"At Coquitlam General & Sedation Dentistr y our top priority is patient care and comfort," says Shainaz, one of the clinic's two administrative assistants. "Our entire team works hard to make sure all patients are comfortable with both, their planned treatment and the actual process."
Microbiological induced calcium carbonate or calcite precipitation (MICP) has become a highly researched issue due to its multiple applications in the construction industry, being a promising alternative with a great biotechnological importance. In this work, potential calcite precipitation inducing bacteria were isolated from mortar and concrete samples of different buildings at the National University of Colombia. Eighteen crystal-precipitating strains were recovered in Urea-CaCl2 solid medium. The 16S rRNA gene sequencing identified isolates as Arthrobacter, Psychrobacillus and Rhodococcus genera. It is reported, for the first time, the calcite precipitation by P. psycrodurans and R. qingshengii. Optical microscopy and Scanning Electron Microscopy showed crystals with irregular and spherical shapes, and beige and white colours. Furthermore, crystals formation appeared to be strain-specific. X-Ray diffraction analysis confirmed crystals composition as CaCO3. Biocementation tests showed that MICP treatments of mortar cubes using P. psycrodurans caused an increase in their compressive strength compared to control samples. The positive action of a native MICP strain in mortar blocks biomineralization is shown, which is of great interest and potential for the construction industry.
Advanced pancreatic ductal adenocarcinoma (PDAC) has typically been resistant to chemotherapy and immunotherapy; therefore, novel strategies are needed to enhance therapeutic response. Cholecystokinin (CCK) has been shown to stimulate growth of pancreatic cancer. CCK receptors (CCKRs) are present on pancreatic cancer cells, fibroblasts, and lymphocytes. We hypothesized that CCKR blockade would improve response to immune checkpoint antibodies by promoting influx of tumor-infiltrating lymphocytes (TILs) and reducing fibrosis. We examined the effects of CCKR antagonists or immune checkpoint blockade antibodies alone or in combination in murine models of PDAC. Monotherapy with CCKR blockade significantly decreased tumor size and metastases in SCID mice with orthotopic PDAC, and in C57BL/6 mice, it reduced fibrosis and induced the influx of TILs. Immune-competent mice bearing syngeneic pancreatic cancer (Panc02 and mT3-2D) that were treated with the combination of CCK receptor antagonists and immune checkpoint blockade antibodies survived significantly longer with smaller tumors. Tumor immunohistochemical staining and flow cytometry demonstrated that the tumors of mice treated with the combination regimen had a significant reduction in Foxp3+ T-regulatory cells and an increase in CD4+ and CD8+ lymphocytes. Masson's trichrome stain analysis revealed 50% less fibrosis in the tumors of mice treated with CCKR antagonist compared to controls and compared to checkpoint antibody therapy. CCKR antagonists given with immune checkpoint antibody therapy represent a novel approach for improving survival of PDAC. The mechanism by which this combination therapy improves the survival of PDAC may be related to the decreased fibrosis and immune cells of the tumor microenvironment.
OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] ... T.R.; RT "Transcriptional variants of serum/glucocorticoid regulated kinase 1 RT .... Nedd4-2 and the serum and glucocorticoid inducible kinase RT SGK1.
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DE RecName: Full=Serine/threonine-protein kinase Sgk1; DE EC=2.7.11.1; DE AltName: Full=Serum/glucocorticoid-regulated kinase 1; GN ...
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A machine learning tool can help identify which high-risk breast lesions are likely to become cancerous, according to a new study appearing online in the journal Radiology. Researchers said the technology has the potential to reduce unnecessary...
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Low-load resistance training (< 50% of one-repetition maximum [1RM]) associated with blood-flow restriction (BFR-RT) has been thought to promote increases in muscle strength and mass. However, it remains unclear if the magnitude of these adaptations is similar to conventional high-load resistance training (> 65% 1RM; HL-RT).
To compare the effects of HL- versus BFR-RT on muscle adaptations using a systematic review and meta-analysis procedure.
Studies were identified via electronic databases based on the following inclusion criteria: (a) pre- and post-training assessment of muscular strength; (b) pre- and post-training assessment of muscle hypertrophy; (c) comparison of HL-RT vs. BFR-RT; (d) score ≥ 4 on PEDro scale; (e) means and standard deviations (or standard errors) are reported from absolute values or allow estimation from graphs. If this last criterion was not met, data were directly requested from the authors.
The main results showed higher increases in muscle strength for HL- as compared with BFR-RT, even when considering test specificity, absolute occlusion pressure, cuff width, and occlusion pressure prescription. Regarding the hypertrophic response, results revealed similar effects between HL- and BFR-RT, regardless of the absolute occlusion pressure, cuff width, and occlusion pressure prescription.
Based on the present data, maximum muscle strength may be optimized by specific training methods (i.e., HL-RT) while both HL- and BFR-RT seem equally effective in increasing muscle mass. Importantly, BFR-RT is a valid and effective approach for increasing muscle strength in a wide spectrum of ages and physical capacity, although it may seem particularly of interest for those individuals with physical limitations to engage in HL-RT.
Publication date: Available online 14 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Francisco Larrosa, Isam Alobid
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Publication date: Available online 14 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Pablo Torrico Román
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Publication date: Available online 16 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Stefano Rubino, Rita De Berardinis, Daniele Colombo, Alessandro De Padova
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Publication date: Available online 13 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Faustino Núñez-Batalla, Carmen Jáudenes-Casaubón, Jose Miguel Sequí-Canet, Ana Vivanco-Allende, Jose Zubicaray-Ugarteche
La incidencia y prevalencia de la otitis media secretora infantil (OMS) son elevadas, sin embargo, existen evidencias de que solo una minoría de profesionales sigue las recomendaciones de las guías para su manejo clínico. Con objeto de mejorar el diagnóstico y el tratamiento de la OMS, para prevenir y/o reducir sus consecuencias sobre el desarrollo del niño, la Comisión para la Detección Precoz de la Hipoacusia (CODEPEH) ha realizado una amplia revisión de la literatura científica sobre la materia y ha elaborado un documento de recomendaciones para una correcta actitud clínica ante la OMS, abordando métodos diagnósticos y tratamiento médico y quirúrgico. Entre otros, no usar ninguna medicación, especialmente corticoides y antibióticos, siendo la espera vigilada la primera medida a tomar durante 3 meses. Si persiste la OMS, el otorrinolaringólogo valorará el tratamiento quirúrgico. En niños que presentan comorbilidades de diversa entidad, el impacto de la OMS es superior por lo que hay que actuar de forma inmediata, sin espera vigilada.The incidence and the prevalence rates of otitis media with effusion (OME) are high. However, there is evidence that only a minority of professionals follow the recommendations provided in clinical practice guidelines. For the purpose of improving diagnosis and treatment of OME in children to prevent and/or reduce its impact on children's development, the Commission for the Early Detection of Deafness (CODEPEH) has deeply reviewed the scientific literature on this field and has drafted a document of recommendations for a correct clinical reaction to of OME, including diagnosis and medical and surgical treatment methodology. Among others, medication, in particular antibiotics and corticoids, should not be prescribed and 3 months of watchful waiting should be the first adopted measure. If OME persists, an ENT doctor should assess the possibility of sugical treatment. The impact of OME in cases of children with a comorbidity is higher, so it requires immediate reaction, without watchful waiting.
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Publication date: Available online 14 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Francisco Larrosa, Isam Alobid
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Publication date: Available online 14 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Pablo Torrico Román
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Publication date: Available online 16 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Stefano Rubino, Rita De Berardinis, Daniele Colombo, Alessandro De Padova
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Publication date: Available online 13 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Faustino Núñez-Batalla, Carmen Jáudenes-Casaubón, Jose Miguel Sequí-Canet, Ana Vivanco-Allende, Jose Zubicaray-Ugarteche
La incidencia y prevalencia de la otitis media secretora infantil (OMS) son elevadas, sin embargo, existen evidencias de que solo una minoría de profesionales sigue las recomendaciones de las guías para su manejo clínico. Con objeto de mejorar el diagnóstico y el tratamiento de la OMS, para prevenir y/o reducir sus consecuencias sobre el desarrollo del niño, la Comisión para la Detección Precoz de la Hipoacusia (CODEPEH) ha realizado una amplia revisión de la literatura científica sobre la materia y ha elaborado un documento de recomendaciones para una correcta actitud clínica ante la OMS, abordando métodos diagnósticos y tratamiento médico y quirúrgico. Entre otros, no usar ninguna medicación, especialmente corticoides y antibióticos, siendo la espera vigilada la primera medida a tomar durante 3 meses. Si persiste la OMS, el otorrinolaringólogo valorará el tratamiento quirúrgico. En niños que presentan comorbilidades de diversa entidad, el impacto de la OMS es superior por lo que hay que actuar de forma inmediata, sin espera vigilada.The incidence and the prevalence rates of otitis media with effusion (OME) are high. However, there is evidence that only a minority of professionals follow the recommendations provided in clinical practice guidelines. For the purpose of improving diagnosis and treatment of OME in children to prevent and/or reduce its impact on children's development, the Commission for the Early Detection of Deafness (CODEPEH) has deeply reviewed the scientific literature on this field and has drafted a document of recommendations for a correct clinical reaction to of OME, including diagnosis and medical and surgical treatment methodology. Among others, medication, in particular antibiotics and corticoids, should not be prescribed and 3 months of watchful waiting should be the first adopted measure. If OME persists, an ENT doctor should assess the possibility of sugical treatment. The impact of OME in cases of children with a comorbidity is higher, so it requires immediate reaction, without watchful waiting.
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Childhood acute lymphoblastic leukemia (C-ALL): A type of cancer of the bone marrow that produces immature lymphocytes (a type of blood cell) in the bloodstream. This is the most common type of cancer in children and progresses quickly if not treated. Symptoms can include easy bruising, fever, weakness, bone or joint pain, loss of appetite, and painless enlargement of the lymph nodes. Past treatment for cancer and certain genetic conditions (including Fanconi anemia, Down syndrome, and ataxia-telangiectasia) affect the risk of having childhood ALL.
The exact cause of C-ALL is poorly understood. Also known as childhood acute lymphocytic leukemia.
Early metastatic dissemination and evolution of disseminated cancer cells (DCCs) outside the primary tumor is one reason for the failure of adjuvant therapies because it generates molecular geno- and phenotypes different from primary tumors which still underlie therapy decisions. Since ERBB2 amplification in esophageal DCCs but not in primary tumor cells predict outcome, we aimed to establish an assay with diagnostic reliability for single DCCs or circulating tumor cells (CTCs). For this we evaluated copy number alterations of more than 600 single DCCs from multiple cancer types to define reference regions suitable for quantification of target regions, such as ERBB2. We then compared ERBB2 quantitative PCR (qPCR) measurements with fluorescent in situ hybridization (FISH) data of various breast cancer cell lines and identified the aberration-calling threshold. The method was applied to two independent cohorts of esophageal cancer patients from Hamburg (n = 59) and Düsseldorf (n = 53). We found a high correlation between the single cell qPCR assay and the standard FISH assay (R = 0.98) and significant associations between amplification and survival for both patient cohorts (Hamburg (HH), p = 0.033; Düsseldorf (D), p = 0.052; pooled HH+D, p = 0.002) when applied to DCCs of esophageal cancer patients. Detection of a single ERBB2-amplified DCC was the most important risk factor for death from esophageal cancer (relative risk = 4.16; 95% CI = 1.887- 9.184; p < 0.001). In our study, we detected ERBB2-amplified cells in 7% of patients. These patients could benefit from anti-ERBB2 targeting therapies. This article is protected by copyright. All rights reserved.
Socioeconomic status (SES) has an impact on prostate cancer (PCa) outcomes. Men with high SES have higher incidence and lower mortality of PCa versus lower SES males. PCa cases diagnosed in Finland in 1985-2014 (N=95076) were identified from the Finnish Cancer Registry. Information on education level (EL) was obtained from Statistics Finland. EL was assessed with three-tiered scale: basic, upper secondary and higher education. PCa stage at diagnosis was defined as localized, metastatic or unknown. Years of diagnosis 1985-1994 were defined as pre-PSA period and thereafter as post-PSA period. We report PCa-specific survival (PCSS) and relative risks (RR) for PCa specific mortality (PCSM) among cancer cases in Finland, where healthcare is 100% publicly reimbursed and inequality in healthcare services low. Men with higher EL had markedly better 10-year PCSS: 68% vs 63% in 1985-1994 and 90% vs 85% in 1995-2004 compared to basic EL in localized PCa. The RR for PCSM among men with localized PCa and higher EL compared to basic EL was 0.76(95%confidence interval (CI) 0.66-0.88) in 1985-1994 and 0.61(95%CI 0.53-0.70) in 1995-2004. Variation in PCSS and PCSM between EL categories was evident in metastatic PCa, too. The difference in PCSM between EL categories was larger in the first 10-year post-PSA period than before that but decreased thereafter in localized PCa, suggesting PSA testing became earlier popular among men with high EL. In summary, higher SES/EL benefit PCa survival both in local and disseminated disease and the effect of EL was more pronounced in early post-PSA period. This article is protected by copyright. All rights reserved.
Colorectal cancer results from the malignant transformation of colonic epithelial cells. Stromal fibroblasts are the main component of the tumour microenvironment, and play an important role in the progression of this and other neoplasias. Wnt/β-catenin signalling is essential for colon homeostasis, but aberrant, constitutive activation of this pathway is a hallmark of colorectal cancer. Here we present the first transcriptomic study on the effect of a Wnt factor on human colonic myofibroblasts. Wnt3A regulates the expression of 1136 genes, of which 662 are upregulated and 474 are downregulated in CCD-18Co cells. A set of genes encoding inhibitors of the Wnt/β-catenin pathway stand out among those induced by Wnt3A, which suggests that there is a feedback inhibitory mechanism. We also show that the PKP2 gene encoding the desmosomal protein Plakophilin-2 is a novel direct transcriptional target of Wnt/β-catenin in normal and colon cancer-associated fibroblasts. PKP2 is induced by β-catenin/TCF through three binding sites in the gene promoter and one additional binding site located in an enhancer 20 kb upstream from the transcription start site. Moreover, Plakophilin-2 antagonizes Wnt/β-catenin transcriptional activity in HEK-293T cells, which suggests that it may act as an intracellular inhibitor of the Wnt/β-catenin pathway. Our results demonstrate that stromal fibroblasts respond to canonical Wnt signalling and that Plakophilin-2 plays a role in the feedback control of this effect suggesting that the response to Wnt factors in the stroma may modulate Wnt activity in the tumour cells. This article is protected by copyright. All rights reserved.
Only a fraction of breast cancer (BC) cases can be yet explained by mutations in genes or genomic variants discovered in linkage, genome-wide association and sequencing studies. The known genes entailing medium or high risk for BC are strongly enriched for a function in DNA double strand repair. Thus, aiming at identifying low frequency variants conferring an intermediate risk, we here investigated 17 variants (MAF: 0.01-0.1) in 10 candidate genes involved in DNA repair or cell cycle control. In an exploration cohort of 437 cases and 1189 controls we show the variant rs3810813 in the SLX4/FANCP gene to be significantly associated with both BC (≤60 years; OR=2.6(1.6-3.9), p=1.6E-05) and decreased DNA repair capacity (≤60 years; beta=37.8(17.9-57.8) p=5.3E-4). BC association was confirmed in a verification cohort (N=2441). Both associations were absent from cases diagnosed >60 years and stronger the earlier the diagnosis. By imputation we show that rs3810813 tags a haplotype with 5 additional variants with the same allele frequency (R2 > 0.9), and a pattern of association very similar for both phenotypes (cases <60 years p<0.001, the Bonferroni threshold derived from unlinked variants in the region). In young cases (≤60 years) carrying the risk haplotype, micronucleus test results are predictive for BC (AUC >0.9). Our findings propose a risk variant with high penetrance on the haplotype spanning SLX4/FANCP to be functionally associated to BC predisposition via decreased repair capacity and suggest this variant is carried by a fraction of these haplotypes that is enriched in early onset BC cases. This article is protected by copyright. All rights reserved.
Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types.
CCDC6 gene product has a proper role in sustaining the DNA damage checkpoints in response to DNA damage. The inactivation of CCDC6 secondary to chromosomal rearrangements or gene mutations could enhance tumor progression by impairing the apoptotic response upon the DNA damage exposure, contributing to the generation of radio- and chemo-resistance. Preclinical studies indicate that the attenuation of CCDC6 in cancer, while conferring a resistance to cisplatinum, sensitizes the cancer cells to the small molecule inhibitors of Poly (ADP-ribose) polymerase (PARP1/2) with a synthetic lethal effect.
Several CCDC6 mutations and gene rearrangements have been described so far in different types of cancer and CCDC6 may represent a possible predictive biomarker of tumor resistance to the conventional anticancer treatments. Nevertheless, the detection of a CCDC6 impairment in cancer patients may help to select, in future clinical trials, those patients who could benefit of PARP-inhibitors treatment alone or in combination with other treatments. This article is protected by copyright. All rights reserved.
Skeletal and connective tissue defects are the most striking symptoms in patients suffering from classical homocystinuria (HCU). Here, we determined body composition and bone mass in three mouse models of HCU and assessed whether a long-term administration of enzyme replacement therapy (ERT) corrected the phenotype. The mouse models of HCU were analyzed using dual-energy X-ray absorptiometry and the data were complemented by plasma biochemical profiles. Both the mouse model lacking CBS (KO) and the one expressing human CBS mutant transgene on a mouse CBS null background (I278T) showed marked bone loss and decreased weight mostly due to a lower fat content compared to negative controls. In contrast, the HO mouse expressing the human CBS WT transgene on a mouse CBS null background showed no such phenotype despite similar plasma biochemical profile to the KO and I278T mice. More importantly, administration of ERT rescued bone mass and changes in body composition in the KO mice treated since birth and reversed bone loss and improved fat content in the I278T mice injected after the development of clinical symptoms. Our study suggests that ERT for HCU may represent an effective way of preventing the skeletal problems in patients without a restricted dietary regime.
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Primary coenzyme Q10 (CoQ10; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ10, and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ10 synthetic pathway, have not been implicated in human disease.
Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures and cognitive disability. Whole exome and subsequent whole genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement and increased the concentrations of CoQ10 in blood.
This is the first report of primary CoQ10 deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological and molecular features, and insights regarding targeted treatment with CoQ10 supplementation.
This article is protected by copyright. All rights reserved
Teaching programming concepts to enhance students' problem solving and computational thinking skills is a challenging task, especially when students enter college with little to no preparation, or they lack the interest or capacity for programming. Online platforms that serve as automated practice and assessment systems have been offered as potential tools for supporting programming skills development, providing feedback, and motivating students. The present article discusses the use of an online automated practice and assessment system called Kattis for homework assignments and final project in three computer science courses. The goal of the present study was to ascertain students' continuance intentions to use Kattis. We attempt to address this by using partial least squares on data from a survey of 50 students. The findings of the present study suggest that continuance intentions to use Kattis is driven by students' level of satisfaction with the system, the degree of students' confirmation of expectations, and the perceived usefulness of the system.
Thyroid , Vol. 0, No. 0.
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Meaghan Mary Durgin and Andrew Currin Katz were married Oct. 14 at Willowdale Estate in Topsfield, Mass. The Rev.
Asthma is the most common childhood illness and disproportionately affects low-income, minority children who live in urban areas. A range of risk factors are associated with asthma morbidity and mortality, suc...
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Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 389-391.
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Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 368-370.
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Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 395-397.
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Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 375-377.
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Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 385-388.
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Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 378-381.
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Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 392-394.
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Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 382-384.
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Clinical Thyroidology Oct 2017, Vol. 29, No. 10: 398-400.
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The Akt pathway is a well-known promoter of tumor malignancy. Akt3 is expressed as two alternatively spliced variants, one of which lacks the key regulatory serine 472 phosphorylation site. Whereas the function of full-length Akt3 isoform (Akt3/+S472) is well-characterized, that of Akt3/-S472 isoform remains unknown. Despite being expressed at a substantially lower level than Akt3/+S472 in triple negative breast cancer cells, specific ablation of Akt3/-S472, enhanced, whereas overexpression, suppressed mammary tumor growth-consistent with a significant association with patient survival duration relative to Akt3/+S472. These effects were due to induction of apoptosis, which was mediated by Bim upregulation, leading to conformational activation of Bax and caspase-3 processing. Bim accumulation was caused by endocytosis of EGF receptors with concomitant ERK attenuation, which stabilizes BIM. These findings demonstrate an unexpected function of an endogenously expressed Akt isoform in promoting - as opposed to suppressing - apoptosis, underscoring that Akt isoforms may exert dissonant functions in malignancy.
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The serine/threonine kinase STK33 has been implicated in cancer cell proliferation. Here we provide evidence of a critical role for STK33 in the pathogenesis and metastatic progression of pancreatic ductal adenocarcinoma (PDAC). STK33 expression in PDAC was regulated by the hypoxia-inducible transcription factor HIF-1α. In human PDAC specimens, STK33 was overexpressed and associated with poor prognosis. Enforced STK33 expression promoted PDAC proliferation, migration, invasion and tumor growth, whereas STK33 depletion exerted opposing effects. Mechanistic investigations showed that HIF-1α regulated STK33 via direct binding to a hypoxia response element in its promoter. In showing that dysregulated HIF-1α/STK33 signaling promotes PDAC growth and progression, our results suggest STK33 as a candidate therapeutic target to improve PDAC treatment.
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Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterised by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells to those in >130 non-SS tumour cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18-SSX family fusion genes are known to alter the composition of the BAF chromatin-remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18-SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but a SSX18-SSX1 Δ71-78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon Cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the anti-tumor cell effect of ATRi, suggesting that either single agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment.
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Clock genes encoding transcription factors that regulate circadian rhythms may inform chrono-modulated chemotherapy, where time-dependent dose alterations might affect drug efficacy and reduce side effects. For example, inhibiting the essential cystine transporter xCT with sulfasalazine induces growth arrest in cancer cells. Although the anticancer effects of sulfasalazine have been studied extensively, its effects on transcriptional control of xCT expression have not been studied. Here we show that sulfasalazine administration during the period of increased xCT expression improves its anticancer effects, and that the Clock gene itself induces xCT expression and regulates its circadian rhythm. Our findings highlight the clinical potential of chrono-modulated chemotherapy and the importance of xCT-mediated transcriptional regulation in the utility of such strategies.
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Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or post-translational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacological evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell cycle progression, proliferation and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analog B13 as a small molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localizaiton to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its antiinvasive and antitumor effects against prostate cancer cells with minimal toxic side-effects in vivo. Structural optimization based on structure-activity relationships enabled the chemical synthesis of LCL204 with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclincal proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression.
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Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8, and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion, and vascular invasion (P<0.05), and with early-stage adenocarcinoma and high budding grade (P<0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells, and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (P<0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front. This article is protected by copyright. All rights reserved.
Diazotrophy is considered as one of the most crucial and dynamic phenomena in the rice field and also a major source of nitrogen input. The objective of this study was to elucidate possible interactions between diverse and dominant diazotrophic bacterial community and organic carbon composition of the paddy soil. Our results suggest that most abundantly found diazotrophs belong to a proteobacteria group and uncultured bacterial forms. A gene abundance study clearly showed significantly higher diazotrophic abundance (P < 0.01) at Chandauli (CHN) as compared to Varanasi (VNS) and Ghazipur (GHJ) districts of Eastern Uttar Pradesh, India, with nitrogenase reductase (nifH) copy number between 1.44 × 103 and 3.34 × 103 copy g−1 soil. Fourier-transform infrared (FT-IR) spectroscopy data identified –CO–, C=O ( \( {\mathrm{NH}}_{2^{-}} \) and –NH–), \( {\mathrm{CH}}_{2^{-}} \) , and OH– as dominant organic functional groups in the paddy soil. Multivariate analysis was performed to get a clear and more accurate picture of interactions between free-living diazotrophs and abiotic soil factors. Regression analysis suggested a similar trend of distribution of different functional groups along each site. Relative abundance and diversity of diazotrophic population increased in response to FT-IR-based soil organic fractions. Maximum number of FT-IR spectral peak at sites in the Chandauli district augmented its bacterial diazotrophic diversity and abundance. Taken together, the present study sheds light on the substrate-driven composition of the microbial population of selected paddy areas.
The aim of this study was to evaluate and compare the antioxidant potential of essential oils of some commonly used Indian spices (black pepper, cinnamon, clove, coriander and cumin) in various in vitro models and in food supplements enriched with omega-6 and omega-3 fatty acids. In vitro antioxidant potential was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging and Fe2+ ion-chelating methods and lipid oxidation stabilisation potential was evaluated in bulk soybean oil-fish oil mixture and their oil-in-water emulsions using peroxide value (PV), p-anisidine value (p-AV) and total oxidation value as indicators of oxidation. Combination effects using DPPH radical scavenging and Briggs-Rauscher oscillating reaction methods were also evaluated. Test essential oils showed varying degrees of radical scavenging and Fe2+ ion-chelating efficacy. Clove and coriander oils showed significantly higher (P < 0.05) radical scavenging and Fe2+ ion-chelating potential over other tested essential oils as well as BHT and ∞-tocopherol. The anti-lipid peroxidative potential of test essential oils was found in the following decreasing order: clove > coriander > BHT > cinnamon > α-tocopherol > cumin > black pepper. Furthermore, clove and coriander oils showed synergistic antioxidant activity in combination both in DPPH radical scavenging and Briggs-Rauscher oscillating reaction methods whereas other possible combinations showed additive effects. Strong radical scavenging and Fe2+-chelating as well as anti-lipid peroxidative activities of clove and coriander oils provide evidence that clove and coriander oils may serve as a potential source of natural antioxidants for retarding lipid oxidation of food supplements enriched with omega-6 and omega-3 fatty acids.
Facultative sexual species employ a dual reproductive strategy (heterogony) comprising primarily asexual reproduction with intermittent sexual reproduction. Given the higher relative costs of sexual reproduction, elucidating the triggers underlying these transitions might help our understanding of the evolution of (obligate) sex in general. Existing hypotheses into how and when facultative sexuals invest into sex focus largely either on environmental (habitat-deterioration and resource-demanding hypotheses) or genetic factors (condition-dependent hypothesis), but tend to lack experimental evidence, especially with respect to within-population variation. To address this deficit, we examined the influence of several variables that potentially affect fitness (food quality, water temperature, physiological acclimation, and all combinations thereof) on both the lifetime reproduction (total number of offspring) and investment into sexual offspring per female in a clonal population of the monogonont rotifer Brachionus rubens. Investment into sex, both absolutely and relative to lifetime reproduction, was tied most closely to and positively correlated with individual fitness (i.e., lifetime reproduction): individuals with higher fitness invested more into sexual reproduction. These results run contra to the condition-dependent hypothesis and indicate an energy-budget analogue of the resource-demanding hypothesis. Furthermore, investment into sex increased after a period of physiological acclimation to the new conditions, probably because of the amelioration of short-term stress effects or clonal selection. Our results underscore that life history and general phenotypic considerations—here, energetic provisioning of offspring, the presence of a sexual resting stage, and the relative timing of sexual versus asexual reproduction—can modify existing hypotheses based either on environmental or genetic factors alone.
October 16, 2017—Three highly regarded professional journals are published by the American Thyroid Association (ATA): Thyroid, Clinical Thyroidology, and VideoEndocrinology™. Each is under the leadership of an editor-in-chief (EIC) with specialized qualifications. The ATA is proud to announce that William B. Inabnet, III, MD, will take over the helm of the video-journal at the beginning of 2018.
The incoming EIC of VideoEndocrinology, William B. Inabnet, III, MD, is Chair of the Department of Surgery at Mount Sinai Beth Israel (New York) and the Eugene W. Friedman, MD, Professor of Surgery and Surgical Director of the Diabetes, Obesity, and Metabolism Institute at the Icahn School of Medicine at Mount Sinai. He is also the inaugural Director of Endocrine Surgery Quality for the Mount Sinai Health System.
Dr. Inabnet received his MD from the University of North Carolina at Chapel Hill, NC, and completed his residency in general surgery at Rush Medical College and Rush-Presbyterian-St Luke's Medical Center in Chicago. He completed a fellowship in endocrine surgery at Cochin Hospital in Paris, where he trained under Professor Yves Chapuis, a world leader in the field of endocrine surgery and targeted parathyroidectomy.
An international authority in the field of minimally invasive endocrine surgery, Dr. Inabnet has pioneered new techniques in minimal-access endocrine neck surgery as well as adrenal and pancreatic surgery. In 1998, he helped perform the first endoscopic thyroid resection in the United States (second in the world), and has since helped advance the field of video-endoscopic neck surgery. Dr. Inabnet was among the first surgeons in the United States to introduce remote access thyroid surgery and is one of the few surgeons in the world who performs transaxillary, bilateral axillo-breast approach (BABA) and transoral endoscopic thyroid surgery.
Dr. Inabnet is also a leader in the field of minimally invasive metabolic surgery with an interest in disorders of the endocrine system in obese patients, especially type 2 diabetes and malignancy. He has participated in national and international clinical trials evaluating the role of gastrointestinal surgery in treating diabetes. He holds numerous leadership positions in the American Association of Endocrine Surgeons, the American Association of Metabolic and Bariatric Surgery, the American College of Surgeons, and the ATA.
He has authored more than 180 peer-reviewed articles and book chapters, as well as five textbooks. He lectures throughout the world and is a member of the Southern Surgical Association, the American Surgical Association, the French National Academy of Surgery, and the French Academy of Medicine.
"Dr. Inabnet was selected as Editor-in-Chief by an ATA search committee from a pool of very strong candidates because of his experience with audiovisual production and presentation, his vision, and his prominent position in the field of endocrine surgery. The interest of this outstanding field of candidates in the position speaks to the importance of VideoEndocrinology™, especially to surgeons performing thyroid, parathyroid, and adrenal procedures," says John C. Morris, III, MD, President of the ATA and Professor of Medicine, Mayo Clinic, Rochester, MN. "With Barry's leadership, we look forward to the continued growth and stature of this groundbreaking video-journal, continuing the trajectory established by its inaugural Editor-in-Chief, Dr. Gerard Doherty."
Gerard M. Doherty, MD, Surgeon-in-Chief, Brigham and Women's Hospital, Harvard University, has provided strong leadership for VideoEndocrinology since its inception in 2014. The ATA is very grateful for his invaluable work and guidance in founding the first broad-based video-journal in endocrinology.
Peter A. Kopp, MD, is Editor-in-Chief of the ATA's flagship journal Thyroid and Professor of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago. Thyroid is a monthly, peer-reviewed forum for topics ranging from the molecular biology of the thyroid gland to clinical management of thyroid disorders. The journal Thyroid also publishes quarterly Chinese editions.
Jerome M. Hershman, MD, MS, MACP, is Editor-in-Chief of the ATA's online journal Clinical Thyroidology, which provides a broad-ranging look at the clinical thyroid literature. Dr. Hershman is Distinguished Professor of Medicine Emeritus at the David Geffen School of Medicine at UCLA and Director of the Endocrine Clinic at the West Los Angeles VA Medical Center. He was the Editor of Thyroid from 1991‒2000.
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The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 94th anniversary, the ATA continues to deliver its mission of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health. These efforts are carried out via several key endeavors:
The publication of the highly regarded professional journals Thyroid, Clinical Thyroidology, and VideoEndocrinology
The ATA promotes thyroid awareness and information online through Clinical Thyroidology for the Public and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet. Every fifth year, the American Thyroid Association joins with the Latin American Thyroid Society, the European Thyroid Association, and the Asia and Oceania Thyroid Association to cosponsor the International Thyroid Congress (ITC).
The post The American Thyroid Association's Professional Journals: New Editor-in-Chief for VideoEndocrinology™ appeared first on American Thyroid Association.
To elucidate the action mechanism of Xingnaojing Injection (醒脑静注射液, XNJI) for sepsis, and to target screen the potential bioactive ingredients.
An integrated protocol that combines in silico target screen (molecular docking) and database mapping was employed to find the potential inhibitors from XNJI for the sepsis-related targets and to establish the compound–target (C-T) interaction network. The XNJI's bioactive components database was investigated and the sepsis-associated targets were comprehensively constructed; the 3D structure of adenosine receptor A2a and 5-lipoxygenase proteins were established and evaluated with homology modeling method; system network pharmacology for sepsis treatment was studied between the bioactive ingredients and the sepsis targets using computational biology methods to distinguish inhibitors from non inhibitors for the selected sepsis-related targets and C-T network construction.
Multiple bioactive compounds in the XNJI were found to interact with multiple sepsis targets. The 32 bioactive ingredients were generated from XNJI in pharmacological system, and 21 potential targets were predicted to the sepsis disease; the biological activities for some potential inhibitors had been experimentally confirmed, highlighting the reliability of in silico target screen. Further integrated C-T network showed that these bioactive components together probably display synergistic action for sepsis treatment.
The uncovered mechanism may offer a superior insight for understanding the theory of the Chinese herbal medicine for combating sepsis. Moreover, the potential inhibitors for the sepsis-related targets may provide a good source to find new lead compounds against sepsis disease.
To elucidate the action mechanism of Xingnaojing Injection (醒脑静注射液, XNJI) for sepsis, and to target screen the potential bioactive ingredients.
An integrated protocol that combines in silico target screen (molecular docking) and database mapping was employed to find the potential inhibitors from XNJI for the sepsis-related targets and to establish the compound–target (C-T) interaction network. The XNJI's bioactive components database was investigated and the sepsis-associated targets were comprehensively constructed; the 3D structure of adenosine receptor A2a and 5-lipoxygenase proteins were established and evaluated with homology modeling method; system network pharmacology for sepsis treatment was studied between the bioactive ingredients and the sepsis targets using computational biology methods to distinguish inhibitors from non inhibitors for the selected sepsis-related targets and C-T network construction.
Multiple bioactive compounds in the XNJI were found to interact with multiple sepsis targets. The 32 bioactive ingredients were generated from XNJI in pharmacological system, and 21 potential targets were predicted to the sepsis disease; the biological activities for some potential inhibitors had been experimentally confirmed, highlighting the reliability of in silico target screen. Further integrated C-T network showed that these bioactive components together probably display synergistic action for sepsis treatment.
The uncovered mechanism may offer a superior insight for understanding the theory of the Chinese herbal medicine for combating sepsis. Moreover, the potential inhibitors for the sepsis-related targets may provide a good source to find new lead compounds against sepsis disease.
To determine whether patterns of enterovirus 71 (EV71)-associated hand, foot, and mouth disease (HFMD) were classified based on symptoms and signs, and explore whether individual characteristics were correlated with membership in particular pattern.
Symptom-based latent class analysis (LCA) was used to determine whether patterns of EV71-HFMD existed in a sample of 433 cases from a clinical data warehouse system. Logistic regression was then performed to explore whether demographic, and laboratory data were associated with pattern membership.
LCA demonstrated a two-subgroup solution with an optimal fifit, deduced according to the Bayesian Information Criterion minima. Hot pattern (59.1% of all patients) was characterized by a very high fever and high endorsement rates for classical HFMD symptoms (i.e., rash on the extremities, blisters, and oral mucosa lesions). Non-hot pattern (40.9% of all patients) was characterized by classical HFMD symptoms. The multiple logistic regression results suggest that white blood cell counts and aspartate transaminase were positively correlated with the hot pattern (adjust odds ratio=1.07, 95% confifidence interval: 1.006–1.115; adjust odds ratio=1.051, 95% confifidence interval: 1.019–1.084; respectively).
LCA on reported symptoms and signs in a retrospective study allowed different subgroups with meaningful clinical correlates to be defifined. These fifindings provide evidence for targeted prevention and treatment interventions.
