Τρίτη 4 Ιουλίου 2017
All-Trans Retinoic Acid Prevents Osteosarcoma Metastasis by Inhibiting M2 Polarization of Tumor-Associated Macrophages
M2-polarized tumor-associated macrophages (TAM) play a critical role in cancer invasion and metastasis. Here, we report that M2 macrophages enhanced metastasis of K7M2 WT osteosarcoma cells to the lungs in mice, thus establishing M2 TAMs as a therapeutic target for blocking osteosarcoma metastasis. We found that all-trans retinoic acid (ATRA) inhibited osteosarcoma metastasis via inhibiting the M2 polarization of TAMs. ATRA suppressed IL13- or IL4-induced M2-type macrophages, and then inhibited migration of osteosarcoma cells as promoted by M2-type macrophages in vitro. ATRA reduced the number of pulmonary metastatic nodes of osteosarcoma and decreased expression of M2-type macrophages in metastatic nodes both in intravenous injection and orthotopic transplantation models. ATRA's effect was independent of conventional STAT3/6 or C/EBPβ signaling, which regulate M2-like polarization of macrophages. Quantitative genomic and functional analyses revealed that MMP12, a macrophage-secreted elastase, was elevated in IL13-skewed TAM polarization, whereas ATRA treatment downregulated IL13-induced secretion of MMP12. This downregulation correlates with the antimetastasis effect of ATRA. Our results show the role of TAM polarization in osteosarcoma metastasis, identify a therapeutic opportunity for antimetastasis treatment, and indicate ATRA treatment as an approach for preventing osteosarcoma metastasis via M2-type polarization intervention. Cancer Immunol Res; 5(7); 547–59. ©2017 AACR.
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Transgenic Expression of IL15 Improves Antiglioma Activity of IL13R{alpha}2-CAR T Cells but Results in Antigen Loss Variants
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CAR) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens, such as IL13 receptor subunit α2 (IL13Rα2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity. Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function. We tested this approach in our IL13Rα2-positive glioma model in which limited IL13Rα2-CAR T-cell persistence results in recurrence of antigen-positive gliomas. T cells were genetically modified with retroviral vectors encoding IL13Rα2-CARs or IL15 (IL13Rα2-CAR.IL15 T cells). IL13Rα2-CAR.IL15 T cells recognized glioma cells in an antigen-dependent fashion, had greater proliferative capacity, and produced more cytokines after repeated stimulations in comparison with IL13Rα2-CAR T cells. No autonomous IL13Rα2-CAR.IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Rα2-CAR T-cell viability in the absence of exogenous cytokines or antigen. In vivo, IL13Rα2-CAR.IL15 T cells persisted longer and had greater antiglioma activity than IL13Rα2-CAR T cells, resulting in a survival advantage. Gliomas recurring after 40 days after T-cell injection had downregulated IL13Rα2 expression, indicating that antigen loss variants occur in the setting of improved T-cell persistence. Thus, CAR T cells for GBM should not only be genetically modified to improve their proliferation and persistence, but also to target multiple antigens.
Summary: Glioblastoma responds imperfectly to immunotherapy. Transgenic expression of IL15 in T cells expressing CARs improved their proliferative capacity, persistence, and cytokine production. The emergence of antigen loss variants highlights the need to target multiple tumor antigens. Cancer Immunol Res; 5(7); 571–81. ©2017 AACR.
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Breast Cancer Neoantigens Can Induce CD8+ T-Cell Responses and Antitumor Immunity
Next-generation sequencing technologies have provided insights into the biology and mutational landscape of cancer. Here, we evaluate the relevance of cancer neoantigens in human breast cancers. Using patient-derived xenografts from three patients with advanced breast cancer (xenografts were designated as WHIM30, WHIM35, and WHIM37), we sequenced exomes of tumor and patient-matched normal cells. We identified 2,091 (WHIM30), 354 (WHIM35), and 235 (WHIM37) nonsynonymous somatic mutations. A computational analysis identified and prioritized HLA class I–restricted candidate neoantigens expressed in the dominant tumor clone. Each candidate neoantigen was evaluated using peptide-binding assays, T-cell cultures that measure the ability of CD8+ T cells to recognize candidate neoantigens, and preclinical models in which we measured antitumor immunity. Our results demonstrate that breast cancer neoantigens can be recognized by the immune system, and that human CD8+ T cells enriched for prioritized breast cancer neoantigens were able to protect mice from tumor challenge with autologous patient-derived xenografts. We conclude that next-generation sequencing and epitope-prediction strategies can identify and prioritize candidate neoantigens for immune targeting in breast cancer. Cancer Immunol Res; 5(7); 516–23. ©2017 AACR.
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Intravesical BCG Induces CD4+ T-Cell Expansion in an Immune Competent Model of Bladder Cancer
Intravesical bacillus Calmette–Guérin (BCG) immunotherapy is the standard of care in treating non–muscle-invasive bladder cancer, yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. Although prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T-cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Our data demonstrate that cancer progression in the N-methyl-N-nitrosourea (MNU) rat model of bladder cancer was characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. In contrast, treatment with intravesical BCG led to a large, transient rise in the CD4+ T-cell population in the urothelium and was both more effective and immunogenic compared with intravesical chemotherapy. Whole-transcriptome expression profiling of posttreatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that although BCG induces T-cell recruitment to the bladder, the T-cell phenotype does not markedly change, implying that combining T-cell–activating agents with BCG might improve clinical activity. Cancer Immunol Res; 5(7); 594–603. ©2017 AACR.
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A Four-Factor Immunoscore System That Predicts Clinical Outcome for Stage II/III Gastric Cancer
The American Joint Committee on Cancer (AJCC) staging system is insufficiently prognostic for operable gastric cancer patients; therefore, complementary factors are under intense investigation. Although the focus is on immune markers, the prognostic impact of a single immune factor is minimal, due to complex antitumor immune responses. A more comprehensive evaluation may engender more accurate predictions. We analyzed immune factors by immunohistochemical staining in two independent cohorts. The association with patients' survival was analyzed by the Kaplan–Meier method. Our immunoscore system was constructed using Cox proportional hazard analysis. PD-L1+ immune cells (IC), PD-L1+ tumor cells (TC), PD-1hi, and CD8More were found among 33.33%, 31.37%, 33.33%, and 49%, respectively, of patients from the discovery cohort, and 41.74%, 17.4%, 38.26%, and 30.43% from the validation cohort. PD-L1+ ICs and PD-1hi ICs correlated with poorer overall survival (OS), but PD-L1+ TCs correlated with better OS and clinical outcomes and infiltration of more CD8+ T cells. These four factors were independently prognostic after tumor/lymph nodes/metastasis (TNM) stage adjustment. An immunoscore system based on hazard ratios of the four factors further separated gastric cancer patients with similar TNM staging into low-, medium-, or high-risk groups, with significantly different survival. Our prognostic model yielded an area under the receiver operating characteristic curve (AUC) of 0.856 for prediction of mortality at 5 years, superior to that of TNM staging (AUC of 0.676). Thus, this more comprehensive immunoscore system can provide more accurate prognoses and is an essential complement to the AJCC staging system for operable gastric cancer patients. Cancer Immunol Res; 5(7); 524–34. ©2017 AACR.
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Converting Lymphoma Cells into Potent Antigen-Presenting Cells for Interferon-Induced Tumor Regression
Anti-hCD20 is a therapeutic mAb that is clinically used to treat B-cell lymphoma. Some lymphomas are resistant to anti-hCD20; others relapse after treatment with anti-hCD20. Using a syngeneic immunocompetent mouse model, we observed that targeting lymphoma with interferon-α (IFNα) abolished resistance of B-cell lymphoma to anti-CD20 while limiting interferon (IFN)-associated systemic toxicity in the host. Control of tumors by a fusion of anti-CD20 and IFNα (anti–CD20-IFNα) depended on existing tumor-infiltrating CD8+ T cells. Although lymphomas were resistant to IFN-directed killing, IFN-exposed tumor cells became the dominant antigen-presenting cells (APC) for the reactivation of tumor-infiltrating CD8+ T cells that then controlled those lymphomas. Anti–CD20-IFNα also abolished checkpoint blockade resistance in advanced B-cell lymphoma. Our findings indicate that anti–CD20-IFNα eradicates B-cell lymphoma by employing tumor cells as APCs to reactivate tumor-infiltrating CD8+ T cells and synergizing with anti–PD-L1 treatment. Cancer Immunol Res; 5(7); 560–70. ©2017 AACR.
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Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy
New immunotherapeutic strategies are needed to induce effective antitumor immunity in all cancer patients. Malignant mesothelioma is characterized by a poor prognosis and resistance to conventional therapies. Infiltration of tumor-associated macrophages (TAM) is prominent in mesothelioma and is linked to immune suppression, angiogenesis, and tumor aggressiveness. Therefore, TAM depletion could potentially reactivate antitumor immunity. We show that M-CSFR inhibition using the CSF-1R kinase inhibitor PLX3397 (pexidartinib) effectively reduced numbers of TAMs, circulating nonclassical monocytes, as well as amount of neoangiogenesis and ascites in mesothelioma mouse models, but did not improve survival. When combined with dendritic cell vaccination, survival was synergistically enhanced with a concomitant decrease in TAMs and an increase in CD8+ T-cell numbers and functionality. Total as well as tumor antigen–specific CD8+ T cells in tumor tissue of mice treated with combination therapy showed reduced surface expression of the programmed cell death protein-1 (PD-1), a phenomenon associated with T-cell exhaustion. Finally, mice treated with combination therapy were protected from tumor rechallenge and displayed superior T-cell memory responses. We report that decreasing local TAM-mediated immune suppression without immune activation does not improve survival. However, combination of TAM-mediated immune suppression with dendritic cell immunotherapy generates robust and durable antitumor immunity. These findings provide insights into the interaction between immunotherapy-induced antitumor T cells and TAMs and offer a therapeutic strategy for mesothelioma treatment. Cancer Immunol Res; 5(7); 535–46. ©2017 AACR.
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Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib
Over 60% of human melanoma tumors bear a mutation in the BRAF gene. The most frequent mutation is a substitution at codon 600 (V600E), leading to a constitutively active BRAF and overactivation of the MAPK pathway. Patients harboring mutated BRAF respond to kinase inhibitors such as vemurafenib. However, these responses are transient, and relapses are frequent. Melanoma cells are efficiently lysed by activated natural killer (NK) cells. Melanoma cells express several stress-induced ligands that are recognized by activating NK-cell receptors. We have investigated the effect of vemurafenib on the immunogenicity of seven BRAF-mutated melanoma cells to NK cells and on their growth and sensitivity to NK-cell–mediated lysis. We showed that vemurafenib treatment modulated expression of ligands for two activating NK receptors, increasing expression of B7-H6, a ligand for NKp30, and decreasing expression of MICA and ULBP2, ligands for NKG2D. Vemurafenib also increased expression of HLA class I and HLA-E molecules, likely leading to higher engagement of inhibitory receptors (KIRs and NKG2A, respectively), and decreased lysis of vemurafenib-treated melanoma cell lines by cytokine-activated NK cells. Finally, we showed that whereas batimastat (a broad-spectrum matrix metalloprotease inhibitor) increased cell surface ULBP2 by reducing its shedding, vemurafenib lowered soluble ULBP2, indicating that BRAF signal inhibition diminished expression of both cell-surface and soluble forms of NKG2D ligands. Vemurafenib, inhibiting BRAF signaling, shifted the balance of activatory and inhibitory NK ligands on melanoma cells and displayed immunoregulatory effects on NK-cell functional activities. Cancer Immunol Res; 5(7); 582–93. ©2017 AACR.
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Antitumor Effects of Epidrug/IFN{alpha} Combination Driven by Modulated Gene Signatures in Both Colorectal Cancer and Dendritic Cells
Colorectal cancer results from the progressive accumulation of genetic and epigenetic alterations. IFN signaling defects play an important role in the carcinogenesis process, in which the inability of IFN transcription regulatory factors (IRF) to access regulatory sequences in IFN-stimulated genes (ISG) in tumors and in immune cells may be pivotal. We reported that low-dose combination of two FDA-approved epidrugs, azacytidine (A) and romidepsin (R), with IFNα2 (ARI) hampers the aggressiveness of both colorectal cancer metastatic and stem cells in vivo and triggers immunogenic cell death signals that stimulate dendritic cell (DC) function. Here, we investigated the molecular signals induced by ARI treatment and found that this drug combination increased the accessibility to regulatory sequences of ISGs and IRFs that were epigenetically silenced in both colorectal cancer cells and DCs. Likewise, specific ARI-induced histone methylation and acetylation changes marked epigenetically affected ISG promoters in both metastatic cancer cells and DCs. Analysis by ChIP-seq confirmed such ARI-induced epigenetically regulated IFN signature. The activation of this signal endowed DCs with a marked migratory capability. Our results establish a direct correlation between reexpression of silenced ISGs by epigenetic control and ARI anticancer activity and provide new knowledge for the development of innovative combined therapeutic strategies for colorectal cancer. Cancer Immunol Res; 5(7); 604–16. ©2017 AACR.
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Meaningless Accelerating Scores Yield Better Performance
Seemingly any behavior can be "gamified" and awarded digital points these days, from tracking the steps you've walked to the online purchases you've made and even the chores you've completed. Tracking behavior in this way helps to spur further action and new research shows that even meaningless scores can serve as effective motivators, as long as those scores are accelerating.
The findings are published in Psychological Science, a journal of the Association for Psychological Science.
"We all know that people like high scores, but what is less known is how to give scores," says researcher Luxi Shen of the Chinese University of Hong Kong Business School. "Our research shows that what matters is neither how high the score is nor how fast the score increases, but rather the way it increases: It's most motivating if the score first increases at a relatively slow rate and then increases faster and faster."
"In this current digital age, it's easy to imagine a number on the panel of a digital device to nudge people to change their actions," adds co-author Christopher K. Hsee of the University of Chicago Booth School of Business. "And it can help practitioners from game designers to marketers make better use of scores and points to influence behavior."
Shen and Hsee became curious about the relationship between scores and behavior after noticing their own fascination with the scores provided on some exercise machines and healthy-eating websites.
"Those changing numbers made no sense to either of us and neither did our obsession with these numbers," explains Shen. "We started with asking ourselves: If we could design a score that changes with our performance, what would a good design look like? How can we improve our performance by designing the pattern of change?"
Drawing on existing theory, Shen and Hsee hypothesized that people would have a hard time gauging a score's rate of change (velocity), a number that is difficult to evaluate without another score for comparison. But people might be more sensitive to a score's acceleration, or how quickly the rate of change increases, because they can sense that the number is going up more quickly over time. This acceleration may give the sense that they're doing increasingly better even when they know the score isn't tied to actual performance.
In three related experiments, the researchers asked participants to type a target word as many times as they could within a 3-minute period. An onscreen display showed participants the number of times they had entered the word and the elapsed time. Some participants also saw a score at the center of this display – they were told the number did not reflect their performance but would increase according to a predetermined pattern.
The results were clear: People who saw an accelerating score outperformed their peers, typing the target words more times within the 3-minute window compared with those who saw a score that increased more slowly over time (decelerating score), a score that increased at a constant rate, or no score at all.
Additional data from an online experiment showed that participants were uniquely sensitive to acceleration: They reported that the accelerating score increased faster relative to decelerating scores and scores that increased at a constant rate. Even though the accelerating score had the same final velocity as the "fast" score that increased at a constant rate, participants reported that the accelerating score increased faster.
To find out whether this acceleration effect would hold up in the context of real-world behavior, Shen and Hsee took their experiment to the gym. Again, they found that participants who saw an arbitrary accelerating score exerted more effort, taking more steps on a step machine compared with those who saw a decelerating score or no score. This effect that did not dissipate over four successive rounds of testing. The findings suggest that an accelerating score can help motivate people to keep going, even when completing a physically demanding task.
The acceleration effect may even hold up over the course of a whole day. Data from an online study showed that participants completed more surveys over an 8-hour period if they saw an accelerating score compared with a decelerating score.
The researchers say that this accelerating score – what they call the X number – could have a wide variety of useful applications.
"Our findings can help designers to strategically structure numerical feedback in a way that costs virtually nothing but has a meaningful impact, whether they're working on an exercise machine, a video game, a loyalty program, or a public policy," says Shen. "Practically, we hope to see empirical validation of the X number in other real-life contexts for good deeds, such as strategic designs of an accelerating X number to motivate people to pay credit card bills on time, save energy, invest in retirement accounts, use public transportation, recycle, donate to charitable causes, and so on."
Support for this research was provided by the Research Grants Council of Hong Kong (Grant ECS 24501215) and the John Templeton Foundation.
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Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease
Abstract
In an increasing proportion of cases, hepatocellular carcinoma (HCC) develops in patients with nonalcoholic fatty liver disease (NAFLD). Mutations in telomerase reverse transcriptase (hTERT) are associated with familial liver diseases. The aim of this study was to examine telomere length and germline hTERT mutations as associated with NAFLD-HCC. In 40 patients with NAFLD-HCC, 45 with NAFLD-cirrhosis and 64 healthy controls, peripheral blood telomere length was evaluated by qRT-PCR and hTERT coding regions and intron–exon boundaries sequenced. We further analyzed 78 patients affected by primary liver cancer (NAFLD-PLC, 76 with HCC). Enrichment of rare coding mutations (allelic frequency <0.001) was evaluated by Burden test. Functional consequences were estimated in silico and by over-expressing protein variants in HEK-293 cells. We found that telomere length was reduced in individuals with NAFLD-HCC versus those with cirrhosis (P = 0.048) and healthy controls (P = 0.0006), independently of age and sex. We detected an enrichment of hTERT mutations in NAFLD-HCC, that was confirmed when we further considered a larger cohort of NAFLD-PLC, and was more marked in female patients (P = 0.03). No mutations were found in cirrhosis and local controls, and only one in 503 healthy Europeans from the 1000 Genomes Project (allelic frequency = 0.025 vs. <0.001; P = 0.0005). Mutations with predicted functional impact, including the frameshift Glu113Argfs*79 and missense Glu668Asp, cosegregated with liver disease in two families. Three patients carried missense mutations (Ala67Val in homozygosity, Pro193Leu and His296Pro in heterozygosity) in the N-terminal template-binding domain (P = 0.037 for specific enrichment). Besides Glu668Asp, the Ala67Val variant resulted in reduced intracellular protein levels. In conclusion, we detected an association between shorter telomeres in peripheral blood and rare germline hTERT mutations and NAFLD-HCC.
Telomere length was reduced in individuals who developed hepatocellular carcinoma in nonalcoholic fatty liver (NAFLD-HCC) versus those with cirrhosis and healthy controls, independently of age and sex. We detected an enrichment of hTERT mutations in NAFLD patients affected by primary liver cancer, predominantly in females and specifically in the N-terminal template-binding domain. In conclusion, shorter telomeres and enrichment of hTERT rare germline mutations are associated with NAFLD-HCC.
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Variation and Impact of Multiple Complications on Failure to Rescue After Inpatient Surgery
Objective: To examine the extent to which multiple, sequential complications impacts variation in institutional postoperative mortality rates. Background: Failure to rescue (FTR) has been proposed as an underlying factor in hospital variation in surgical mortality. However, little is currently known about hospital variation in FTR after multiple complications or the contribution of sequential complications to variation. Methods: Retrospective cohort study of 266,101 patients within the Veterans Affairs Surgical Quality Improvement Program (2000–2014) who underwent a subset of high-mortality inpatient general, vascular, or thoracic procedures. The association between number of postoperative complications (0, 1, 2, or ≥3) and 30-day mortality across quintiles of hospital risk-adjusted mortality was evaluated with multivariable, multilevel mixed-effects models. Results: Among patients who had a complication, over half (60.9%) had 1, but those with more than 1 accounted for the majority of the deaths (63.1%). Across hospital quintiles, there were no differences in complications (23.5% very low mortality vs 23.6% very high mortality; trend test P = 0.15). FTR increased significantly (12.0% vs 18.1%; trend test Phttp://ift.tt/2qYr44Z
Do Aspirin and Other NSAIDs Confer a Survival Benefit in Men Diagnosed with Prostate Cancer? A Pooled Analysis of NIH-AARP and PLCO Cohorts
Prostate cancer is one of the leading causes of cancer-related death in U.S. men. There is an unmet need to identify modifiable risk factors for prostate cancer survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through antithrombotic and anti-inflammation mechanisms. Results from previous observational studies have been equivocal, and few have assessed whether an etiologically relevant time window of exposure exists. We sampled incident prostate cancer cases from two large U.S. prospective cohorts, NIH-AARP Diet and Health Study and PLCO Cancer Screening Trial, to investigate whether pre- and postdiagnostic aspirin and non-aspirin NSAID use were associated with prostate cancer-specific and all-cause mortality. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Study-specific results were meta-analyzed using fixed-effects models. Pre- and postdiagnostic aspirin or non-aspirin NSAID use were not statistically significantly associated with prostate cancer–specific mortality. However, occasional (less than daily) and daily aspirin users five years or more before prostate cancer diagnosis had 18% (HR = 0.82; 95% CI = 0.75–0.90) and 15% (HR = 0.85; 95% CI = 0.77–0.94) reduced all-cause mortality versus nonusers. Similarly, postdiagnostic occasional and daily aspirin use were associated with 17% (HR = 0.83; 95% CI=0.72–0.95) and 25% (HR = 0.75; 95% CI = 0.66–0.86) reduced all-cause mortality, independent of prediagnostic aspirin use. This study suggests that aspirin or non-aspirin NSAIDs are not associated with prostate cancer survival. However, aspirin use both before and after prostate cancer diagnosis was associated with longer overall survival, highlighting the importance of comorbidity prevention among prostate cancer survivors. Cancer Prev Res; 10(7); 410–20. ©2017 AACR.
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Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice
Intestinal cyclic guanosine monophosphate (cGMP) signaling regulates epithelial homeostasis and has been implicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5 (PDE5) inhibitor sildenafil to prevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS) inflammation-driven colorectal cancer model. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against dextran-sulfate sodium (DSS)-induced barrier dysfunction. In mice treated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared with untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared with polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cell infiltration and reduced expression of iNOS, IFN, and IL6 compared with untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38% reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration of sildenafil suppresses polyp formation and inflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans. Cancer Prev Res; 10(7); 377–88. ©2017 AACR.
See related editorial by Piazza, p. 373.
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Fusobacterium Nucleatum Subspecies Animalis Influences Proinflammatory Cytokine Expression and Monocyte Activation in Human Colorectal Tumors
Chronic infection and associated inflammation have long been suspected to promote human carcinogenesis. Recently, certain gut bacteria, including some in the Fusobacterium genus, have been implicated in playing a role in human colorectal cancer development. However, the Fusobacterium species and subspecies involved and their oncogenic mechanisms remain to be determined. We sought to identify the specific Fusobacterium spp. and ssp. in clinical colorectal cancer specimens by targeted sequencing of Fusobacterium 16S ribosomal RNA gene. Five Fusobacterium spp. were identified in clinical colorectal cancer specimens. Additional analyses confirmed that Fusobacterium nucleatum ssp. animalis was the most prevalent F. nucleatum subspecies in human colorectal cancers. We also assessed inflammatory cytokines in colorectal cancer specimens using immunoassays and found that expression of the cytokines IL17A and TNFα was markedly increased but IL21 decreased in the colorectal tumors. Furthermore, the chemokine (C-C motif) ligand 20 was differentially expressed in colorectal tumors at all stages. In in vitro co-culture assays, F. nucleatum ssp. animalis induced CCL20 protein expression in colorectal cancer cells and monocytes. It also stimulated the monocyte/macrophage activation and migration. Our observations suggested that infection with F. nucleatum ssp. animalis in colorectal tissue could induce inflammatory response and promote colorectal cancer development. Further studies are warranted to determine if F. nucleatum ssp. animalis could be a novel target for colorectal cancer prevention and treatment. Cancer Prev Res; 10(7); 398–409. ©2017 AACR.
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Tamoxifen Acceptance and Adherence among Patients with Ductal Carcinoma In Situ (DCIS) Treated in a Multidisciplinary Setting
Tamoxifen and other endocrine agents have proven benefits for women with ductal carcinoma in situ (DCIS), but low patient acceptance is widely reported. We examined factors associated with tamoxifen acceptance and adherence among DCIS patients who received a recommendation for therapy in a multidisciplinary setting. Using our institutional database, we identified women diagnosed with DCIS, 1998 to 2009, who were offered tamoxifen. We recorded data on demographics, tumor and therapy variables, tamoxifen acceptance, and adherence to therapy for ≥4 years. Univariable and multivariable analyses were conducted using logistic regression to identify factors specific to each group that were related to acceptance and adherence. A total of 555 eligible women identified, of whom 369 were offered tamoxifen; 298 (81%) accepted, among whom 214 (72%) were adherent, 59 of 298 (20%) were nonadherent, and for 25 (8%), adherence was undetermined. After stepwise elimination in adjusted logistic regression models, acceptance of breast radiotherapy was associated with acceptance of tamoxifen [OR, 2.22; 95% confidence interval (CI), 1.26–3.90; P < 0.01], as was a medical oncology consultation (OR, 1.76; 95% CI, 0.99–3.15; P = 0.05). Insured patients were more likely to adhere to tamoxifen (OR, 6.03; 95% CI, 2.60–13.98; P < 0.01). The majority of nonadherent women (n = 38/56, 68%) discontinued the drug during the first year of treatment with 48 (86%) citing adverse effect(s) as the reason. In a multidisciplinary, tertiary care setting, we observed relatively high rates of acceptance and adherence of tamoxifen. Acceptance of tamoxifen and radiotherapy were associated, and adherence was influenced by insurance status.
Key Message: Tamoxifen acceptance and adherence following resection of DCIS of the breast is related to acceptance of radiotherapy and may be improved by confirmation of the recommendation by a medical oncologist. Despite the low cost of tamoxifen, adherence to therapy is significantly impacted by lack of insurance; those who discontinue therapy report adverse effects as a major reason. Cancer Prev Res; 10(7); 389–97. ©2017 AACR.
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Development of a Cancer Risk Prediction Tool for Use in the UK Primary Care and Community Settings
Several multivariable risk prediction models have been developed to asses an individual's risk of developing specific cancers. Such models can be used in a variety of settings for prevention, screening, and guiding investigations and treatments. Models aimed at predicting future disease risk that contains lifestyle factors may be of particular use for targeting health promotion activities at an individual level. This type of cancer risk prediction is not yet available in the UK. We have adopted the approach used by the well-established U.S.-derived "YourCancerRisk" model for use in the UK population, which allow users to quantify their individual risk of developing individual cancers relative to the population average risk. The UK version of "YourCancerRisk" computes 10-year cancer risk estimates for 11 cancers utilizing UK figures for prevalence of risk factors and cancer incidence. Because the prevalence of risk factors and the incidence rates for cancer are different between the U.S. and the UK population, this UK model provides more accurate estimates of risks for a UK population. Using an example of breast cancer and data from UK Biobank cohort, we demonstrate that the individual risk factor estimates are similar for the U.S. and UK populations. Assessment of the performance and validation of the multivariate model predictions based on a binary score confirm the model's applicability. The model can be used to estimate absolute and relative cancer risk for use in Primary Care and community settings and is being used in the community to guide lifestyle change. Cancer Prev Res; 10(7); 421–30. ©2017 AACR.
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Age-Associated Intracellular Superoxide Dismutase Deficiency Potentiates Dermal Fibroblast Dysfunction During Wound Healing
Abstract
Reactive oxygen species (ROS) impair wound healing through destructive oxidation of intracellular proteins, lipids, and nucleic acids. Intracellular superoxide dismutase (SOD1) regulates ROS levels and plays a critical role in tissue homeostasis. Recent evidence suggests that age-associated wound healing impairments may partially result from decreased SOD1 expression. We investigated the mechanistic basis by which increased oxidative stress links to age-associated impaired wound healing. Fibroblasts were isolated from unwounded skin of young and aged mice, and myofibroblast differentiation was assessed by measuring α-smooth muscle actin and collagen gel contraction. Excisional wounds were created on young and aged mice to study the healing rate, ROS levels, and SOD1 expression. A mechanistic link between oxidative stress and fibroblast function was explored by assessing the TGF-β1 signaling pathway components in young and aged mice. Age-related wounds displayed reduced myofibroblast differentiation and delayed wound healing, consistent with a decrease in the in vitro capacity for fibroblast-myofibroblast transition following oxidative stress. Young fibroblasts with normal SOD1 expression exhibited increased phosphorylation of ERK in response to elevated ROS. In contrast, aged fibroblasts with reduced SOD1 expression displayed a reduced capacity to modulate intracellular ROS. Collectively, age-associated wound healing impairments are associated with fibroblast dysfunction that is likely the result of decreased SOD1 expression and subsequent dysregulation of intracellular ROS. Strategies targeting these mechanisms may suggest a new therapeutic approach in the treatment of chronic non-healing wounds in the aged population.
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Neurological and psychiatric associations in bullous pemphigoid – more than skin deep?
Abstract
In elderly patients, bullous pemphigoid (BP) is associated with several comorbidities; the strongest association occurs between BP and neurological diseases. Different types of dementia, Parkinson's disease, cerebrovascular disorders and epilepsy all have a significant association with BP but patients with multiple sclerosis have the highest risk of BP. An existing neurological disorder appears to increase the risk for subsequent BP, but an increased risk for developing some neurological diseases has also been reported following BP diagnosis. BP seems to be associated with several psychiatric diseases such as schizophrenia, uni- and bipolar disorder, schizotypal and delusional disorders, and personality disorders, but the risk ratios are usually lower than with neurological diseases. In addition to the skin, the BP autoantigens BP180 and BP230 are expressed in the central nervous system. This finding together with the strong epidemiological association between neurological disorders and BP has led to an assumption that neurodegeneration or neuroinflammation could lead to a cross-reactive immunoresponse between neural and cutaneous antigens and the failure of self-tolerance. A subpopulation of patients with Alzheimer's disease or Parkinson's disease have circulating IgG autoantibodies against BP180, but currently their significance for the development of BP is unclear, since these anti-neural BP180 antibodies neither bind to the cutaneous basement membrane nor cause BP like symptoms. Further studies analyzing large and well-characterized populations of neurological and psychiatric patients are required to understand better the role of autoimmunization against neural BP autoantigens in the pathogenesis of BP.
This article is protected by copyright. All rights reserved.
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Imiquimod-applied Interleukin-10 deficient mice better reflects severe and persistent psoriasis with systemic inflammatory state
Abstract
Previous studies have shown that imiquimod-induced psoriasis-like skin inflammation in mice resembles phenotypic changes and cytokine profiles of human psoriasis. However, a psoriasis animal model reflecting the chronic inflammatory course and comorbidities has not yet been established. We aimed to evaluate the imiquimod-applied interleukin (IL)-10 deficient mouse model in comparison to previous models. IL-10 deficient and wild type (WT) mice received either imiquimod or vehicle cream for 12 days and were sacrificed on day 15. For earlier time point data, either imiquimod or vehicle cream was applied for 2 days and the mice were sacrificed on day 3.
Imiquimod-applied IL-10 deficient mice showed more persistent psoriasis-like inflammation and higher severity index than did WT between day 8 and 15. Histopathologically, they demonstrated significantly thicker epidermis and larger number of CD45+, myeloperoxidase+, and IL-17+ cell counts on day 15. Quantitative reverse transcription-polymerase chain reaction with skin tissue revealed significantly higher imiquimod-induced IL-23p19 expression in imiquimod-applied IL-10 deficient mice on day 15. IL-10 deficient mice also showed significantly higher serum levels of imiquimod-induced IL-17A and tumour necrosis factor-α by enzyme-linked immunosorbent assay on day 15. Furthermore, IL-10 deficient mice showed more prominent increase of spleen weight and decrease of bodyweight in response to imiquimod application on day 3 and 15. In conclusion, IL-10 deficient mice model with imiquimod application may better reflect severe and persistent psoriasis with systemic inflammatory state.
This article is protected by copyright. All rights reserved.
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Ultraviolet radiation and skin mast cells: Effects, mechanisms, and relevance for skin diseases
Abstract
Mast cells (MCs) are well-known as versatile effector cells in allergic reactions and several other immune responses. Skin MCs and cutaneous MC responses are subject to the effects of environmental factors including ultraviolet radiation (UVR). Numerous studies have assessed the effects of UVR on MCs, in vitro and in vivo. Interestingly, UVR seems to have variable effects on nonactivated and activated mast cells. In general, UV therapy is beneficial in the treatment of urticaria and mastocytosis, but the effects are variable depending on treatment regimen and type of UVR.
Here, we review and summarize key reports from the older and current literature on the crosstalk of UVR and skin MCs. Specifically, we present the literature and discuss published reports on the effects of UVR on skin MCs in rodents and humans. In addition, we review the role of MCs in UVR-driven skin diseases and the influence of UV light on MC-mediated skin diseases. This summary of our current understanding of the interplay of skin MCs and UVR may help to improve the management of patients with urticaria and other MC disorders, to identify current gaps of knowledge, and to guide further research.
This article is protected by copyright. All rights reserved.
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Review article: new treatments in non-alcoholic fatty liver disease
Summary
Background
Non-alcoholic fatty liver disease is the fastest growing cause of liver disease in the Western world, yet there is no approved pharmacotherapy. While lifestyle modifications remain the mainstay of treatment, only a proportion of individuals are able to make or sustain them, and so more treatment options are required.
Aim
To review the potential benefit of drugs used in clinical practice, those entering phase II trials, and compounds being investigated in pre-clinical studies.
Methods
A literature search was performed using PubMed to identify relevant studies; linked references were also reviewed.
Results
Vitamin E and pioglitazone have shown efficacy in non-alcoholic steatohepatitis (NASH), but long-term safety concerns, specifically bladder cancer and osteoporosis with pioglitazone, have limited their use. GLP-1 analogues and SGLT-2 inhibitors are currently approved for use in diabetes, have shown early efficacy in NASH and also have beneficial cardiovascular effects. Peroxisome proliferator-activator receptors and FXR agonists have potent effects on lipogenesis, inflammation and fibrosis, respectively, with their efficacy and safety being currently tested in phase 3. As inflammation and apoptosis are key features of NASH agents modulating these pathways are of interest; CCR2/5 antagonists downregulate inflammatory pathways and reduce fibrosis with caspase and apoptosis signal-regulating kinase 1 inhibitors reducing apoptosis and fibrosis.
Conclusions
Rising demand and an improved understanding of NASH pathophysiology has led to a surge in development of new therapies. Tailoring pharmacotherapy to the dominant pathogenic pathway in a given patient along with use of combination therapy is likely to represent the future direction in treatment of patients with NASH.
http://ift.tt/2sEtAlN
A survey of Australian midwives’ knowledge, experience, and training needs in relation to female genital mutilation
Publication date: Available online 4 July 2017
Source:Women and Birth
Author(s): Sabera Turkmani, Caroline Homer, Nesrin Varol, Angela Dawson
BackgroundFemale genital mutilation (FGM) involves partial or total removal of the external female genitalia or any other injury for non-medical reasons. Due to international migration patterns, health professionals in high income countries are increasingly caring for women with FGM. Few studies explored the knowledge and skills of midwives in high income countries.AimTo explore the knowledge, experience and needs of midwives in relation to the care of women with FGM.MethodsAn online self-administered descriptive survey was designed and advertised through the Australian College of Midwives' website.ResultsOf the 198 midwives (24%) did not know the correct classification of FGM. Almost half of the respondents (48%) reported they had not received FGM training during their midwifery education. Midwives (8%) had been asked, or knew of others who had been asked to perform FGM in Australia. Many midwives were not clear about the law or health data related to FGM and were not aware of referral paths for affected women.ConclusionAs frontline providers, midwives must have appropriate up-to-date clinical skills and knowledge to ensure they are able to provide women with FGM the care they need and deserve. Midwives have a critical role to play in the collection of FGM related data to assist with health service planning and to prevent FGM by working closely with women and communities they serve to educate and advocate for its abandonment. Therefore, addressing educational gaps and training needs are key strategies to deliver optimal quality of care.
http://ift.tt/2tKps2V
The associations between religion, bereavement and depression among Hong Kong nurses
This paper is to examine the associations between religion, bereavement and depression among nursing professionals using a cross-sectional survey design. There is little empirical evidence in Asia suggesting t...
http://ift.tt/2so2AmC
Chronic scrotal pain in young adults
Chronic scrotal pain (CSP) is a common and well recognized symptom of young males presenting to primary care units. Historically, CSP is defined as a testicular pain lasting for over 3 months. However, its eti...
http://ift.tt/2tH1ZA8
A 5 year trend analysis of malaria prevalence with in the catchment areas of Felegehiwot referral Hospital, Bahir Dar city, northwest-Ethiopia: a retrospective study
Malaria is one of the killer diseases in Ethiopia and it is still the first leading cause of death in health facilities. However, there is no information yet regarding the trends of malaria prevalence at healt...
http://ift.tt/2soorKq
One year symptom severity and health-related quality of life changes among Black African patients undergoing uterine fibroid embolisation
The main aim in the treatment of symptomatic fibroids by various modalities including uterine fibroid embolisation (UFE) is to alleviate symptoms and ultimately improve the quality of life. The efficacy of thi...
http://ift.tt/2snXBSZ
Investigation of implantable signal transmission characteristics based on visible data of the human leg
Signal transmission characteristics between implanted medical devices and external equipment has been a common key issue, as has the problem of supplying energy to the devices. It can be used to enable signal ...
http://ift.tt/2uHVbyX
Incidence, clinical characteristics, and outcomes of nosocomial Enterococcus spp. bloodstream infections in a tertiary-care hospital in Beijing, China: a four-year retrospective study
Enterococcus spp. are the common cause of nosocomial bloodstream infections (BSIs) with high morbidity and mortality. The purpose of this study was to characterize the incidence, clini...
http://ift.tt/2tOzUar
A Rare Case of Primary Bilateral Adrenal Lymphoma
Lymphoma may involve the adrenal glands, but primary lymphoma is rare. Only a few cases have been reported in medical literature. Primary adrenal lymphoma is extremely rare, accounting for
http://ift.tt/2tK9eXP
Nasal administration of the neuroprotective candidate NeuroEPO to healthy volunteers: a randomized, parallel, open-label safety study
Delivery of therapeutic agents as erythropoietin (EPO) into Central Nervous System through intranasal route could benefit patients with neurological disorders. A new nasal formulation containing a non-hematopo...
http://ift.tt/2sEmoX3
Adjuvant intensity-modulated whole abdominal radiotherapy for high-risk patients with ovarian cancer FIGO stage III– first results of a prospective phase-II-study
Patients with advanced stage ovarian cancer have a poor prognosis with intraperitoneally disease recurrence being a common pattern of relapse. This prospective multicenter phase-II-study tested treatment tolerability of whole abdominal radiotherapy using IMRT as one possible treatment option to improve survival. Results show excellent treatment tolerability rates of 95% (lower limit of the one-sided 95% CI 80.4%), thus making IMRT a promising treatment option in addition to established chemotherapy regimens.
http://ift.tt/2tKcYIR
Subsquamous intestinal metaplasia is common in treatment-naïve Barrett’s esophagus
Barrett's intestinal metaplasia may extent beneath normal squamous epithelium at the squamocolumnar junction (SCJ) and therefore escape surveillance biopsies. The prevalence of subsquamous intestinal metaplasia (SSIM) in patients undergoing Barrett's esophagus (BE) surveillance is unknown. Our aim was to examine the prevalence and distribution of SSIM proximal to the SCJ in patients undergoing BE surveillance.
http://ift.tt/2tewBYG
Suppression of a cancer stem-like phenotype mediated by alpha-lipoic acid in human lung cancer cells through down-regulation of β-catenin and Oct-4
Abstract
Purpose
Cancer stem cells (CSCs) that possess the ability of self-renewal and multi-potency have been shown to drive tumor progression and metastasis. The majority of recent studies has focused on potential molecules targeting CSCs so as to develop novel strategies for efficient cancer treatment or protection. Here, we show how alpha-lipoic acid (LA), an endogenous mitochondrial anti-oxidant, affects the CSC-like phenotypes of human non-small cell lung cancer-derived H23, H292 and H460 cells.
Methods
CSC-like phenotypes were verified by anchorage-independent growth, three-dimensional (3D) spheroid formation and the expression of CSC markers. Enriched CSC populations were used to confirm the effects of LA. Protein ubiquitination and degradation were assessed using immunoprecipitation.
Results
We found that treatment with LA reduced the CSC-like phenotype, as indicated by a decreased expression of known CSC markers (CD133, CD44, ALDH1A1, Oct-4 and Nanog) in H460 cells. In addition, we found that LA reduced the CSC-related abilities of anchorage-independent growth and 3D spheroid formation, and suppressed factors related to epithelial-mesenchymal transition, such as E-cadherin, Vimentin, Slug and Snail. Mechanistically, we found that LA suppresses CSC through depletion of the cellular stemness proteins β-catenin and Oct-4 via decreasing the level of active (phosphorylated) Akt. This resulted in the induction of GSK3β-dependent β-catenin ubiquitin-proteasomal degradation and a decrease in the stabilized (phosphorylated) form of Oct-4. The effects of LA on the CSC-like phenotypes were confirmed in CSC enriched H460, H292 and H23 non-small cell lung cancer-derived cells.
Conclusion
Our data are indicative for a novel regulatory role and underlying mechanism of LA in the negative regulation of a CSC-like phenotype in non-small cell lung cancer-derived cells.
http://ift.tt/2tGzsdW
Dissemination of Carbapenem-resistant Klebsiella pneumoniae clinical isolates with various combinations of Carbapenemases (KPC-2, NDM-1, NDM-4, and OXA-48) and 16S rRNA Methylases (RmtB and RmtC) in Vietnam
Twenty-seven clinical isolates of carbapenem-resistant Klebsiella pneumoniae with MICs ≥4 mg/L for imipenem or meropenem were obtained from inpatients in a hospital in Vietnam. Antimicrobial susceptibility tests ...
http://ift.tt/2tJvi4H
Prevalence of hepatitis B and delta according to HIV-type: a multi-country cross-sectional survey in West Africa
In West Africa where HIV-1 and HIV-2 co-circulate, the co-infection with hepatitis B virus (HBV) and hepatitis Delta virus (HDV) is not well described. This study aimed at estimating the prevalence of HBV and ...
http://ift.tt/2uHLrET
Incidence, temporal trend and factors associated with ventilator-associated pneumonia in mainland China: a systematic review and meta-analysis
Data to date is far from sufficient to describe the recent epidemiology of ventilator-associated pneumonia (VAP) in mainland China. This study aimed to estimate the overall incidence of VAP, with a special foc...
http://ift.tt/2tJPvHK
Pharmacokinetics of Caffeic Acid, Ferulic Acid, Formononetin, Cryptotanshinone, and Tanshinone IIA after Oral Administration of Naoxintong Capsule in Rat by HPLC-MS/MS
Naoxintong capsule (NXTC) was a famous patent medicine of Traditional Chinese Medicine (TCM) to treat cerebrovascular diseases in China. An LC-MS/MS method was developed for simultaneous determination of 11 major ingredients (paeoniflorin, ecdysterone, amygdalin, mulberroside A, caffeic acid, ferulic acid, salvianolic acid B, astragaloside IV, formononetin, cryptotanshinone, and tanshinone IIA) in NXTC in rat plasma. All analytes were separated on an Eclipse plus C18 column using a gradient mobile phase system of acetonitrile-0.1% formic acid aqueous solution. The lower limits of quantification of 11 ingredients were between 0.075 and 10 ng mL−1. The precision was less than 15% and the accuracies were between 85% and 115%. The results showed that caffeic acid, ferulic acid, formononetin, cryptotanshinone, and tanshinone IIA could be detected after oral administration of NXTC. The validated method was successfully applied to pharmacokinetic study of the caffeic acid, ferulic acid, formononetin, cryptotanshinone, and tanshinone IIA in rats after oral administration of NXTC at single and triple dose.
http://ift.tt/2uI0zlE
An in vitro study ascertaining the role of H 2 O 2 and glucose oxidase in modulation of antioxidant potential and cancer cell survival mechanisms in glioblastoma U-87 MG cells
Abstract
Glial cells protect themselves from the elevated reactive oxygen species (ROS) via developing unusual mechanisms to maintain the genomic stability, and reprogramming of the cellular antioxidant system to cope with the adverse effects. In the present study non-cytotoxic dose of oxidants, H2O2 (100 μM) and GO (10 μU/ml) was used to induce moderate oxidative stress via generating ROS in human glioblastoma cell line U-87 MG cells, which showed a marked increase in the antioxidant capacity as studied by measuring the modulation in expression levels and activities of superoxide dismutase (SOD1 and SOD2) and catalase (CAT) enzymes, and the GSH content. However, pretreatment (3 h) of Curcumin and Quercetin (10 μM) followed by the treatment of oxidants enhanced the cell survival, and the levels/activities of the antioxidants studied. Oxidative stress also resulted in an increase in the nitrite levels in the culture supernatants, and further analysis by immunocytochemistry showed an increase in iNOS expression. In addition, phytochemical pretreatment decreased the nitrite level in the culture supernatants of oxidatively stressed U-87 MG cells. Elevated ROS also increased the expression of COX-2 and APE1 enzymes and pretreatment of Curcumin and Quercetin decreased COX-2 expression and increased APE1 expression in the oxidatively stressed U-87 MG cells. The immunocytochemistry also indicates for APE1 enhanced stress-dependent subcellular localization to the nuclear compartment, which advocates for enhanced DNA repair and redox functions of APE1 towards survival of U-87 MG cells. It can be concluded that intracellular oxidants activate the key enzymes involved in antioxidant mechanisms, NO-dependent survival mechanisms, and also in the DNA repair pathways for glial cell survival in oxidative-stress micro-environment.
http://ift.tt/2tnceqM
Parasitological and biochemical studies on cutaneous leishmaniasis in Shara’b District, Taiz, Yemen
The leishmaniasis is a group of diseases caused by intracellular haemoflagellate protozoan parasites of the genus Leishmania. Leishmaniasis has diverse clinical manifestations; cutaneous leishmaniasis (CL) is the...
http://ift.tt/2tJEp5q
HIF prolyl hydroxylase PHD3 regulates translational machinery and glucose metabolism in clear cell renal cell carcinoma
Abstract
Background
A key feature of clear cell renal cell carcinoma (ccRCC) is the inactivation of the von Hippel-Lindau tumour suppressor protein (pVHL) that leads to the activation of hypoxia-inducible factor (HIF) pathway also in well-oxygenated conditions. Important regulator of HIF-α, prolyl hydroxylase PHD3, is expressed in high amounts in ccRCC. Although several functions and downstream targets for PHD3 in cancer have been suggested, the role of elevated PHD3 expression in ccRCC is not clear.
Methods
To gain insight into the functions of high PHD3 expression in ccRCC, we used PHD3 knockdown by siRNA in 786-O cells under normoxic and hypoxic conditions and performed discovery mass spectrometry (LC-MS/MS) of the purified peptide samples. The LC-MS/MS results were analysed by label-free quantification of proteome data using a peptide-level expression-change averaging procedure and subsequent gene ontology enrichment analysis.
Results
Our data reveals an intriguingly widespread effect of PHD3 knockdown with 91 significantly regulated proteins. Under hypoxia, the response to PHD3 silencing was wider than under normoxia illustrated by both the number of regulated proteins and by the range of protein expression levels. The main cellular functions regulated by PHD3 expression were glucose metabolism, protein translation and messenger RNA (mRNA) processing. PHD3 silencing led to downregulation of most glycolytic enzymes from glucose transport to lactate production supported by the reduction in extracellular acidification and lactate production and increase in cellular oxygen consumption rate. Moreover, upregulation of mRNA processing-related proteins and alteration in a number of ribosomal proteins was seen as a response to PHD3 silencing. Further studies on upstream effectors of the translational machinery revealed a possible role for PHD3 in regulation of mTOR pathway signalling.
Conclusions
Our findings suggest crucial involvement of PHD3 in the maintenance of key cellular functions including glycolysis and protein synthesis in ccRCC.
http://ift.tt/2uHzAab
Chenopodium ambrosioides as a bone graft substitute in rabbits radius fracture
Bone defects caused by trauma, infection or tumor resection are common in orthopedic clinic and depending on the extent of the fracture; the vast majority require treatment with bone substitutes. Among the bon...
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Antibacterial activities and toxicological study of the aqueous extract from leaves of Alchornea cordifolia (Euphorbiaceae)
A. cordifolia is a plant widely used in Africa to solve many health problems. In Cameroon, it is used in the treatment of urogenital infections. As a continuation of our search for pha...
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Reviewing the impact of lipid synthetic flux on Th17 function
Yoko Kidani | Steven J Bensinger
http://ift.tt/2uElRAZ
New dental materials developed, with bioactive glass doped with fluoride, to stop degradation of demineralized dentin and evoke remineralization
Innovative new dental biomaterials have now been developed for the regeneration of dental hard tissues, outlines a new report.
http://ift.tt/2sDpLNN
The Effect of Interfacial Chemical Bonding in TiO2-SiO2 Composites on Their Photocatalytic NOx Abatement Performance
The focus of the present work is to establish means to generate and quantify levels of Ti-O-Si linkages and to correlate these with the photocatalytic properties of the supported TiO2.
http://ift.tt/2snlQ3C
Incorporating Context Dependency of Species Interactions in Species Distribution Models
Abstract
Species distribution models typically use correlative approaches that characterize the species–environment relationship using occurrence or abundance data for a single species. However, species distributions are determined by both abiotic conditions and biotic interactions with other species in the community. Therefore, climate change is expected to impact species through direct effects on their physiology and indirect effects propagated through their resources, predators, competitors, or mutualists. Furthermore, the sign and strength of species interactions can change according to abiotic conditions, resulting in context-dependent species interactions that may change across space or with climate change. Here, we incorporated the context dependency of species interactions into a dynamic species distribution model. We developed a multi-species model that uses a time-series of observational survey data to evaluate how abiotic conditions and species interactions affect the dynamics of three rocky intertidal species. The model further distinguishes between the direct effects of abiotic conditions on abundance and the indirect effects propagated through interactions with other species. We apply the model to keystone predation by the sea star Pisaster ochraceus on the mussel Mytilus californianus and the barnacle Balanus glandula in the rocky intertidal zone of the Pacific coast, USA. Our method indicated that biotic interactions between P. ochraceus and B. glandula affected B. glandula dynamics across >1000 km of coastline. Consistent with patterns from keystone predation, the growth rate of B. glandula varied according to the abundance of P. ochraceus in the previous year. The data and the model did not indicate that the strength of keystone predation by P. ochraceus varied with a mean annual upwelling index. Balanus glandula cover increased following years with high phytoplankton abundance measured as mean annual chlorophyll-a. M. californianus exhibited the same pattern to a lesser degree, although this pattern was not significant. This work bridges the disciplines of biogeography and community ecology to develop tools to better understand the direct and indirect effects of abiotic conditions on ecological communities.http://ift.tt/2te3R2a
Do Bar-Headed Geese Train for High Altitude Flights?
Abstract
Exercise at high altitude is extremely challenging, largely due to hypobaric hypoxia (low oxygen levels brought about by low air pressure). In humans, the maximal rate of oxygen consumption decreases with increasing altitude, supporting progressively poorer performance. Bar-headed geese (Anser indicus) are renowned high altitude migrants and, although they appear to minimize altitude during migration where possible, they must fly over the Tibetan Plateau (mean altitude 4800 m) for much of their annual migration. This requires considerable cardiovascular effort, but no study has assessed the extent to which bar-headed geese may train prior to migration for long distances, or for high altitudes. Using implanted loggers that recorded heart rate, acceleration, pressure, and temperature, we found no evidence of training for migration in bar-headed geese. Geese showed no significant change in summed activity per day or maximal activity per day. There was also no significant change in maximum heart rate per day or minimum resting heart rate, which may be evidence of an increase in cardiac stroke volume if all other variables were to remain the same. We discuss the strategies used by bar-headed geese in the context of training undertaken by human mountaineers when preparing for high altitude, noting the differences between their respective cardiovascular physiology.http://ift.tt/2sJqR5K
Metamorphosis Is Ancestral for Crown Euarthropods, and Evolved in the Cambrian or Earlier
Abstract
Macroevolutionary developmental biology employs fossilized ontogenetic data and phylogenetic comparative methods to probe the evolution of development at ancient nodes. Despite the prevalence of ecologically differentiated larval forms in marine invertebrates, it has been frequently presumed that the ancestors of arthropods were direct developers, and that metamorphosis may not have evolved until the Ordovician or later. Using fossils and new dated phylogenies, I infer that metamorphosis was likely ancestral for crown arthropods, contradicting this assumption. Based on a published morphological dataset encompassing 217 exceptionally preserved fossil and 96 extant taxa, fossils were directly incorporated into both the topology and age estimates, as in "tip dating" analyses. Using data from post-embryonic fossils representing 25 species throughout stem and crown arthropod lineages (as well as most of the 96 extant taxa), characters for metamorphosis were assigned based on inferred ecological changes in development (e.g., changes in habitat and adaptive landscape). Under all phylogenetic hypotheses, metamorphosis was supported as most likely ancestral to both ecdysozoans and euarthropods. Care must be taken to account for potential drastic post-embryonic morphological changes in evolutionary analyses. Many stem group euarthrpods may have had ecologically differentiated larval stages that did not preserve in the fossil record. Moreover, a complex life cycle and planktonic ecology may have evolved in the Ediacaran or earlier, and may have typified the pre-Cambrian explosion "wormworld" prior to the origin of crown group euarthropods.http://ift.tt/2tdI7DE
Ontogeny of Flight Capacity and Pectoralis Function in a Precocial Ground Bird ( Alectoris chukar )
Synopsis
Flight is the defining characteristic of birds, yet the mechanisms through which flight ability develops are only beginning to be understood. Wing-assisted incline running (WAIR) and controlled flapping descent (CFD) are behaviors that may offer significant adaptive benefits to developing birds. Recent research into these forms of locomotion has focused on species with precocial development, with a particularly rich data set from chukar partridge (Alectoris chukar). Here we briefly review the kinematics and aerodynamics of flight development in this species. We then present novel measurements of the development of pectoralis contractile behavior during the ontogenetic transition toward powered flight. To obtain these new empirical data, we used indwelling electromyography (EMG) and sonomicrometry and tested WAIR and CFD in seven age classes of chukar (n = 2–4 birds per age) from 5 days post hatching (dph) to adult (300+ dph). For each age class, we measured muscle activity during maximal performance, which was WAIR at 65° in birds 5 dph, CFD in birds 9 dph, WAIR at 80° in birds 14 dph, level flight in birds 25–61 dph, and ascending flight in adults. We also measured muscle activity during sub-maximal performance in all age classes. Flapping chukar chicks use near-continuous activation of their pectoralis at relatively low electromyography amplitudes for the first 8 days and progress to stereotypic higher-amplitude activation bursts by Day 12. The pectoralis undergoes increasing strain at higher strain rates with age, and length trajectory becomes more asymmetrical with greater variation in contractile velocity within the shortening phase of individual contractions. At 20–25 days (12–15% adult chukar mass), pectoralis activity and locomotor performance approaches that of adults, although strain rate exhibits a temporary decrease at 61 dph concurrent with using newly-replaced primary feathers. To better understand how these patterns relate to the evolution of life-history strategy and locomotion, we encourage future efforts to explore these behaviors in altricial and semi-altricial bird species.http://ift.tt/2sJOWJP
Scaling from Metabolism to Population Growth Rate to Understand How Acclimation Temperature Alters Thermal Performance
Synopsis
The mean and variance of environmental temperature are changing as a consequence of human activities. Ectotherms are sensitive to these temperature changes in the short term, typically displaying a unimodal response of most biological rates to temperature (thermal performance curves; TPCs). Many organisms, however, may acclimate or evolve in response to new temperature regimes. In particular, population growth rate TPCs (r TPCs) reflect the ability to maintain positive growth under a range of temperatures, and therefore shifts in r TPCs due to acclimation are fundamental to our understanding of how ectotherms will respond to changes in climate. Here, we derive a model for r TPCs rooted in temperature dependent metabolic rate (through enzyme kinetics and activity). We then use this model to interpret the effects of acclimation to different temperatures on r TPCs of the protist Paramecium bursaria. Intermediate acclimation temperatures generally resulted in higher upper critical thermal limits, thermal optima, maximum population growth rate, and the area under the TPC. Lower critical thermal limits increased linearly with acclimation temperature, causing a decrease in thermal breadth with increased acclimation temperature. Thus, rather than showing improved performance at the acclimation temperature, P. bursaria appeared to pay a price at all temperatures for acclimating to higher temperatures. The fits of our data to our model also suggest that changes in the structure and function of metabolic enzymes may underlie the changes in the TPCs. Specifically, our results suggest that both the delta heat capacity and delta enthalpy of formation of metabolic enzymes may have increased with acclimation. Since these two factors are correlated across acclimation temperatures, our data also suggest potential trade-offs that may constrain changes in TPCs.http://ift.tt/2te7Xrr
Social Aggression, Experience, and Brain Gene Expression in a Subsocial Bee
Abstract
The genetic mechanisms behind aggressive behaviors are important for understanding the formation of dominance hierarchies, and thus social systems in general. Studies into the effects of social experience and agonistic contest outcomes have shown significant changes in brain gene expression resulting from repeated winning and losing, as well as changing dominance rank, primarily in obligately social species. However, our knowledge of the genetic underpinnings of behavior in subsocial organisms is relatively poor, yet understanding the behavioral genetics of this simplest form of sociality provides the basis for understanding all other forms of social living. Here, we measured the effects of aggression on brain gene expression in the subsocial bee, Ceratina calcarata, in individuals that had experienced repeated winning, repeated losing, or a change in rank during repeated encounters. Consistent winning accounted for the majority of variation in brain gene expression, followed by changing rank over maintaining rank. Candidate genes for aggression are identified through comparative transcriptomics across 21 invertebrate and 6 vertebrate taxa. Lastly, we identified significantly over-represented cis-regulatory elements, namely transcription factor binding motifs deeply conserved across a wide range of taxa and broadly implicated in differential regulation of genes related to aggressive/dominant behavior. We present evidence for both genetic and cis-regulatory mechanisms for aggression that may have broad importance to social evolution.http://ift.tt/2sJqOXC
Bisdemethoxycurcumin sensitizes cisplatin-resistant lung cancer cells to chemotherapy by inhibition of CA916798 and PI3K/AKT signaling
Abstract
Curcumin, a dietary supplement or herbal medicine from Curcuma longa, has shown antitumor activity in different cancer cell lines and clinical trials. CA916798, a novel protein, is overexpressed in multidrug-resistant tumor cells. This study aimed to assess the effects of curcumin on regulating chemosensitivity in cisplatin-resistant non-small cell lung cancer (NSCLC) cells in vitro and to explore the underlying molecular mechanisms. Human cisplatin-sensitive A549 and cisplatin-resistant A549/CDDP lung adenocarcinoma cells were treated with curcumin to assess cell viability and gene modulations using quantitative reverse transcription–polymerase chain reaction (qRT-PCR) and western blotting. CA916798 shRNA and point mutations were used to assess the CA916798 functions and phosphorylation sites. Bisdemethoxycurcumin sensitized cisplatin-resistant lung cancer cells to various chemotherapeutic agents, including cisplatin. Bisdemethoxycurcumin reduced the levels of CA916798 mRNA and protein in A549 and A549/CDDP cells, while it also suppressed phosphatidylinositol-3-kinase (PI3K)/AKT signaling. CA916798, as a downstream gene, interacted with AKT after bisdemethoxycurcumin treatment in A549 and A549/CDDP cells. Moreover, A549/CDDP cells expressing the point-mutated CA916798-S20D protein were more resistant to cisplatin and bisdemethoxycurcumin, whereas tumor cells expressing CA916798-S20A, CA916798-S31A, CA916798-S60A, CA916798-S93A, or CA916798-T97A (different sites of amino acid phosphorylation) showed similar sensitivity or resistance to cisplatin and bisdemethoxycurcumin, compared with the control cells. Bisdemethoxycurcumin is able to sensitize cisplatin-resistant NSCLC cells to chemotherapeutic agents by inhibition of CA916798 and PI3K/AKT activities. Moreover, phosphorylation of CA916798 at the S20 residue plays a critical role in mediating bisdemethoxycurcumin antitumor activity.
http://ift.tt/2umHFBG
Electrophysiological evidence for a self-processing advantage during audiovisual speech integration
Abstract
Previous electrophysiological studies have provided strong evidence for early multisensory integrative mechanisms during audiovisual speech perception. From these studies, one unanswered issue is whether hearing our own voice and seeing our own articulatory gestures facilitate speech perception, possibly through a better processing and integration of sensory inputs with our own sensory-motor knowledge. The present EEG study examined the impact of self-knowledge during the perception of auditory (A), visual (V) and audiovisual (AV) speech stimuli that were previously recorded from the participant or from a speaker he/she had never met. Audiovisual interactions were estimated by comparing N1 and P2 auditory evoked potentials during the bimodal condition (AV) with the sum of those observed in the unimodal conditions (A + V). In line with previous EEG studies, our results revealed an amplitude decrease of P2 auditory evoked potentials in AV compared to A + V conditions. Crucially, a temporal facilitation of N1 responses was observed during the visual perception of self speech movements compared to those of another speaker. This facilitation was negatively correlated with the saliency of visual stimuli. These results provide evidence for a temporal facilitation of the integration of auditory and visual speech signals when the visual situation involves our own speech gestures.
http://ift.tt/2tG7DT1
Non-perforated peptic ulcer disease: multidetector CT findings, complications, and differential diagnosis
Abstract
Despite availability of effective therapies, peptic ulcer disease (PUD) remains a major global disease, resulting from a combination of persistent Helicobacter pylori infection and widespread use of nonsteroidal anti-inflammatory drugs. Albeit endoscopy definitely represents the mainstay diagnostic technique, patients presenting to emergency departments with unexplained abdominal pain generally undergo multidetector CT as an initial investigation. Although superficial ulcers generally remain inconspicuous, careful multiplanar CT interpretation may allow to detect deep ulcers, secondary mural and extraluminal signs of peptic gastroduodenitis, thereby allowing timely endoscopic verification and appropriate treatment. This pictorial essay aims to provide radiologists with an increased familiarity with CT diagnosis of non-perforated PUD, with emphasis on differential diagnosis. Following an overview of current disease epidemiology and complications, it explains the appropriate CT acquisition and interpretation techniques, and reviews with several examples the cross-sectional findings of uncomplicated PUD. Afterwards, the CT features of PUD complications such as ulcer haemorrhage, gastric outlet obstruction, biliary and pancreatic fistulisation are presented.
Teaching points
• Gastric and duodenal peptic ulcers are increasingly caused by nonsteroidal anti-inflammatory drugs
• Multiplanar CT interpretation allows detecting deep ulcers and secondary signs of gastroduodenitis
• CT diagnosis of uncomplicated peptic disease relies on direct and indirect signs
• Currently the commonest complication, haemorrhage may be treated with transarterial embolisation
• Other uncommon complications include gastric outlet obstruction and biliopancreatic fistulisation
http://ift.tt/2tmnaVF
Giant desmoplastic cutaneous squamous cell carcinoma of the gluteal region
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the most common type of skin tumour with the ability of metastatic spread. It represents about 20% of all malignancies diagnosed worldwide each year. Despite increased knowledge regarding the causes of skin cancer, the incidence of cSCC rises. The disease originates from epidermal keratinocytes, but it may occur on all areas of the body. It has an invasive nature and the potential to metastasise. We report unusual case of a giant metastatic desmoplastic cSCC of the gluteal region in a patient with previously resected desmoplastic cSCC presenting 8 months later with multiple liver and lung metastases.
http://ift.tt/2snfReS
Magnetic and Thermal-sensitive Poly(N-isopropylacrylamide)-based Microgels for Magnetically Triggered Controlled Release
http://ift.tt/2tdXfAV
Novel pyrrolocycloalkylpyrazole analogues as CB1 ligands
Abstract
Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide based compounds were designed and synthesized for cannabinoid CB1 and CB2 receptor interaction. Any of the new synthesized compounds showed high affinity for CB2 receptor with Ki values superior to 314 nM, whereas some of them showed moderate affinity for CB1 receptor with Ki values inferior to 400 nM. 7-Chloro-1-(2,4-dichlorophenyl)-N-(homopiperidin-1-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizine-3-carboxamide (2j) exhibited good affinity for CB1 receptor (KiCB1 = 81 nM) and the highest CB2/CB1 selectively ratio (>12). Docking studies carried out on such compounds were performed by using the hCB1 X-ray in complex with the close pyrazole analogue AM6538, and disclosed specific pattern of interactions related to the tricyclic pyrrolopyrazole scaffolds as CB1 ligands.
This article is protected by copyright. All rights reserved.
Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide based compounds were designed and synthesized for cannabinoid CB1 and CB2 receptor interaction. Among all derivatives, 7-chloro-1-(2,4-dichlorophenyl)-N-(homopiperidin-1-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizine-3-carboxamide (2j) exhibited a good affinity for CB1 receptor (KiCB1 = 81 nM) and the highest CB2/CB1 selectively ratio (>12). Docking studies carried out on such compounds were performed by using the hCB1 X-ray in complex with the close pyrazole analogue AM6538, and disclosed specific pattern of interactions related to the tricyclic pyrrolopyrazole scaffolds as CB1 ligands.
http://ift.tt/2tNARjg
Study protocol: multi-parametric magnetic resonance imaging for therapeutic response prediction in rectal cancer
Abstract
Background
Response to neoadjuvant chemoradiotherapy (CRT) of rectal cancer is variable. Accurate imaging for prediction and early assessment of response would enable appropriate stratification of management to reduce treatment morbidity and improve therapeutic outcomes. Use of either diffusion weighted imaging (DWI) or dynamic contrast enhanced (DCE) imaging alone currently lacks sufficient sensitivity and specificity for clinical use to guide individualized treatment in rectal cancer. Multi-parametric MRI and analysis combining DWI and DCE may have potential to improve the accuracy of therapeutic response prediction and assessment.
Methods
This protocol describes a prospective non-interventional single-arm clinical study. Patients with locally advanced rectal cancer undergoing preoperative CRT will prospectively undergo multi-parametric MRI pre-CRT, week 3 CRT, and post-CRT. The protocol consists of DWI using a read-out segmented sequence (RESOLVE), and DCE with pre-contrast T1-weighted (VIBE) scans for T1 calculation, followed by 60 phases at high temporal resolution (TWIST) after gadoversetamide injection. A 3-dimensional voxel-by-voxel technique will be used to produce colour-coded ADC and Ktrans histograms, and data evaluated in combination using scatter plots. MRI parameters will be correlated with surgical histopathology. Histopathology analysis will be standardized, with chemoradiotherapy response defined according to AJCC 7th Edition Tumour Regression Grade (TRG) criteria. Good response will be defined as TRG 0–1, and poor response will be defined as TRG 2–3.
Discussion
The combination of DWI and DCE can provide information on physiological tumour factors such as cellularity and perfusion that may affect radiotherapy response. If validated, multi-parametric MRI combining DWI and DCE can be used to stratify management in rectal cancer patients. Accurate imaging prediction of patients with a complete response to CRT would enable a 'watch and wait' approach, avoiding surgical morbidity in these patients. Consistent and reliable quantitation from standardised protocols is essential in order to establish optimal thresholds of ADC and Ktrans and permit the role of multi-parametric MRI for early treatment prediction to be properly evaluated.
Trial registration
Australian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12616001690448 (retrospectively registered 8/12/2016).
http://ift.tt/2umx7CA
Effects of an interactive mHealth innovation for early detection of patient-reported symptom distress with focus on participatory care: protocol for a study based on prospective, randomised, controlled trials in patients with prostate and breast cancer
Abstract
Background
Cancer patients are predominantly treated as out-patients and as they often experience difficult symptoms and side effects it is important to facilitate and improve patient-clinician communication to support symptom management and self-care. Although the number of projects within supportive cancer care evaluating mobile health is increasing, few evidence-based interventions are described in the literature and thus there is a need for good quality clinical studies with a randomised design and sufficient power to guide future implementations. An interactive information and communications technology platform, including a smartphone/computer tablet app for reporting symptoms during cancer treatment was created in collaboration with a company specialising in health care management. The aim of this paper is to evaluate the effects of using the platform for patients with breast cancer during neo adjuvant chemotherapy treatment and patients with locally advanced prostate cancer during curative radiotherapy treatment. The main hypothesis is that the use of the platform will improve clinical management, reduce costs, and promote safe and participatory care.
Method
The study is a prospective, randomised, controlled trial for each patient group and it is based on repeated measurements. Patients are consecutively included and randomised. The intervention groups report symptoms via the app daily, during treatment and up to three weeks after end of treatment, as a complement to standard care. Patients in the control groups receive standard care alone. Outcomes targeted are symptom burden, quality of life, health literacy (capacity to understand and communicate health needs and promote healthy behaviours), disease progress and health care costs. Data will be collected before and after treatment by questionnaires, registers, medical records and biomarkers. Lastly, participants will be interviewed about participatory and meaningful care.
Discussion
Results will generate knowledge to enhance understanding about how to develop person-centred care using mobile technology. Supporting patients' involvement in their care to identify problems early, promotes more timely initiation of necessary treatment. This can benefit patients treated outside the hospital setting in regard to maintaining their safety.
Clinical trial registration
June 12 2015 NCT02477137 (Prostate cancer) and June 12 2015 NCT02479607 (Breast cancer).
http://ift.tt/2umisaE
Acute administration of methionine and/or methionine sulfoxide impairs redox status and induces apoptosis in rat cerebral cortex
Abstract
High plasma levels of methionine (Met) and its metabolites such as methionine sulfoxide (MetO) may occur in several genetic abnormalities. Patients with hypermethioninemia can present neurological dysfunction; however, the neurotoxicity mechanisms induced by these amino acids remain unknown. The aim of the present work was to study the effects of Met and/or MetO on oxidative stress, genotoxicity, cytotoxicity and to evaluate whether the cell death mechanism is mediated by apoptosis in the cerebral cortex of young rats. Forty-eight Wistar rats were divided into groups: saline, Met 0.4 g/Kg, MetO 0.1 g/Kg and Met 0.4 g/Kg + MetO 0.1 g/Kg, and were euthanized 1 and 3 h after subcutaneous injection. Results showed that TBARS levels were enhanced by MetO and Met+MetO 1 h and 3 h after treatment. ROS was increased at 3 h by Met, MetO and Met+MetO. SOD activity was increased in the Met group, while CAT was reduced in all experimental groups 1 h and 3 h after treatment. GPx activity was enhanced 1 h after treatment by Met, MetO and Met+MetO, however it was reduced in the same experimental groups 3 h after administration of amino acids. Caspase-3, caspase-9 and DNA damage was increased and cell viability was reduced by Met, MetO and Met+MetO at 3 h. Also, Met, MetO and Met+MetO, after 3 h, enhanced early and late apoptosis cells. Mitochondrial electrochemical potential was decreased by MetO and Met+MetO 1 h and 3 h after treatment. These findings help understand the mechanisms involved in neurotoxicity induced by hypermethioninemia.
http://ift.tt/2tmQhs0
A Novel Method to Model Chronic Traumatic Encephalopathy in Drosophila
http://ift.tt/2tFRxZN
A Rat Tibial Growth Plate Injury Model to Characterize Repair Mechanisms and Evaluate Growth Plate Regeneration Strategies
http://ift.tt/2tFycaV
Calcium intake and risk of colorectal cancer according to expression status of calcium-sensing receptor (CASR)
Objective
Although evidence suggests an inverse association between calcium intake and the risk of colorectal cancer, the mechanisms remain unclear. The calcium-sensing receptor (CASR) is expressed abundantly in normal colonic epithelium and may influence carcinogenesis. We hypothesized that calcium intake might be associated with lower risk of CASR-positive, but not CASR-negative, colorectal cancer.
DesignWe assessed tumour CASR protein expression using immunohistochemistry in 779 incident colon and rectal cancer cases that developed among 136 249 individuals in the Nurses' Health Study and Health Professionals Follow-Up Study. Duplication method Cox proportional hazards regression analysis was used to assess associations of calcium intake with incidence of colorectal adenocarcinoma subtypes by CASR status.
ResultsTotal calcium intake was inversely associated with the risk of developing colorectal cancer (ptrend=0.01, comparing ≥1200 vs <600 mg/day: multivariable HR=0.75, 95% CI 0.60 to 0.95). For the same comparison, higher total calcium intake was associated with a lower risk of CASR-positive tumours (ptrend=0.003, multivariable HR=0.67, 95% CI 0.51 to 0.86) but not with CASR-negative tumours (ptrend=0.67, multivariable HR=1.15, 95% CI 0.75 to 1.78; pheterogeneity=0.06 between the CASR subtypes). The stronger inverse associations of calcium intake with CASR-positive but not CASR-negative tumours generally appeared consistent regardless of sex, tumour location and source of calcium.
ConclusionsOur molecular pathological epidemiology data suggest a causal relationship between higher calcium intake and lower colorectal cancer risk, and a potential role of CASR in mediating antineoplastic effect of calcium.
http://ift.tt/2uGEyUn
Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer
Abstract
Purpose
Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor that exhibits antitumor activity in renal cell carcinoma and mantle cell lymphoma. The metabolism of temsirolimus and its active metabolite sirolimus mainly depends on cytochrome P450 3A4/5 (CYP3A4/A5) and the ABCB1 transporter. Differently from sirolimus, no pharmacogenetic study on temsirolimus has been conducted. Therefore, the aim of this pilot study was to identify genetic determinants of the inter-individual variability in temsirolimus pharmacokinetics and toxicity.
Methods
Pharmacokinetic profiles were obtained for 16 patients with bladder cancer after intravenous infusion of 25 mg temsirolimus. Non-compartmental analysis was performed to calculate the pharmacokinetic parameters of temsirolimus and sirolimus, its main metabolite. The presence of single nucleotide polymorphisms (SNPs) in CYP3A5, ABCB1 and in their transcriptional regulator NR1I2 (PXR) was assessed by genotyping. Non-parametric statistical tests were used to assess associations between candidate SNPs and temsirolimus pharmacokinetics and toxicity.
Results
The ratio between sirolimus AUC and temsirolimus AUC was 1.6-fold higher in patients who experienced serious toxic events (p = 0.034). The frequency of adverse events was significantly higher in patients homozygous for the NR1I2-rs6785049 A allele (OR = 0.065, p = 0.04) or NR1I2-rs3814055 C allele (OR = 0.032, p = 0.006). These NR1I2 SNPs were also predictive of temsirolimus half-life and global exposure to temsirolimus and sirolimus. Finally, the effect of the ABCB1-rs1128503, ABCB1-rs2032582 and CYP3A5*3 SNPs on sirolimus pharmacokinetics was confirmed.
Conclusions
Our findings suggest that SNPs of NR1I2 and its target genes CYP3A5 and ABCB1 are genetic determinants of temsirolimus pharmacokinetics and toxicity in patients with bladder cancer.
http://ift.tt/2sCDLqY
Correlation between delivered radiation doses to the brainstem or vestibular organ and nausea & vomiting toxicity in patients with head and neck cancers – an observational clinical trial
Abstract
Objective
Today intensity modulated radiation therapy (IMRT) can be considered the standard of care in patients with head and neck tumors. IMRT treatment plans are proven to reduce acute treatment related side effects by optimal sparing of organs at risk (OAR). At the same time, areas that were out of the former 3D fields now receive low radiation doses. Amongst those areas the brainstem (BS) and the vestibular system (VS) are known to be physiologically connected to nausea and vomiting (NV). In our study we tried to find out, if doses to these areas are linked to NV.
Material & Methods
NV were assessed at different time points during treatment in 26 patients leading to 98 documented toxicity scores that were later correlated to dose deposition in the described areas. Patients were either treated with normo-fractionated or simultaneously integrated boost IMRT plans in a curative approach. Subareas of the BS as well as the VS were delineated. Toxicity was rated based on the common toxicity criteria (CTCAE Version 4.0). Other factors such as age, gender, chemotherapy, location of the tumor, irradiated volume and unilateral dose to the VS were taken into account and analyzed also.
Results
The majority (65.4%) of our patients experienced an episode of NV at least once during treatment. NV was more frequent when treating the oropharyngeal region compared to the hypopharyngeal region, as well as when patients were female and/ or of a younger age. Nevertheless, upon statistical analysis (ROC analysis, 'within/ between analysis') no significant association between delivered doses to subareas and toxicity could be demonstrated.
Conclusion
In our analysis, no significant correlation between radiation dose to the BS or the VS and the occurrence of NV could be found. Therefore, until conclusive data are available, we recommend to rely on the published data regarding OAR tolerance within the BS and not to compromise on dose coverage.
http://ift.tt/2sn48Nz
Retinal and visual cortex distance from transcranial magnetic stimulation of the vertex affects phosphene perception
Abstract
Recent studies claim that the perception of flashes of light (i.e., phosphenes) can be induced by stimulation of higher visual areas, including parietal cortex, suggesting a critical role of these regions in generating visual percepts. In this study, we show that transcranial magnetic stimulation (TMS) of even the vertex can induce phosphenes, but that their neural origins are likely to be a consequence of current spread into visual areas (e.g., retina or visual cortex). After vertex stimulation, subjects with smaller head circumferences—for whom the distances from the coil to retina and visual cortex are smaller—report a two-fold increase in perceiving phosphenes. In contrast, both smaller and larger headed individuals perceived phosphenes equivalently and on nearly all trials following TMS of early visual cortex. These results demonstrate a critical role of early visual areas but not higher ones in generating visual perceptions. These findings further suggest that phosphenes perceived from TMS of the vertex or parietal cortex arise from induced activity in the retina or nearby early visual cortex and warn against the use of the vertex as a control site for TMS experiments of visual perception.
http://ift.tt/2smTuX7
Genomic analyses provide insights into the microbiome of patients with early Parkinson's disease
Read the original article here: http://ift.tt/2tFtIRZ
Video summarizes research in Genome Medicine, 'Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson's disease patients', Bedarf and Hildebrand et al.
https://www.youtube.com/watch?v=CoSVurB-fxY
Cancers, Vol. 9, Pages 77: Epithelial-to-Pericyte Transition in Cancer
During epithelial-to-mesenchymal transition (EMT), cells lose epithelial characteristics and acquire mesenchymal properties. These two processes are genetically separable and governed by distinct transcriptional programs, rendering the EMT outputs highly heterogeneous. Our recent study shows that the mesenchymal products generated by EMT often express multiple pericyte markers, associate with and stabilize blood vessels to fuel tumor growth, thus phenotypically and functionally resembling pericytes. Therefore, some EMT events represent epithelial-to-pericyte transition (EPT). The serum response factor (SRF) plays key roles in both EMT and differentiation of pericytes, and may inherently confer the pericyte attributes on EMT cancer cells. By impacting their intratumoral location and cell surface receptor expression, EPT may enable cancer cells to receive and respond to angiocrine factors produced by the vascular niche, and develop therapy resistance.
http://ift.tt/2sC8Ye0
Morphological Analysis of Bronchial Arteries and Variants with Computed Tomography Angiography
The aim of our study was to determine the prevalence of anatomical variants of bronchial arteries using computed tomographic angiography in a population of northeastern Mexico. An observational, transversal, descriptive, comparative, retrospective study was performed using 139 imaging studies of Mexican patients in which we evaluated the following parameters from the left and right bronchial arteries: artery origin, branching pattern, arterial ostium, vertebral level of origin, diameter, and mediastinal trajectory. The anatomies of the bronchial arteries were similar in both genders, except distribution for vertebral origin level () and the diameter (). Left and right arteries were similar, except for the mediastinal trajectory in reference to the esophagus () as well as the arterial diameter () and lumen diameter.
http://ift.tt/2tIkmo9
Erratum
Moskowitz MA. Holes in the leaky migraine blood–brain barrier hypothesis? Brain 2017; 140: 1537-1539; 10.1093/brain/awx099.
http://ift.tt/2sIDz4X
http://ift.tt/2sIDz4X
Podophyllotoxin Extracted from Juniperus sabina Fruit Inhibits Rat Sperm Maturation and Fertility by Promoting Epididymal Epithelial Cell Apoptosis
This study aimed to investigate the antifertility effect of Juniperus sabina fruit on male rats and its possible mechanism, and hence it might be developed as a potential nonhormonal male contraceptive. Male rats were intragastrically fed for consecutive 8-week and 4-week recovery with the fruit of J. Sabina, and sperm maturation, serum testosterone level, and histopathology were analyzed. Epididymal epithelial cell culture was prepared for detection of podophyllotoxin activities. Furthermore, cell proliferation, transmission electron microscopy, Annexin V/Propidium iodide, TUNEL, RT-PCR, ELISA, and western blotting were examined. The results showed that rat sperm motility and fertility were remarkably declined after feeding the fruit. Moreover, the fruit targeted the epididymis rather than the testis. After 4-week recovery, more than half of the male rats resumed normal fertility. It was found that podophyllotoxin significantly inhibited epididymal epithelial cell proliferation, promoted cell apoptosis, and increased the mRNA and protein levels of TNF-α and the expression levels of cytochrome c, caspase-8, caspase-9, and caspase-3. Our findings suggest that the fruit of J. sabina could inhibit male rat sperm maturation and fertility. The potential mechanism might be related to podophyllotoxin, inducing epididymal epithelial cell apoptosis through TNF-α and caspase signaling pathway.
http://ift.tt/2sIllAc
Ethnobotany of Indigenous Saraguros: Medicinal Plants Used by Community Healers “Hampiyachakkuna” in the San Lucas Parish, Southern Ecuador
This paper reports the results of an ethnobotanical survey on the use of medicinal plants by community healers "Hampiyachakkuna" in the San Lucas Parish, province of Loja, Ecuador. A particular ethnic group, the indigenous Saraguros, inhabits this region. This study reports 183 plant species used in 75 different curative therapies by the Saraguro healers.
http://ift.tt/2sIjfAC
The Oxidative Stress Response in Elite Water Polo Players: Effects of Genetic Background
Acute exercise is known to induce oxidative stress. Here we assessed the effects of gene polymorphisms SOD2 A16V, CAT −844 G>A, and GPx-1 rs1800668 C>T on oxidative stress markers in 28 elite water polo male players prior to and after a routinely programmed friendly match. The mean plasma concentrations of derivatives of reactive oxygen metabolites (dROMs), as well as lactic dehydrogenase (LDH) activity, creatine kinase (CK) activity, CK-MB, and myoglobin, were significantly increased after exercise, while blood antioxidant potential (BAP) and total free thiols were significantly decreased, compared with those measured before exercise. Advanced oxidation protein products (AOPP) were also increased after exercise but not significantly. We observed that water polo players having either AV16 or VV16 SOD genotype exhibited a significant increase of postexercise AOPP, LDH, CK, and myoglobin plasma levels in comparison with wild-type athletes. Water polo players having either CAT −844 GA or GPx1 CT genotype showed a significant increase of postexercise dROMs plasma levels and, respectively, GPx and CAT enzyme activities in comparison with wild-type subjects. These preliminary results suggest that the screening for gene variants of antioxidant enzymes could be useful to assess individual susceptibility to oxidative stress and muscle damage in water polo players.
http://ift.tt/2tcUkss
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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