α-Cleavage of 2,2-Diazido-2,3-dihydroinden-1-one in Solution and Cryogenic Matrices.

The Norrish type I (α-cleavage) reaction is an excellent photochemical method for radical-pair formation in solution. However, in cryogenic matrices, the starting material typically re-forms before the radical pair diffuses apart. This study focused on N2 extrusion from an azido alkyl radical to prevent radical-pair recombination. Irradiation of 2,2-diazido-2,3-dihydroinden-1-one (1) in methanol mainly yielded methyl 2-cyanomethylbenzoate (2) and 2-cyanomethylbenzoic acid (3) via α-cleavage. Laser flash photolysis of 1 in argon-saturated acetonitrile resulted in α-cleavage to form triplet biradical 31Br1 (λmax ∼ 410 nm, τ ∼ 400 ns). In contrast, upon irradiation in glassy 2-methyltetrahydrofuran matrices, triplet alkylnitrene 31N was directly detected using electron spin resonance (D/hc = 1.5646 cm-1, E/hc = 0.00161 cm-1) and absorption spectroscopy (λmax = 276 and 341 nm). Irradiation of 1 in argon matrices generated 31N, benzoyl azide 4, singlet benzoylnitrene 14N, and isocyanide 5, as revealed by IR spectroscopy. The experimental results supported by density functional theory calculations [B3PW91/6-311++G(d,p)] suggest that irradiation of 1 in matrices results in α-cleavage to form biradical 31Br1, which extrudes N2 to yield 31Br2. Rearrangement of 31Br2 into 31N competes with cleavage of a N3 radical to form radical 1Ra3. The N3/1Ra3 radical pair combines to form 4, which upon irradiation yields 14N and 5.

Spinal Solitary Plasmacytoma With Minimal Marrow Involvement Presenting With Epidural Spinal Cord Compression.

Solitary plasmacytoma (SPC) is a rare type of plasma cell dyscrasia characterized by the proliferation of neoplastic monoclonal plasma cells. It can involve bone or soft tissue without signs of systemic disease. The solitary bone plasmacytoma typically involves the axial skeleton, most commonly the vertebrae. This article presents a 58-year-old male with a history of Parkinson's disease, hypertension, and cervical spine degenerative joint disease. He arrived at the emergency department with severe thoracic and lumbar back pain, accompanied by numbness and weakness in both legs, which worsened with movement and deep breathing. Magnetic resonance imaging (MRI) findings revealed a sizable mass in the T11 vertebra, leading to thoracic spinal cord compression. Treatment included high-dose dexamethasone, and surgical intervention was undertaken. Subsequent pathology confirmed plasma cell dyscrasia. Radiotherapy and chemotherapy (lenalidomide and dexamethasone) were administered, resulting in no recurrence or new masses after two years. Solitary plasmacytoma is a rare disease with limited clinical trials due to the inability to accrue larger cohorts. Prompt diagnosis and staging of plasmacytomas, involving robust histopathological and radiographic methods, are needed to prevent further complications and possible progression to multiple myeloma. Radiation therapy is the primary treatment, with some studies showing the benefits of lenalidomide and dexamethasone. Further studies are needed to improve treatment options for these patients. This case report adds to the current literature the importance of a multidisciplinary approach to the treatment of SPC.

Evaluation of a large-scale aptamer proteomics platform among patients with kidney failure on dialysis.

BACKGROUND: Patients with kidney failure suffer high mortality, and we currently lack markers for risk stratification for these patients. We carried out a quality control study of a modified aptamer assay (SomaScan v.4.0) that measures ~ 5000 proteins, in preparation for a larger study using this platform in cohorts with kidney failure. METHODS: Forty participants from the Cardiac, Endothelial Function and Arterial Stiffness in End-Stage Renal Disease (CERES study) were selected to analyze technical and short-term biological variability, orthogonal correlations and differential protein expression in plasma from patients who died during 2.5 year follow-up. Long-term (one year) variability was studied in 421 participants in the Chronic Renal Insufficiency Cohort. We evaluated 4849 aptamers (4607 unique proteins) using data formats including raw data and data formatted using Adaptive Normalization by Maximum Likelihood (ANML), an algorithm developed for SomaScan data in individuals with normal kidney function. RESULTS: In ANML format, median[IQR] intra-assay coefficient of variation (CV) was 2.38%[1.76, 3.40] and inter-assay CV was 7.38%[4.61, 13.12]. Short-term within-subject CV was 5.76% [3.35, 9.72]; long-term CV was 8.71%[5.91, 13.37]. Spearman correlations between aptamer and traditional assays for PTH, NT-proBNP, FGF-23 and CRP were all > 0.7. Fold-change (FC) in protein levels among non-survivors, significant after Bonferroni correction, included SVEP1 (FC[95% CI] 2.14 [1.62, 2.82]), keratocan (1.74 [1.40, 2.15]) and LanC-like protein 1 (0.56 [0.45, 0.70]). Compared to raw aptamer data, technical and short-term biological variability in paired samples was lower in ANML-formatted data. ANML formatting had minimal impact on orthogonal correlations with traditional assays or the associations of proteins with the phenotype of mortality. CONCLUSIONS: SomaScan had excellent technical variability and low within-subject short-term variability. ANML formatting could facilitate comparison of biomarker results with other studies that utilize this format. We expect SomaScan to provide novel and reproducible information in patients with kidney failure on dialysis.

Photo-Uncaging by C(sp3)-C(sp3) Bond Cleavage Restores ß-Lapachone Activity.

ß-Lapachone is an ortho-naphthoquinone natural product with significant antiproliferative activity but suffers from adverse systemic toxicity. The use of photoremovable protecting groups to covalently inactivate a substrate and then enable controllable release with light in a spatiotemporal manner is an attractive prodrug strategy to limit toxicity. However, visible light-activatable photocages are nearly exclusively enabled by linkages to nucleophilic functional sites such as alcohols, amines, thiols, phosphates, and sulfonates. Herein, we report covalent inactivation of the electrophilic quinone moiety of ß-lapachone via a C(sp3)-C(sp3) bond to a coumarin photocage. In contrast to ß-lapachone, the designed prodrug remained intact in human whole blood and did not induce methemoglobinemia in the dark. Under light activation, the C-C bond cleaves to release the active quinone, recovering its biological activity when evaluated against the enzyme NQO1 and human cancer cells. Investigations into this report of a C(sp3)-C(sp3) photoinduced bond cleavage suggest a nontraditional, radical-based mechanism of release beginning with an initial charge-transfer excited state. Additionally, caging and release of the isomeric para-quinone, α-lapachone, are demonstrated. As such, we describe a photocaging strategy for the pair of quinones and report a unique light-induced cleavage of a C-C bond. We envision that this photocage strategy can be extended to quinones beyond ß- and α-lapachone, thus expanding the chemical toolbox of photocaged compounds.

Left atrial strain is associated with adverse cardiovascular events in patients with end-stage renal disease: Findings from the Cardiac, Endothelial Function and Arterial Stiffness in ESRD (CERES) study.

INTRODUCTION: We lack cardiovascular (CV) markers for patients with end-stage renal disease (ESRD), and left atrial (LA) strain has not been studied definitively in this population. We examined associations of LA reservoir, conduit, and booster strain with major adverse cardiovascular events (MACE) among stable patients with ESRD on dialysis. METHODS: One hundred and ninety patients in the Cardiac, Endothelial and Arterial Stiffness in ESRD study underwent echocardiography, including strain imaging. The primary outcome was 2-year composite non-fatal MACE or CV death. We performed Cox proportional hazards regression for LA strain measures, adjusting for demographics, comorbidities, left ventricular global longitudinal strain (LV GLS), E/e' and LA volume index. FINDINGS: Mean ± SD LA reservoir strain was 24.1 ± 7.0%, and LA conduit strain 11.9 ± 5.1%. In age-adjusted analyses, lower LA reservoir strain and LA conduit strain were associated with the primary outcome (HR per 1-SD worsening LA strain parameter = 1.57 [95% CI 1.2-2.1], p = 0.003 and 1.68 [95% CI 1.2-2.3], p = 0.002, respectively). After adjusting for comorbidities, LA reservoir strain remained associated with the primary outcome and with deaths alone, and LA conduit strain with the primary outcome and hospitalizations alone (p < 0.05 for all). Associations of LA conduit strain were independent of LV GLS. Associations were stronger in participants with serum albumin <3.6 mg/dl (p for interaction 0.008). DISCUSSION: Left atrial reservoir strain and conduit strain were independently associated with MACE among patients with ESRD. Our study provides unique ascertainment of CV hospitalizations not attributed to missed dialysis, and LA conduit strain was a strong marker for this outcome.

Trends of Cardiac Complications in Patients With Rheumatoid Arthritis: Analysis of the United States National Inpatient Sample; 2005-2014.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory condition. Chronic inflammation is associated with atherosclerosis, hypertension, diabetes, chronic obstructive pulmonary disease (COPD), chronic kidney disease. But sparse data are available regarding the trends of cardiovascular diseases and complications in RA. We conducted a National Inpatient Sample database analysis to demonstrate the trends of cardiac complications in patients with RA. METHODS: We used National Inpatient Sample data from 2005 to 2014 to identify admissions with the diagnosis of RA and identified who had associated cardiovascular complications also. The International Classification of Diseases-9th Revision-Clinical Modification codes were used for the diagnoses of RA; congestive heart failure (CHF), acute myocardial infarction (AMI), and atrial fibrillation (AF). RESULTS: A statistically significant increasing trend of AMI, CHF, and AF was found. Independent predictors of mortality in RA patients with AMI were age (OR 1.03, CI 1.02-1.04; P < 0.001), COPD (OR 1.67, CI 1.40-2.00; P < 0.001), cerebrovascular disease (OR 2.207, CI 1.71-2.86; P < 0.001), renal disease (OR 1.42, CI 1.16-1.75; P = 0.001), and alcohol abuse (OR 2.73, CI 1.73-4.32; P < 0.001). Independent predictors of mortality in RA patients with CHF were age (odds ratio [OR] 1.02, confidence interval [CI] 1.017-1.024; P < 0.001]), COPD (OR 1.09, CI 1.01-1.18; P = 0.023), cerebrovascular disease (OR 1.67, CI 1.44-1.95; P < 0.001), renal disease (OR 1.16, CI 1.07-1.27; P = 0.001). Independent predictors of mortality in RA patients with AF were age (OR 1.02, CI 1.02-1.03; P < 0.001), race (OR 1.16, CI 1.02-1.31; P = 0.022), COPD (OR 1.56, CI 1.42-1.71; P < 0.001), peripheral arterial disease (OR 1.34, CI 1.16-1.53; P < 0.001), cerebrovascular disease (OR 2.27, CI 1.0-2.58; P < 0.001), renal disease (OR 1.60, CI 1.44-1.80; P < 0.001). The mortality trend has increased significantly in the CHF (P = 0.025) and AF (P = 0.042) groups during this study period. CONCLUSIONS: We have found a significant increase in trend of cardiovascular complications in RA patients. The proportion of patients, with cardiovascular comorbidities, have also been increased significantly.

Trends and Impact of the Use of Mechanical Circulatory Support for Cardiogenic Shock Secondary to Takotsubo Cardiomyopathy.

Data on the trend and impact of mechanical circulatory support (MCS) in patients with Takotsubo cardiomyopathy (TC) are scarce. We evaluated the incidence and outcomes of cardiogenic shock (CS) in TC patients and the trend in use of MCS over time. The National Inpatient Sample from 2005 to 2014 was used to identify patients admitted with TC and those receiving MCS. Multivariate logistic regression was performed to identify predictors of mortality. The Cochran-Armitage test was used for the trend analysis across the years. Admissions for TC showed a linear increase for the study period. From 2005 to 2014 the proportion of TC managed with MCS remained stable, with some yearly fluctuations. Crude in-hospital mortality rate was 2.5% in the patients admitted with TC but was significantly higher in those with CS (15.81% vs 1.68%, p < 0.001). There was no difference in mortality in TC patients with CS, both with and without the use of MCS. However, patients managed with MCS were more likely to be discharged to a skilled nursing facility (31% vs 25.55, p = 0.015) compared with TC patients with CS who were medically managed. The cost of care for patients with TC and CS, managed with MCS was significantly higher than those managed medically ($171K vs $128K, p <0.001). In patients managed with MCS, only sepsis was associated with a higher likelihood of death using multivariate analysis (Odds Ratio 2.538, Confidence Interval 1.245 to 5.172; p = 0.011). In conclusion, the incidence of TC has increased over the years, but the proportion of patients requiring MCS has declined. Crude mortality rate for TC was 2.5%, but was 15.8% in the TC patients with CS. The use of MCS did not lead to improved mortality but was associated with higher cost and increased likelihood of skilled nursing facility discharge.

Photoinduced α-Cleavage of 2-Azido-2-phenyl-1,3-indandione at Cryogenic Temperatures.

To expand the utility of α-cleavage at cryogenic temperatures, we investigated the photoreactivity of 2-azido-2-phenyl-1,3-indandione (1). EPR spectroscopy revealed that irradiating 1 in 2-methyltetrahydrofuran (mTHF) matrices forms alkylnitrene 32, which has zero-field splitting parameters (D/hc = 1.5837 cm-1; E/hc = 0.0039 cm-1) typical of an alkylnitrene. IR spectroscopy demonstrated that irradiating 1 in argon matrices results in the concurrent formation of 32, imine 3, benzocyclobutenedione 4, and benzonitrile 5.

Photolysis of 5-Azido-3-Phenylisoxazole at Cryogenic Temperature: Formation and Direct Detection of a Nitrosoalkene.

To enhance the versatility of organic azides in organic synthesis, a better understanding of their photochemistry is required. Herein, the photoreactivity of azidoisoxazole 1 was characterized in cryogenic matrices with IR and UV-Vis absorption spectroscopy. The irradiation (λ = 254 nm) of azidoisoxazole 1 in an argon matrix at 13 K and in glassy 2-methyltetrahydrofuran (mTHF) at 77 K yielded nitrosoalkene 3. Density functional theory (DFT) and complete active space self-consistent field (CASSCF) calculations were used to aid the characterization of nitrosoalkene 3 and to support the proposed mechanism for its formation. It is likely that nitrosoalkene 3 is formed from the singlet excited state of azidoisoxazole 1 via a concerted mechanism or from cleavage of an intermediate singlet nitrene that does not undergo efficient intersystem crossing to its triplet configuration.

Comprehensive pharmacogenomic profiling of human papillomavirus-positive and -negative squamous cell carcinoma identifies sensitivity to aurora kinase inhibition in KMT2D mutants.

To address the unmet need for effective biomarker-driven targeted therapy for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) and cervical cancer, we conducted a high-throughput drug screen using 1122 compounds in 13 HPV-positive and 11 matched HPV-negative cell lines. The most effective drug classes were inhibitors of polo-like kinase, proteasomes, histone deacetylase, and Aurora kinases. Treatment with a pan-Aurora inhibitor, danusertib, led to G2M arrest and apoptosis in vitro. Furthermore, danusertib decreased tumor size compared with controls in patient derived xenograft models of HNSCC. To identify biomarkers predicting response, we determined associations between mutations and drug sensitivity. Our data and the Genomics of Drug Sensitivity in Cancer database showed that cancer cells with KMT2D mutations were more sensitive to Aurora kinase inhibitors than were cells without mutations. Knockdown of KMT2D in wild-type cells led to increased Aurora kinase inhibitor-induced apoptosis. We identified Aurora kinase inhibitors as effective and understudied drugs in HNSCC and CESC. This is the first published study to demonstrate that mutations in KMT2D, which are common in many cancers, correlate with drug sensitivity in two independent datasets.

Association between intravenous acetaminophen and reduction in intraoperative opioid consumption during transsphenoidal surgery for pituitary tumors.

BACKGROUND AND AIMS: Pain during and after transsphenoidal surgeries originates from stimulation of branches of the trigeminal cranial nerve that supply the inner aspect of the nose cavity and dura mater. Thereby, patients undergoing transsphenoidal surgery may require moderate-to-large amounts of analgesics including opioids. Intravenous acetaminophen provides analgesia and reduces opioid consumption for a wide variety of surgeries. We hypothesized that the use of intravenous acetaminophen is associated with a reduction in intraoperative opioid consumption and provides significant analgesia during and after transsphenoidal surgery. MATERIAL AND METHODS: This retrospective study included 413 patients who underwent transsphenoidal surgery for pituitary adenomas. The primary outcome of this study was intraoperative opioid consumption. Secondary outcomes included pain intensity, Richmond Agitation Sedation Scale scores, and nausea and vomiting upon arrival to postoperative anesthesia care unit. Patients were divided into two groups based on the intraoperative acetaminophen use. A prospensity score matching analysis was used to balance for important variables between the two groups of treatment. Regression models were fitted after matching the covariates. A P < 0.05 was considered statistically significant. RESULTS: After matching, 126 patients were included in each group of treatment. Patients in the acetaminophen group required significantly less amount (a decrease by 14.9%) of opioids during surgery than those in the non-acetaminophen group. Postoperative pain, postoperative nausea and vomiting, and sedation scores were not significantly different between patients who received intravenous acetaminophen and those who did not. CONCLUSION: Intravenous acetaminophen is associated with a reduction in intraoperative opioids during transsphenoidal pituitary surgery.

Protein expression of TTF1 and cMYC define distinct molecular subgroups of small cell lung cancer with unique vulnerabilities to aurora kinase inhibition, DLL3 targeting, and other targeted therapies.

Small cell lung cancer (SCLC) is a recalcitrant cancer for which no new treatments have been approved in over 30 years. While molecular subtyping now guides treatment selection for patients with non-small cell lung cancer and other cancers, SCLC is still treated as a single disease entity. Using model-based clustering, we found two major proteomic subtypes of SCLC characterized by either high thyroid transcription factor-1 (TTF1)/low cMYC protein expression or high cMYC/low TTF1. Applying "drug target constellation" (DTECT) mapping, we further show that protein levels of TTF1 and cMYC predict response to targeted therapies including aurora kinase, Bcl2, and HSP90 inhibitors. Levels of TTF1 and DLL3 were also highly correlated in preclinical models and patient tumors. TTF1 (used in the diagnosis lung cancer) could therefore be used as a surrogate of DLL3 expression to identify patients who may respond to the DLL3 antibody-drug conjugate rovalpituzumab tesirine. These findings suggest that TTF1, cMYC or other protein markers identified here could be used to identify subgroups of SCLC patients who may respond preferentially to several emerging targeted therapies.

Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics.

Mammalian exchange protein directly activated by cAMP isoform 1 (EPAC1), encoded by the RAPGEF3 gene, is one of the two-membered family of cAMP sensors that mediate the intracellular functions of cAMP by acting as guanine nucleotide exchange factors for the Ras-like Rap small GTPases. Extensive studies have revealed that EPAC1-mediated cAMP signaling is highly coordinated spatiotemporally through the formation of dynamic signalosomes by interacting with a diverse array of cellular partners. Recent functional analyses of genetically engineered mouse models further suggest that EPAC1 functions as an important stress response switch and is involved in pathophysiological conditions of cardiac stresses, chronic pain, cancer and infectious diseases. These findings, coupled with the development of EPAC specific small molecule modulators, validate EPAC1 as a promising target for therapeutic interventions.

Design, synthesis, and evaluation of hybrid vitamin D3 side chain analogues as hedgehog pathway inhibitors.

Vitamin D3 (VD3) is a moderately potent and non-selective inhibitor of the Hedgehog (Hh) signaling cascade. Previous studies have established that the CD-ring region of VD3 serves as the Hh inhibitory pharmacophore. Subsequently, compound 3, an ester linked aromatic A-ring and CD-ring derivative was identified as an improved and selective Hh inhibitor. Herein, we report modifications of the CD-ring side chain that afford enhancement of selectivity for Hh modulation thereby diminishing the detrimental effects of concomitant vitamin D receptor activation. In general, linear or moderately branched alkyl chains of five or six carbons were optimal for potent and selective inhibition of Hh signaling. Moreover, hybrid VD3 side chain derivative 20 demonstrated 4-fold improvement in Hh antagonistic activity over VD3(IC50=1.1-1.6 µM) while gaining greater than a 1000-fold selectivity for Hh signaling over canonical activation of the vitamin D receptor pathway.

Chronic nickel bioaccumulation and sub-cellular fractionation in two freshwater teleosts, the round goby and the rainbow trout, exposed simultaneously to waterborne and dietborne nickel.

Rainbow trout and round goby were exposed for 30 days to waterborne and dietary Ni in combination at two waterborne concentration ranges (6.2-12 µmol/L, 68-86 µmol/L), the lower of which is typical of contaminated environments. The prey (black worms; Lumbriculus variegatus) were exposed for 48 h in the effluent of the fish exposure tanks before being fed to the fish (ration=2% body weight/day). Ni in gills, gut, and prey was fractionated into biologically inactive metal [BIM=metal-rich granules (MRG) and metallothionein-like proteins (MT)] and biologically active metal [BAM=organelles (ORG) and heat-denaturable proteins (HDP)]. Gobies were more sensitive than trout to chronic Ni exposure. Possibly, this greater sensitivity may have been due to the goby's pre-exposure to pollutants at their collection site, as evidenced by ∼2-fold greater initial Ni concentrations in both gills and gut relative to trout. However, this was followed by ∼2-16× larger bioaccumulation in both the gills and the gut during the experimental exposure. On a subcellular level, ∼3-40× more Ni was associated with the BAM fraction of goby in comparison to trout. Comparison of the fractional distribution of Ni in the prey versus the gut tissue of the predators suggested that round goby were more efficient than rainbow trout in detoxifying Ni taken up from the diet. Assessing sub-cellular distribution of Ni in the gills and gut of two fish of different habitat and lifestyles revealed two different strategies of Ni bioaccumulation and sub-cellular distribution. On the one hand, trout exhibited an ability to regulate gill Ni bioaccumulation and maintain the majority of the Ni in the MT fraction of the BIM. In contrast goby exhibited large Ni spillovers to both the HDP and ORG fractions of the BAM in the gill. However, the same trend was not observed in the gut, where the potential acclimation of goby to pollutants from their collection site may have aided their ability to regulate Ni spillover to the BAM more so than in trout. Overall, chronic mortality observed in goby may be associated more with Ni bioaccumulation in gills than in gut; the former at either 4-d or 30-d was predictive of chronic Ni toxicity. BIM and BAM fractions of the goby gills were equally predictive of chronic (30-d) mortality. However, critical body residue (CBR50) values of the BIM fraction were ∼2-4× greater than CBR50 values of the BAM fraction, suggesting that goby are more sensitive to Ni bioaccumulation in the BAM fraction. There was insufficient mortality in trout to assess whether Ni bioaccumulation was predictive of chronic mortality.

Recent advances in the design of Hedgehog pathway inhibitors for the treatment of malignancies.

INTRODUCTION: The Hedgehog (Hh) signaling pathway is known to be dysregulated in several forms of cancer. Hence, specifically targeting this signaling cascade is a valid and promising strategy for successful therapeutic intervention. Several components within the Hh pathway have been proven to be druggable; however, challenges in the discovery and development process for small molecules targeting this pathway have been identified. AREAS COVERED: This review details both the current state and future potential of Hh pathway inhibitors as anticancer chemotherapeutics that target a variety of human malignancies. EXPERT OPINION: The initial development of Hh pathway inhibitors focused on small-molecule antagonists of Smoothened, a transmembrane protein that is a key regulator of pathway signaling. More recently, efforts to identify and develop inhibitors of pathway signaling that function through alternate mechanisms have been increasing. However, none of these have advanced into clinical trials. Further, early evidence suggesting the broad application of Hh pathway inhibitors as a monotherapy in a wide range of human cancers has not been validated. The potential for Hh pathway inhibitors as combination therapy has demonstrated promising preclinical results. However, more research to identify rational drug combinations to fully explore the potential of this anticancer drug class is warranted.

Assessment of Nutritional Risk and Its Associated Factors among Elderly Women of Old Age Homes of South Suburban Kolkata, West Bengal, India.

BACKGROUND: Different physiological, social and psychological factors contribute to nutritional risk in elderly population. Elderly women residing at old age homes are particularly susceptible. OBJECTIVES: To find out psychological and financial factors, if any, associated with malnutrition and risk of malnutrition. METHODS: A cross sectional descriptive study was conducted on 200 residents belonging to > 65 years age group of nine old age homes selected randomly among eighteen old age homes located at south suburban areas of Kolkata from September 2010 to April 2011 using a pre-designed, pilot tested schedule containing Mini Nutritional Assessment (MNA) Scale and Geriatric Depression Scale (GDS). Intergroup comparison was performed using chi-square test.The study was approved by Institutional Ethics Committee of All India Institute of Hygiene & Public Health, Kolkata,India. Written informed consent was taken from each study participant. RESULTS: Among 158 'possibly malnourished' women, 114 (57%) were 'at risk of malnutrition' and 44 (22%) were malnourished according to MNA. Psychological stress was present among 44% of 'at risk of malnutrition' and 56% 'malnourished' population (df=1, x2= 28.852, p<0.001). About 77% of women having moderate depression were 'at risk of malnutrition' whereas 52% of women having severe depression were 'malnourished' (df =2, x2= 23.769, p<0.001). CONCLUSION: High proportion of 'at risk malnutrition' and 'malnutrition' associated with presence of psychological stress and different grades of depression were the major areas of concern.

Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors.

A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 µM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.