Per- and Poly-fluoroalkyl substances (PFAS) are major persistent environmental contaminants. Epidemiological studies have linked PFAS exposures to altered immunity and increased occurrence of ...infections in children. However, the mechanisms leading to immune susceptibility to bacterial infections remains unclear. To elucidate the mechanism, transcriptional alteration in the Caenorhabditis elegans model caused by a PFAS contaminated environmental water and two reconstituted PFAS solutions were evaluated using RNA-sequencing. PFAS affected the expression of several genes involved in C. elegans immune surveillance to Gram-positive bacteria (cpr-2, tag-38, spp-1, spp-5, clec-7, clec-172). The combined exposure to PFAS and Staphylococcus aureus significantly reduced C. elegans survival and increased intestinal membrane permeability. Furthermore, the growth of S. aureus in the presence of PFAS increased the expression of virulence genes, specifically, the virulence gene regulator saeR and α-hemolysin, hla, which resulted in increased hemolytic activity. The present study demonstrated that PFAS exposure not only increased C. elegans susceptibility to pathogens by reducing host immunity and increasing intestinal membrane permeability, but also increased bacteria virulence. This presents a broader implication for humans and other animals, where environmental contaminants simultaneously reduce host resilience, while, increasing microbial pathogenicity.
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•PFAS affected C. elegans innate immune response gene expression.•PFAS reduced C. elegans immune surveillance to Gram-positive bacteria.•PFAS increased expression of hemolysin A and virulence gene regulator in S. aureus.•PFAS increased S. aureus mediated intestinal permeability and death in C. elegans.•PFAS exposed C. elegans were more susceptible to infection with S. aureus.
•RE (root extract) and LE (leaf extract) of Sida cordifolia promotes osteoblastogenesis without any change in osteoclast differentiation.•RE and LE up-regulates the osteogenic genes expression by ...activating ERK/MAPK and AKT signaling pathway.•RE and LE restores the biomechanical strength of femur and improves both trabecular and cortical bone microarchitecture in mice after oral administration for 8 weeks.•RE and LE exerts osteo-protective effect in ovariectomized mice by enhancing osteoblast activity and inhibiting osteoclast activity.•Sida cordifolia extract could be a potential agent to have preventive and therapeutic effects on post-menopausal osteoporosis.
Sida cordifolia is traditionally found in the Indian system of medicine, well known for its medicinal and nutritional properties among local natives.
The present study aims to investigate the osteo-protective effect of root and leaf ethanolic extract of S. cordifolia (RE and LE) and its underlying mechanism.
Antioxidant activity of RE and LE was assessed. Total phenolic and flavonoid content were determined. HPLC profiling of RE and LE was performed to examine the polyphenol content. The effect of RE and LE on osteoblast cells proliferation, differentiation, mineralization, and expression of the protein associated with osteogenesis were evaluated using primary calvarial osteoblast culture. Skeletal effects of RE and LE of S. cordifolia were investigated in C57BL/6J ovariectomized mice. Micro CT was employed to evaluate the alteration in trabecular and cortical bone microarchitecture. Histology studies were performed on the isolated vertebra. qPCR analysis and western blotting was done to check the key bone markers.
RE and LE showed a potent antioxidant activity, owing to a notable polyphenol content. Both RE and LE did not alter the cell viability but significantly increased the osteoblast cell proliferation, differentiation, and mineralization. Moreover, they enhanced the mRNA expression of osteogenic genes. Both RE and LE stimulated the activation of ERK, AKT, and CREB. Both RE and LE had no direct effect on osteoclastogenesis, but both increased Opg/Rankl ratio expression in osteoblast cells. Both RE and LE at 750 mg/kg/day significantly improved the trabecular and cortical microarchitecture of femur and tibia by increasing bone mineral density, bone volume fraction, trabecular number, and trabecular thickness, and decreasing trabecular separation and structural model index in ovariectomized mice. Furthermore, vertebral histology of lumbar vertebrae revealed that RE and LE significantly enhance the vertebral bone mass and exert osteo-protective effects by stimulating osteoblast function and inhibiting osteoclast function.
In conclusion, both RE and LE stimulate osteoblast differentiation through activating ERK, AKT, and CREB signalling pathways and indirectly inhibits osteoclast differentiation. RE and LE also improve the trabecular and cortical microarchitecture of ovariectomized mice, making it a promising agent to prevent postmenopausal bone loss.
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To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as ...predictive markers.
The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance.
Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in pre-analytic variables, thresholds for positivity, and interpretation criteria.
The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.
Purpose To update the Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline published on May 31, 2016. The October 2016 update focuses solely on new ...evidence that pertains to clinical question 4 of the guideline: What is the appropriate adjuvant regimen for patients with pancreatic cancer who have undergone an R0 or R1 resection of their primary tumor? Methods The recently published results of a randomized phase III study prompted an update of this guideline. The high quality of the reported evidence and the potential for its clinical impact prompted the Expert Panel to revise one of the guideline recommendations. Results The ESPAC-4 study, a multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy compared gemcitabine and capecitabine with gemcitabine monotherapy in 730 evaluable patients with resected pancreatic ductal adenocarcinoma. Median overall survival was improved in the doublet arm to 28.0 months (95% CI, 23.5 to 31.5 months) versus 25.5 months (95% CI, 22.7 to 27.9 months) for gemcitabine alone (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = .032). Grade 3 and 4 adverse events were similar in both arms, although higher rates of hand-foot syndrome and diarrhea occurred in patients randomly assigned to the doublet arm. Recommendations All patients with resected pancreatic cancer who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy in the absence of medical or surgical contraindications. The doublet regimen of gemcitabine and capecitabine is preferred in the absence of concerns for toxicity or tolerance; alternatively, monotherapy with gemcitabine or fluorouracil plus folinic acid can be offered. Adjuvant treatment should be initiated within 8 weeks of surgical resection, assuming complete recovery. The remaining recommendations from the original 2016 ASCO guideline are unchanged.
Salinity is one of the most important environmental constraints limiting agricultural productivity. Considering the importance of the accumulation of osmolytes, myo-inositol in particular, in ...halophytic plant's adaptive response to salinity, an effort was made to overexpress the SaINO1 gene from the grass halophyte Spartina alterniflora encoding myo-inositol 1-phosphate synthase (MIPS) in Arabidopsis thaliana. We demonstrated that SaINO1 is a stress-responsive gene and its constitutive over expression in Arabidopsis provides significantly improved tolerance to salt stress during germination and seedling growth and development. The transgenics retained more chlorophyll and carotenoid by protecting the photosystem II. The low level of stress-induced cellular damage in the transgenics was clearly evident by lower accumulation of proline in comparison to WT. Our results indicated that possible overaccumulation of MIPS enzyme in the cytosol protected the transgenic Arabidopsis plants overexpressing SaINO1 from the toxic effect of Na+ under salt stress by reducing cellular damage and chlorophyll loss.
► Arabidopsis plants overexpressing SaINO1 showed enhanced tolerance to salt stress. ► SaINO1-Arabidopsis transgenics germinated and grew better than WT under 150 mM NaCl. ► SaINO1-Arabidopsis plants accumulated less proline than WT under salt stress. ► SaINO1-Arabidopsis plants protected their photosystem II from stress-induced damage. ► The transgenics had higher chlorophyll and carotenoid than WT under salt stress.
To review the evidence about the efficacy and utility of radiofrequency ablation (RFA) for hepatic metastases from colorectal cancer (CRHM).
The American Society of Clinical Oncology (ASCO) convened ...a panel to conduct and analyze a comprehensive systematic review of the RFA literature from Medline and the Cochrane Collaboration Library.
Because data were considered insufficient to form the basis of a practice guideline, ASCO has instead published a clinical evidence review. The evidence is from single-arm, retrospective, and prospective trials. No randomized controlled trials have been included. The following three clinical issues were considered by the panel: the efficacy of surgical hepatic resection versus RFA for resectable tumors; the utility of RFA for unresectable tumors; and RFA approaches (open, laparoscopic, or percutaneous). Evidence suggests that hepatic resection improves overall survival (OS), particularly for patients with resectable tumors without extrahepatic disease. Careful patient and tumor selection is discussed at length in the literature. RFA investigators report a wide variability in the 5-year survival rate (14% to 55%) and local tumor recurrence rate (3.6% to 60%). The reported mortality rate was low (0% to 2%), and the major complications rate was commonly reported to be between 6% and 9%. RFA is currently performed with all three approaches.
There is a compelling need for more research to determine the efficacy and utility of RFA to increase local recurrence-free, progression-free, and disease-free survival as well as OS for patients with CRHM. Clinical trials have established that hepatic resection can improve OS for patients with resectable CRHM.
In this paper, a control strategy for power flow management of a grid-connected hybrid photovoltaic (PV)-wind-battery-based system with an efficient multi-input transformer-coupled bidirectional ...dc-dc converter is presented. The proposed system aims to satisfy the load demand, manage the power flow from different sources, inject the surplus power into the grid, and charge the battery from the grid as and when required. A transformer-coupled boost half-bridge converter is used to harness power from wind, while a bidirectional buck-boost converter is used to harness power from PV along with battery charging/discharging control. A single-phase full-bridge bidirectional converter is used for feeding ac loads and interaction with the grid. The proposed converter architecture has reduced number of power conversion stages with less component count and reduced losses compared with existing grid-connected hybrid systems. This improves the efficiency and the reliability of the system. Simulation results obtained using MATLAB/Simulink show the performance of the proposed control strategy for power flow management under various modes of operation. The effectiveness of the topology and the efficacy of the proposed control strategy are validated through detailed experimental studies to demonstrate the capability of the system operation in different modes.
To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as ...predictive markers.
The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance.
Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in preanalytic variables, thresholds for positivity, and interpretation criteria.
The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.
To update the American Society of Clinical Oncology (ASCO) Technology Assessment guidelines on chemotherapy sensitivity and resistance assays (CSRAs) published in 2004.
An Update Working Group ...reviewed data published between December 1, 2003, and May 31, 2010. MEDLINE and the Cochrane Library were searched. The literature search yielded 11,313 new articles. The limits for "human and English" were used, and then standard ASCO search strings for randomized controlled trials, meta-analyses, guidelines, and reviews were added, yielding 1,298 articles for abstract review. Of these, only 21 articles met predefined inclusion criteria and underwent full text review, and five reports of randomized controlled trials were included for data extraction.
Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice.
The use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations based on published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.
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