Synthesis, Characterization and Antimicrobial Studies of Some Novel 1,3,4-Thiadiazolium-2-thiolate Derivatives

In this study, ten new 5-substituted-3-[4,6-di(morpholine-4-yl)-1,3,5-triazine 2-yl]-1,3,5-thiadiazolium-2-thiolate 6(a–j) were prepared via a five step procedure from the starting material 1,3,5-triazine (1). Structures of all synthesized compounds were confirmed by spectral data and elemental analyses. Newly synthesized compounds were tested for their antibacterial and antifungal activities against some important bacterial and fungal species. Some of the compounds were found to be moderately active against the tested organisms.Keywords: Thiadiazol, s-triazine, Mesoionic, NMR spectroscopy, IR spectroscop

Novel concepts for risk stratification in prostate cancer

Since Partin introduced the analysis of prostate-specific antigen, clinical T-stage and Gleason scores to estimate the risk of progression in men with localised prostate cancer, our understanding of factors that modify this risk has changed drastically. There are now multiple risk stratification tools available, including look-up tables, risk stratification/classification analyses, regression-tree analyses, nomograms and artificial neural networks. Concurrently, descriptions of novel biopsy strategies, imaging modalities and biomarkers are frequently published with the aim of improving risk stratification. With an abundance of new information available, incorporating advances into clinical practice can be confusing. This article aims to outline the major novel concepts in prostate cancer risk stratification for men with biopsy confirmed prostate cancer. We will detail which of these novel techniques and tools are likely to be adopted to aid treatment decisions and enable more accurate post-diagnosis, pretreatment risk stratification

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

BACKGROUND: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent. METHODS: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. RESULTS: Data for 237 patients (85 placebo; 152 sunitinib (n=66.50 mg \u274-weeks on/2-weeks off\u27 schedule; n=86 \u2737.5 mg continuous daily dosing (CDD)\u27)) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6-12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P CONCLUSIONS: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design

Alveolar macrophages support interferon gamma-mediated viral clearance in RSVinfected neonatal mice

Background: Poor interferon gamma (IFNγ) production during respiratory syncytial virus (RSV) is associated with prolonged viral clearance and increased disease severity in neonatal mice and humans. We previously showed that intra-nasal delivery of IFNγ significantly enhances RSV clearance from neonatal lungs prior to observed T-lymphocyte recruitment or activation, suggesting an innate immune mechanism of viral clearance. We further showed that alveolar macrophages dominate the RSV-infected neonatal airways relative to adults, consistent with human neonatal autopsy data. Therefore, the goal of this work was to determine the role of neonatal alveolar macrophages in IFNγ-mediated RSV clearance. Methods: Clodronate liposomes, flow cytometry, viral plaque assays, and histology were used to examine the role of alveolar macrophages (AMs) and the effects of intra-nasal IFNγ in RSV infected neonatal Balb/c mice. The functional outcomes of AM depletion were determined quantitatively by viral titers using plaque assay. Illness was assessed by measuring reduced weight gain. Results: AM activation during RSV infection was age-dependent and correlated tightly with IFNγ exposure. Higher doses of IFNγ more efficiently stimulated AM activation and expedited RSV clearance without significantly affecting weight gain. The presence of AMs were independently associated with improved RSV clearance, whereas AM depletion but not IFNγ exposure, significantly impaired weight gain in RSV-infected neonates. Conclusion: We show here for the first time, that IFNγ is critical for neonatal RSV clearance and that it depends, in part, on alveolar macrophages (AMs) for efficient viral clearing effects. Early reductions in viral burden are likely to have profound short- and long-term immune effects in the vulnerable post-natally developing lung environment. Studies are ongoing to elucidate the pathologic effects associated with early versus delayed RSV clearance in developing neonatal airways

Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246

TP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific mutp53 proteins gain oncogenic functions (GOFs) distinct from the tumor suppressor activity of the wild-type protein. Tumor-associated macrophages (TAMs), a hallmark of solid tumors, are typically correlated with poor prognosis. Here, we report a non-cell-autonomous mechanism, whereby human mutp53 cancer cells reprogram macrophages to a tumor supportive and anti-inflammatory state. The colon cancer cells harboring GOF mutp53 selectively shed miR-1246-enriched exosomes. Uptake of these exosomes by neighboring macrophages triggers their miR-1246-dependent reprogramming into a cancerpromoting state. Mutp53-reprogammed TAMs favor anti-inflammatory immunosuppression with increased activity of TGF-β. These findings, associated with poor survival in colon cancer patients, strongly support a microenvironmental GOF role for mutp53 in actively engaging the immune system to promote cancer progression and metastasis

Simulation method for investigating the use of transition-edge sensors as spectroscopic electron detectors

Transition-edge sensors (TESs) are capable of highly accurate single particle energy measurement. TESs have been used for a wide range of photon detection applications, particularly in astronomy, but very little consideration has been given to their capabilities as electron calorimeters. Existing electron spectrometers require electron filtering optics to achieve energy discrimination, but this step discards the vast majority of electrons entering the instrument. TESs require no such energy filtering, meaning they could provide orders of magnitude improvement in measurement rate. To investigate the capabilities of TESs in electron spectroscopy, a simulation pipeline has been devised. The pipeline allows the results of a simulated experiment to be compared with the actual spectrum of the incident beam, thereby allowing measurement accuracy and efficiency to be studied. Using Fisher information, the energy resolution of the simulated detectors was also calculated, allowing the intrinsic limitations of the detector to be separated from the specific data analysis method used. The simulation platform has been used to compare the performance of TESs with existing X-ray photoelectron spectroscopy (XPS) analysers. TESs cannot match the energy resolution of XPS analysers for high-precision measurements but have comparable or better resolutions for high count rate applications. The measurement rate of a typical XPS analyser can be matched by an array of 10 TESs with 120 microsecond response times and there is significant scope for improvement, without compromising energy resolution, by increasing array size

Disruption of the Key Ca2+ Binding Site in the Selectivity Filter of Neuronal Voltage-Gated Calcium Channels Inhibits Channel Trafficking

Voltage-gated calcium channels are exquisitely Ca2+ selective, conferred primarily by four conserved pore-loop glutamate residues contributing to the selectivity filter. There has been little previous work directly measuring whether the trafficking of calcium channels requires their ability to bind Ca2+ in the selectivity filter or to conduct Ca2+. Here, we examine trafficking of neuronal CaV2.1 and 2.2 channels with mutations in their selectivity filter and find reduced trafficking to the cell surface in cell lines. Furthermore, in hippocampal neurons, there is reduced trafficking to the somatic plasma membrane, into neurites, and to presynaptic terminals. However, the CaV2.2 selectivity filter mutants are still influenced by auxiliary α2δ subunits and, albeit to a reduced extent, by β subunits, indicating the channels are not grossly misfolded. Our results indicate that Ca2+ binding in the pore of CaV2 channels may promote their correct trafficking, in combination with auxiliary subunits. Furthermore, physiological studies utilizing selectivity filter mutant CaV channels should be interpreted with caution

Park availability and major depression in individuals with chronic conditions: Is there an association in urban India?

Green space exposure has been positively correlated with better mental-health indicators in several high income countries, but has not been examined in low- and middle-income countries undergoing rapid urbanization. Building on a study of mental health in adults with a pre-existing chronic condition, we examined the association between park availability and major depression among 1208 adults surveyed in Delhi, India. Major depression was measured using the Mini International Neuropsychiatric Interview. The ArcGIS platform was used to quantify park availability indexed as (i) park distance from households, (ii) area of the nearest park; and within one km buffer area around households - the (iii) number and (iv) total area of all parks. Mixed-effects logistic regression models adjusted for socio-demographic characteristics indicated that relative to residents exposed to the largest nearest park areas (tertile 3), the odds [95% confidence interval] of major depression was 3.1 [1.4-7.0] times higher among residents exposed to the smallest nearest park areas (tertile 1) and 2.1 [0.9-4.8] times higher in residents with mid-level exposure (tertile 2). There was no statistically significant association between other park variables tested and major depression. We hypothesized that physical activity in the form of walking, perceived stress levels and satisfaction with the neighborhood environment may have mediating effects on the association between nearest park area and major depression. We found no significant mediation effects for any of our hypothesized variables. In conclusion, our results provide preliminary and novel evidence from India that availability of large parks in the immediate neighborhood positively impacts mental well-being of individuals with pre-existing chronic conditions, at the opportune time when India is embarking on the development of sustainable cities that aim to promote health through smart urban design - one of the key elements of which is the inclusion of urban green spaces