Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations ...have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.
Objective: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to guide the use of diagnostic tests for this condition in clinical practice.
...Participants: Interested professional societies selected a representative for the consensus committee and provided funding for a one-day meeting. A subgroup of this committee set the program and developed key questions for review. Consensus was established at a closed meeting that followed. The conclusions were then circulated to the participating professional societies.
Evidence: Each question was addressed by a relevant literature search (on PubMed), and the data were presented for discussion at the group meeting.
Consensus Process: Consensus was achieved by a group meeting. Statements were prepared by all authors, with comments relating to accuracy from the diagnosis subgroup and by representatives from the participating professional societies.
Conclusions: We conclude that: 1) reference ranges should be established for serum PTH in vitamin D-replete healthy individuals; 2) second- and third-generation PTH assays are both helpful in the diagnosis of PHPT; 3) DNA sequence testing can be useful in familial hyperparathyroidism or hypercalcemia; 4) normocalcemic PHPT is a variant of the more common presentation of PHPT with hypercalcemia; 5) serum 25-hydroxyvitamin D levels should be measured and, if vitamin D insufficiency is present, it should be treated as part of any management course; and 6) the estimated glomerular filtration rate should be used to determine the level of kidney function in PHPT: an estimated glomerular filtration rate of less than 60 ml/min · 1.73 m2 should be a benchmark for decisions about surgery in established asymptomatic PHPT.
Responses to key questions about the diagnosis of asymptomatic primary hyperparathyroidism are provided based on the Third International Workshop on primary hyperparathyroidism.
A study was conducted to analyse the association of osmotic adjustment (OA) with drought tolerance and yield in castor (
Ricinus communis L.). Hybrids (GCH4, DCH32 and DCH177) and their respective ...parents (VP-1, 48-1, LRES17, DCS5, DPC9 and DCS9) were assessed for their osmotic adjustment, leaf water relations, accumulation of compatible solutes in relation to seed yield in response to moisture stress at primary spike development stage. OA increased with increasing stress period up to 33 days and the increase was more rapid in the high OA (HOA) genotypes. HOA genotypes also had higher leaf RWC and ELWRC and maintained higher leaf water potentials (
Ψ
l) compared to LOA genotypes under water deficit. Genotypes with HOA accumulated greater levels of proline, total soluble sugars (TSS), total free amino acids (FAA) and potassium than those with LOA in response to water deficit. Contribution of TSS was the maximum (61%), compared to FAA (17%), proline (12%) and potassium (2.8%) to the
Ψ
s at 33 days after imposing water deficit indicating that sugars were the major contributors towards OA in castor leaves. A positive relationship existed between OA of expanded leaf 33 days after imposing stress (
r
=
0.8539) and total seed yield under water-limited conditions in various castor genotypes tested and HOA genotypes had higher total seed yield than genotypes with LOA. Genotype variability exists for OA and it is a heritable trait in castor. Hybrids followed their superior parents in terms of OA. HOA genotypes of castor produced significantly higher seed yield than LOA genotypes. Accumulation of TSS contributed largely to the OA in castor.
Trismus refers to restriction in the ability to open the mouth. Comprehensive evaluation of trismus and its treatment outcomes needs a multidimensional, self-administered, trismus specific tool. In ...the present scenario, Gothenburg trismus questionnaire is the only reliable instrument to quantify trismus. Translation of this questionnaire helps in providing standardized documentation of trismus related problems and to obtain a patient's perspective on treatment outcomes within various populations. The aim of this study was to translate the Gothenburg trismus questionnaire-2 (GTQ 2) into Telugu (one of the Indian Languages) and validation of the translation for its effective use in regional Telugu speaking patients. The GTQ 2 was translated according to the guidelines framed by the International Society for Pharmacoeconomics and Outcomes Research: (1) forward translation, (2) reconciliation and back translation, (3) cognitive debriefing, and (4) pilot testing. The psychometric properties of the translated version were evaluated by testing its internal consistency, construct validity, known-group validity and floor and ceiling effects. Patients who reported with or without trismus to the Head and Neck Oncology outpatient clinic were enrolled for the study. Comparison of the GTQ scores was done using Mann–Whitney U-test. The Pearson correlation coefficient was used for assessing convergent and divergent validity. Internal Consistency was calculated using Cronbach’s alpha coefficient. The translated version of the GTQ 2 was administered to 60 patients (30 trismus patients and 30 non-trismus patients). GTQ 2 was successfully translated without any significant issues. Construct validity of the translated version was confirmed and it has a good internal consistency (α > 0.7). The translated instrument can differentiate between those with and without trismus (p < 0.0005). A valid and reliable Telugu version of the Gothenburg Trismus Questionnaire-2 is now available for the benefit of Indian patients.
Aims/hypothesis
This study reports the results of the first phase of a national study to determine the prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose ...tolerance) in India.
Methods
A total of 363 primary sampling units (188 urban, 175 rural), in three states (Tamilnadu, Maharashtra and Jharkhand) and one union territory (Chandigarh) of India were sampled using a stratified multistage sampling design to survey individuals aged ≥20 years. The prevalence rates of diabetes and prediabetes were assessed by measurement of fasting and 2 h post glucose load capillary blood glucose.
Results
Of the 16,607 individuals selected for the study, 14,277 (86%) participated, of whom 13,055 gave blood samples. The weighted prevalence of diabetes (both known and newly diagnosed) was 10.4% in Tamilnadu, 8.4% in Maharashtra, 5.3% in Jharkhand, and 13.6% in Chandigarh. The prevalences of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were 8.3%, 12.8%, 8.1% and 14.6% respectively. Multiple logistic regression analysis showed that age, male sex, family history of diabetes, urban residence, abdominal obesity, generalised obesity, hypertension and income status were significantly associated with diabetes. Significant risk factors for prediabetes were age, family history of diabetes, abdominal obesity, hypertension and income status.
Conclusions/interpretations
We estimate that, in 2011, Maharashtra will have 6 million individuals with diabetes and 9.2 million with prediabetes, Tamilnadu will have 4.8 million with diabetes and 3.9 million with prediabetes, Jharkhand will have 0.96 million with diabetes and 1.5 million with prediabetes, and Chandigarh will have 0.12 million with diabetes and 0.13 million with prediabetes. Projections for the whole of India would be 62.4 million people with diabetes and 77.2 million people with prediabetes.
Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the ...accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of “dedifferentiated” vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsoninsensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don’t eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.
Alzheimer's disease (AD) has been genetically and pathologically associated with neuroinflammation. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor involved in ...innate immunity. TREM2 rare protein coding genetic variants have been linked to AD. A soluble TREM2 (sTREM2) cleavage product is elevated in AD. It is unclear whether there is a relationship between elevated sTREM2 and markers of inflammation. The hypothesis of this investigation was that central and peripheral inflammation play a role in sTREM2 levels in AD. A consistent association of peripheral or central markers of inflammation and CSF sTREM2 levels was not found, suggesting a limited impact of general inflammation on sTREM2 levels. An association between peripheral sTREM2 levels and CSF sTREM2, as well as an association between CSF sTREM2 and a marker of blood brain barrier integrity, was observed in AD, suggesting a potential role of peripheral TREM2 in central TREM2 biology.
A correlation between CSF sTREM2 and blood brain barrier integrity was observed. Furthermore, CSF sTREM2 correlated with plasma sTREM2 in AD. Taken together, these results implicate a potential role of peripheral TREM2 in central TREM2 biology in AD. Display omitted
•We confirmed previous findings of elevated CSF sTREM2 in Mild Cognitive Impairment and Alzheimers disease.•CSF sTREM2 levels had only a few significant correlations with markers of central or peripheral inflammation.•There were significantly positive correlations between CSF sTREM2 and plasma sTREM2 as well as between CSF sTREM2 and a marker for blood brain barrier integrity.•These results suggest that peripheral TREM2 may play a role in central TREM2 biology that is unrelated to general inflammation in the periphery.
Profit maximization is critical in the control of power system networks for both power providers and users. Electrical energy is freely accessible in the electrical grid during off-peak hours, with ...storage units helping to store excess energy and assist the electrical grid during high-demand situations. Such techniques promote grid stability and ensure safe operation. Because renewable resources are intermittent, energy storage technologies are especially significant in renewable-associated power systems. Vehicle-to-grid (V2G) technology has recently acquired popularity in preserving power grid stability in the presence of renewable resources.V2G technology employs automobiles as mobile storage devices and focuses on the efficient utilization of extra power available during off-peak hours. The goal of this work is to improve the functioning of a V2G system in a power network to reduce energy production costs while increasing system profitability. This study for deregulated power environments also depicts the influence of V2G mixing on system voltage profile and locational marginal pricing (LMP), as well as the performance of the Unified Power Flow Controller (UPFC) on system economics. The MiPower simulation program is used in the study to find the best placement of the power storage unit for the modified IEEE 14-bus system.
The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome ...13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17∼92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P=0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17∼92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17∼92 cluster. Overexpression of miR-17∼92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17∼92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17∼92 cluster may therefore provide a novel therapeutic approach for patients with MCL.
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