in a xenograft animal model by decreasing the density of microvessels, and attenuated the distance metastasis of human PDAC in a mouse model. Taken together, these data suggest that DMKN may be a potential prognostic biomarker and therapeutic target in pancreatic cancer.

This article is protected by copyright. All rights reserved.

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CENP-R acts bilaterally as a tumor suppressor and an oncogene in the two-stage skin carcinogenesis model

Abstract

CENP-R is a component of the CENP-O complex, including CENP-O, CENP-P, CENP-Q, CENP-R, and CENP-U and is constitutively localized to kinetochores throughout the cell cycle in vertebrates. CENP-R deficient chicken DT40 cells are viable and show very minor effect on mitosis. To investigate the functional roles of CENP-R in vivo, we generated CENP-R deficient mice (Cenp-r^-/-). Mice heterozygous or homozygous for Cenp-r null mutation are viable and healthy, with no apparent defect in growth and morphology, indicating Cenp-r is not essential for normal development. Accordingly, to investigate the role of the Cenp-r gene in skin carcinogenesis, we subjected Cenp-r^-/- mice to the DMBA/TPA chemical carcinogenesis protocol and monitored their tumor development. As a result, Cenp-r^-/- mice initially developed significantly more papillomas than control wild type mice. However, papillomas in Cenp-r^-/- mice showed a decrease of proliferative cells and an increase of apoptotic cells. As a result, they did not grow bigger and some papillomas showed substantial regression. Furthermore, papillomas in Cenp-r^-/- mice showed lower frequency of malignant conversion to squamous cell carcinomas. These results indicate Cenp-r functions bilaterally in cancer development: during early developmental stages, Cenp-r behaves as a tumor suppressor, but during the expansion and progression of papillomas it behaves as a tumor-promoting factor.

This article is protected by copyright. All rights reserved.

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Comparison of three different assays for measuring thyroglobulin and thyroglobulin antibodies in patients with chronic lymphocytic thyroiditis

Publication date: Available online 9 August 2017
Source:Clinical Biochemistry
Author(s): Xinqi Cheng, Songlin Yu, Cheng Jin, Song Han, Yingying Hu, Kui Zhang, Huaicheng Liu, Ling Qiu
ObjectiveTo evaluate how thyroglobulin (Tg) and thyroglobulin antibody (TgAb) results compare among different chemiluminescence methods.MethodsSerum specimens from 153 patients with thyroiditis and 127 apparently healthy individuals were collected at the Peking Union Medical College Hospital from September 2014 to December 2014. TgAb and Tg levels were analyzed by using three different platforms manufactured by Roche, Beckman, and Siemens. The χ² test was performed to analyze the TgAb results from the different methods. Passing-Bablok regression equations and Bland-Altman plots were used to estimate the relationship and bias among the Tg results obtained with the different analyses.ResultsThe overall coincidence rates for the TgAb results were 82.9% between the Beckman and Roche methods, 78.6% between the Siemens and Roche methods, and 81.1% between the Siemens and Beckman methods. The borderline positive coincidence rate among the different TgAb methods was very poor (9.1–24.2%). Of the 280 samples, the TgAb results for 26.4% of the samples differed among the three CLIA platforms. A good linear relationship among the Tg levels was shown in TgAb-negative subjects analyzed with the different CLIA systems. However, for TgAb-positive subjects, the linear relationship of the Tg levels measured with the Siemens system, compared with the other two systems, was poor. Bland-Altman plots demonstrated significant differences among the different Tg assays.ConclusionsCurrent Tg and TgAb methods are highly variable and cannot be used interchangeably.



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Overweight and Body Image Perception in Adolescents with Triage of Eating Disorders

Purpose. To verify the influence of overweight and alteration in the perception of the corporal image during the triage of eating disorders. Method. A food disorder triage was performed in adolescents with 10 to 19 years of age using the Eating Attitudes Test (EAT-26), Children's Eating Attitudes Test (ChEAT), and Bulimic Investigatory Test Edinburgh (BITE), as well as a nutritional status evaluation. The perception of body image was evaluated in a subsample of adolescents with 10 to 14 years of age, using the Brazilian Silhouette Scale. The project was approved by the Human Research Ethics Committee of the Federal University of Viçosa, Minas Gerais, Brazil. Results. The prevalence of eating disorder triage was 11.4% () for the 2,123 adolescents evaluated. Overweight was present in 21.1% () of the students, being more prevalent in the early adolescence phase, which presented levels of distortion of 56.9% () and dissatisfaction of 79.3% (). Body dissatisfaction was considered as a risk factor, increasing by more than 13 times the chance of TA screening. Conclusion. Overweight was correlated with the ED triage and body dissatisfaction was considered as a risk factor, increasing the chances of these disorders by more than 13 times.

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A Review of Neurogenic Stunned Myocardium

Neurologic stunned myocardium (NSM) is a phenomenon where neurologic events give rise to cardiac abnormalities. Neurologic events like stroke and seizures cause sympathetic storm and autonomic dysregulation that result in myocardial injury. The clinical presentation can involve troponin elevation, left ventricular dysfunction, and ECG changes. These findings are similar to Takotsubo cardiomyopathy and acute coronary syndrome. It is difficult to distinguish NSM from acute coronary syndrome based on clinical presentation alone. Because of this difficulty, a patient with NSM who is at high risk for coronary heart disease may undergo cardiac catheterization to rule out coronary artery disease. The objective of this review of literature is to enhance physician's awareness of NSM and its features to help tailor management according to the patient's clinical profile.

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Expression, Docking, and Molecular Dynamics of Endo-β-1,4-xylanase I Gene of Trichoderma virens in Pichia stipitis

It is essential that major carbohydrate polymers in the lignocellulosic biomass are converted into fermentable sugars for the economical production of energy. Xylan, the major component of hemicelluloses, is the second most naturally abundant carbohydrate polymer comprising 20–40% of the total biomass. Endoxylanase (EXN) hydrolyzes xylan into mixtures of xylooligosaccharides. The objective of this study was to genetically modify Pichia stipitis, a pentose sugar fermenting yeast species, to hydrolyze xylan into xylooligosaccharides via cloning and heterologous extracellular expression of EXNI gene from locally isolated Trichoderma virens species. Pichia stipitis was engineered to carry the EXNI gene of T. virens using pGAPZα expression vector. The open reading frame encodes 191 amino acids and SDS-PAGE analysis revealed a 24 kDA recombinant protein. The EXNI activity expressed by recombinant P. stipitis clone under standard conditions using 1% beechwood xylan was 31.7 U/ml. Molecular docking and molecular dynamics simulations were performed to investigate EXNI-xylan interactions. Free EXNI and xylan bound EXNI exhibited similar stabilities and structural behavior in aqueous medium. Furthermore, this in silico work opens avenues for the development of newer generation EXN proteins that can perform better and have enhanced catalytic activity.

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Noncommutative Spacetime Symmetries from Covariant Quantum Mechanics

In the last decades, noncommutative spacetimes and their deformed relativistic symmetries have usually been studied in the context of field theory, replacing the ordinary Minkowski background with an algebra of noncommutative coordinates. However, spacetime noncommutativity can also be introduced into single-particle covariant quantum mechanics, replacing the commuting operators representing the particle's spacetime coordinates with noncommuting ones. In this paper, we provide a full characterization of a wide class of physically sensible single-particle noncommutative spacetime models and the associated deformed relativistic symmetries. In particular, we prove that they can all be obtained from the standard Minkowski model and the usual Poincaré transformations via a suitable change of variables. Contrary to previous studies, we find that spacetime noncommutativity does not affect the dispersion relation of a relativistic quantum particle, but only the transformation properties of its spacetime coordinates under translations and Lorentz transformations.

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Numerical Simulation of Barite Sag in Pipe and Annular Flow

With the ever increasing global energy demand and diminishing petroleum reserves, current advances in drilling technology have resulted in numerous directional wells being drilled as operators strive to offset the ever-rising operating costs. In as much as deviated-well drilling allows drillers to exploit reservoir potential by penetrating the pay zone in a horizontal, rather than vertical, fashion, it also presents conditions under which the weighting agents can settle out of suspension. The present work is categorized into two parts. In the first part, governing equations were built inside a two-dimensional horizontal pipe geometry and the finite element method utilized to solve the equation-sets. In the second part, governing equations were built inside a three-dimensional horizontal annular geometry and the finite volume method utilized to solve the equation-sets. The results of the first part of the simulation are the solid concentration, mixture viscosity, and a prediction of the barite bed characteristics. For the second part, simulation results show that the highest occurrence of barite sag is at low annular velocities, nonrotating drill pipe, and eccentric drill pipe. The CFD approach in this study can be utilized as a research study tool in understanding and managing the barite sag problem.

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Niemeier Lattices in the Free Fermionic Heterotic–String Formulation

The spinor–vector duality was discovered in free fermionic constructions of the heterotic string in four dimensions. It played a key role in the construction of heterotic–string models with an anomaly-free extra symmetry that may remain unbroken down to low energy scales. A generic signature of the low scale string derived model is via diphoton excess that may be within reach of the LHC. A fascinating possibility is that the spinor–vector duality symmetry is rooted in the structure of the heterotic–string compactifications to two dimensions. The two-dimensional heterotic–string theories are in turn related to the so-called moonshine symmetries that underlie the two-dimensional compactifications. In this paper, we embark on exploration of this connection by the free fermionic formulation to classify the symmetries of the two-dimensional heterotic–string theories. We use two complementary approaches in our classification. The first utilises a construction which is akin to the one used in the spinor–vector duality. Underlying this method is the triality property of representations. In the second approach, we use the free fermionic tools to classify the twenty-four-dimensional Niemeier lattices.

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CFD Analysis of a Decay Tank and a Siphon Breaker for an Innovative Integrated Passive Safety System for a Research Reactor

An innovative integrated passive safety system for a research reactor is proposed in this study to improve the safety of the research reactor. This integrated system has three functions in the facility as a decay tank, siphon breaker, and long-term cooling tank. This paper also deals with the process of designing and optimizing the decay tank and the siphon breaker of the integrated passive safety system. At first, the decay tank was designed and improved step by step, while considering the computational fluid dynamics analysis results. Consequently, we could satisfy the design requirements of the decay tank. In addition, the performance of a new type of siphon breaker that was installed in the final decay tank model was tested. We designed an 18-inch diameter siphon breaker at the top of the decay tank's third section, and we could observe the breaking of the siphon that prevented the occurrence of a severe accident in the research reactor. By locating the siphon breaker at the third section of the decay tank, we could also use the coolant of the front three sections for long-term cooling of the research reactor.

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Impact of Cyclic Loading on Chloride Diffusivity and Mechanical Performance of RC Beams under Seawater Corrosion

An experimental study was conducted to investigate the impact of cyclic loading on the mechanical performance and chloride diffusivity of RC beams exposed to seawater wet-dry cycles. To induce initial damage to RC beam specimen, cyclic loading controlled by max load and cycles was applied. Then beam specimens underwent 240 wet-dry cycles of seawater. Results show that the chloride content increased as max load and cycle increased. The chloride content at steel surface increased approximatively linearly as average crack width increased. Moreover, the max load had more influence on chloride content at steel surface than cycle. The difference of average chloride diffusion coefficient between tension and compression concrete was little at uncracked position. Average chloride diffusion coefficient increased as crack width increased when crack width was less than 0.11 mm whereas the increasing tendency was weak when crack width exceeded 0.11 mm. The residual yield load and ultimate load of RC beams decreased as max load and cycle increased. Based on univariate analysis of variance, the max load had more adverse effect on yield load and ultimate load than cycle.

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DriverFinder: A Gene Length-Based Network Method to Identify Cancer Driver Genes

Integration of multi-omics data of cancer can help people to explore cancers comprehensively. However, with a large volume of different omics and functional data being generated, there is a major challenge to distinguish functional driver genes from a sea of inconsequential passenger genes that accrue stochastically but do not contribute to cancer development. In this paper, we present a gene length-based network method, named DriverFinder, to identify driver genes by integrating somatic mutations, copy number variations, gene-gene interaction network, tumor expression, and normal expression data. To illustrate the performance of DriverFinder, it is applied to four cancer types from The Cancer Genome Atlas including breast cancer, head and neck squamous cell carcinoma, thyroid carcinoma, and kidney renal clear cell carcinoma. Compared with some conventional methods, the results demonstrate that the proposed method is effective. Moreover, it can decrease the influence of gene length in identifying driver genes and identify some rare mutated driver genes.

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Efficacy of Prompt Initiation of Antiretroviral Therapy in the Treatment of Hemophagocytic Lymphohistiocytosis Triggered by Uncontrolled Human Immunodeficiency Virus

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, rapidly progressive hematologic disorder involving uncontrolled immune system activation. HLH has been associated with viral infections, including human immunodeficiency virus (HIV) infections. We report a case of a critically ill 30-year-old female who was hospitalized with HIV-associated HLH, with a CD4 count of 4 cells/mL and HIV viral load of 1,842,730 copies/mL. After ruling out other potential infectious causes of HLH, antiretroviral therapy (ART) was initiated with darunavir, ritonavir, tenofovir, and emtricitabine. Within one week of initiation of ART, the patient began to improve clinically and hematologically and was stable enough for discharge from the hospital three weeks after starting therapy. This case suggests that treatment with ART in patients with HIV-associated HLH should be considered even in critically ill patients with low CD4 counts.

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Alternative Mathematical Models and Solution Approaches for Lot-Sizing and Scheduling Problems in the Brewery Industry: Analyzing Two Different Situations

This research proposes new approaches to deal with the production planning and scheduling problem in brewery facilities. Two real situations found in factories are addressed, which differ by considering (or not) the setup operations in tanks that provide liquid for bottling lines. Depending on the technology involved in the production process, the number of tank swaps is relevant (Case A) or it can be neglected (Case B). For both scenarios, new MIP (Mixed Integer Programming) formulations and heuristic solution methods based on these formulations are proposed. In order to evaluate the approach for Case A, we compare the results of a previous study with the results obtained in this paper. For the solution methods and the result analysis of Case B, we propose adaptations of Case A approaches yielding an alternative MIP formulation to represent it. Therefore, the main contributions of this article are twofold: (i) to propose alternative MIP models and solution methods for the problem in Case A, providing better results than previously reported, and (ii) to propose new MIP models and solution methods for Case B, analyzing and comparing the results and benefits for Case B considering the technology investment required.

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