Stepwise Formation Constants of the Chelates of Substituted Azobenzenes with Cu(II), Ni(II), Co(II), Zn(II) & Cd(II)

154-15

Nd(III), Pr(III), Ce(III) & La(III) Complexes with 3-Formyl-4-hydroxy- & 3-Oximinomethyl-4'- nitroazobenzenes

81

Stepwise Formation Constants of La(III), Ce(III), Pr(III) & Nd(III) with 4-H'ydroxy- 3-formyl-(2'/4')-methylazobenzenes

54

Breast cancer stem-like cells are inhibited by diosgenin, a steroidal saponin, by the attenuation of the Wnt ß-catenin signaling via the Wnt antagonist secreted frizzled related protein-4

Background: Identification of breast cancer stem cells as the chemo-resistant and tumor-initiating population represents an important milestone in approaching anticancer therapies. Targeting this minor subpopulation of chemo- and radio-resistant stem-like cells, termed as the cancer stem cells (CSCs) and their eradication could significantly enhance clinical outcomes. Most of the presently administered chemotherapeutics target the tumor bulk but are ineffective against the CSCs. We report here that diosgenin (DG), a naturally occurring steroidal saponin, could effectively inhibit CSCs from three breast cancer cell lines, MCF7, T47D and MDA-MB-231, by inducing apoptosis and inhibiting the CSC associated phenotypes. Methods: CSCs were enriched in these cells lines, characterized for CSC traits by immunocytochemistry and flow cytometry. Proliferation and apoptosis assays were performed in these breast CSCs in the presence of DG to obtain the inhibitory concentration. Apoptosis was confirmed with gene expression analysis, Western blotting and propidium iodide staining. TCF-LEF reporter assay, sFRP overexpression and RNAi silencing studies were performed to study regulation of the Wnt pathway. Statistical significance was evaluated by a two-sided Student's t-test. Results: Using the TCF-LEF reporter system, we show the effect of DG on CSCs is predominantly through the network regulating CSC self renewal, the Wnt ß-catenin pathway. Specifically, the Wnt antagonist, the secreted frizzled related protein 4, (sFRP4), had a defining role in the action of DG. Gain-of-function of sFRP4 in CSCs could improve the response to DG wherein CSC mediators were inhibited, ß-catenin was down regulated and the effectors of epithelial to mesenchymal transition and pro-invasive markers were repressed. Conversely, the loss-of-function of sFRP4 had a reverse effect on the CSC population which therein became enriched, their response to DG treatment was modest, ß-catenin levels increased, GSK3ß expression decreased and the expression of epithelial markers of CSC was completely abrogated. Conclusion: These findings demonstrate the effect of DG on inhibiting the resilient breast CSCs which could provide a benchmark for the development of DG-based therapies in breast cancer treatment. © 2017 Bhuvanalakshmi, Basappa, Rangappa, Dharmarajan, Sethi, Kumar and Warrier

Applying Mendelian randomization to appraise causality in relationships between smoking, depression and inflammation

Smoking, inflammation and depression commonly co-occur and may be mechanistically linked. However, key questions remain around the direction of association and the influence of residual confounding. We aimed to characterize the association between lifetime smoking and depression, as well as to assess the role that genetically-predicted C-reactive protein (CRP) level, (an archetypal generalized inflammatory marker) and/or IL-6 activity, as a potential explanation for this association. We performed inverse variance weighted Mendelian randomization (MR) analyses using recently published summary-level GWAS data for lifetime smoking index, CRP levels, and depression. A subset of inflammatory-related genetic variants from the lifetime smoking GWAS were also used to assess the potential inflammatory causal pathways between smoking and depression. The analysis indicated reciprocal relationships of lifetime smoking with depression (ORSmk–Dep = 2.01, 95% CI 1.71–2.37, p &lt; 0.001; ORDep–Smk = 1.09, 95% CI 1.06–1.13, p &lt; 0.001), CRP levels and IL-6 activity (ORSmk–CRP = 1.40, 95% CI 1.21–1.55, p &lt; 0.001; ORCRP–Smk = 1.03, 95% CI 1.02–1.05, p &lt; 0.001, ORIL-6/CRP–Smk = 1.06 (1.03–1.09), p &lt; 0.001). These associations were also supported by the majority of the robust MR methods performed. We did not find evidence for a reciprocal relationship between CRP levels (using &gt; 500 genetic instruments for CRP) and depression (ORCRP–Dep = 1.01, 95% CI 0.99–1.04; ORDep–CRP = 1.03, 95% CI 0.99–1.07). We observed little variation in the IVW estimates between smoking and depression when we limited the genetic variants assessed to those related to measures of generalized inflammation, but we found evidence for an attenuation of the smoking-depression association in multivariable mendelian randomization when adjusting for IL-6 activity, suggesting that the IL-6 pathway may be at least in part responsible for the association of smoking and depression. Our study supports potential bidirectional causal associations between lifetime smoking and depression which may be at least in part explained by the IL-6 signalling pathway. The IL-6 pathway may represent a putative therapeutic target for smoking and to mitigate the effects of smoking on depression.</p

Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Metaanalysis of Oncological and Operative Outcomes

Background: Total neoadjuvant therapy in rectal cancer refers to the administration of chemoradiotherapy plus chemotherapy before surgery. Recent studies have shown improved pathological complete response and disease-free survival with this approach. However, survival benefits remain unproven. Our objective is to present a metaanalysis of oncological outcomes of total neoadjuvant therapy in locally advanced rectal cancer. Patients and methods: A comprehensive search was performed on PubMed, Medline, and Google Scholars. Studies comparing total neoadjuvant therapy with standard&nbsp;neoadjuvant chemoradiotherapy were included. Data extracted from the individual studies were pooled and a metaanalysis performed. The outcomes of interest are the rate of complete pathological response, nodal response, resection margin, anal preservation, anastomotic leak, local recurrence, distant recurrence, disease-free survival, and overall survival. Results: There were 15 comparative studies with 2437 patients in the neoadjuvant chemoradiotherapy group and 2284 in the total neoadjuvant therapy group. The pooled complete pathological response was 22.3% in the total neoadjuvant therapy group, compared with 14.2% in the standard neoadjuvant chemoradiotherapy group (p&nbsp;&lt;&nbsp;0.001). Even though there was no difference in local recurrence rate, there was a significantly lower rate of distant recurrence (OR 0.81, p&nbsp;=&nbsp;0.02), and better 3-year disease-free survival (70.6% vs. 65.3%, respectively, p&nbsp;&lt;&nbsp;0.001) and overall survival (84.9% vs. 82.3%, respectively, p&nbsp;=&nbsp;0.006), favoring the total neoadjuvant therapy group. Due to significant heterogeneity in the study protocols, there remains uncertainty on the ideal chemotherapy/radiotherapy sequence. Conclusions: This study provides supporting evidence on the favorable immediate and intermediate oncological outcomes with the use of total neoadjuvant therapy for locally advanced rectal cancer

Experimental and Theoretical Investigations of Fe-Doped Hexagonal MnNiGe

We report a comprehensive investigation of MnNi0.7Fe0.3Ge Heusler alloy to explore its magnetic, caloric, and electrical transport properties. The alloy undergoes a ferromagnetic transition across TC∼212 K and a weak-antiferromagnetic transition across Tt∼180 K followed by a spin-glass transition below Tf∼51.85 K. A second-order phase transition across TCwith mixed short and long-range magnetic interactions is confirmed through the critical exponent study and universal scaling of magnetic entropy and magnetoresistance. A weak first-order phase transition is evident across Ttfrom magnetization and specific heat data. The frequency dependent cusp in χAC(T) along with the absence of a clear magnetic transition in specific heat C(T) and resistivity ρ(T) establish the spin glass behavior below Tf. Mixed ferromagnetic and antiferromagnetic interactions with dominant ferromagnetic coupling, as revealed by density functional calculations, are experimentally evident from the large positive Weiss temperature, magnetic saturation, and negative magnetic-entropy and magnetoresistance. © 2022 American Chemical Society. All rights reserved.CSR-IC-256/2017-18/1337; Department of Physics, Harvard University; Council of Scientific and Industrial Research, India, CSIR: 09/926(0011)2K18, DST/INT/RFBR/IDIR/P-01/2016; Ministry of Education and Science of the Russian Federation, Minobrnauka: AAAA-A18-118020190098-5; Indian Institute of Technology Bombay, IITB; Russian Science Foundation, RSF: 22-42-02021; UGC-DAE Consortium for Scientific Research, University Grants Commission, UGC-DAE CSR; Industrial Research and Consultancy Centre, IRCCS.S.S., A.K.P., and K.G.S. thank IRCC and the Department of Physics, IIT Bombay, for X-ray diffraction and magnetization facilities. S.S.S. acknowledges UGC-DAE CSR, Indore, for financial support under the Collaborative Research Scheme (CSR-IC-256/2017-18/1337). V.G. acknowledges UGC-DAE CSR, Indore, for the support. A.K.M. thanks CSIR India, for SRF [File No.: 09/926(0011)2K18]. K.G.S. acknowledges financial support through Indo-Russian project: DST/INT/RFBR/IDIR/P-01/2016. The theoretical studies are supported by the Russian Science Foundation (Project No. 22-42-02021) for the electronic structure calculations and Ministry of Science and Higher Education of the Russian Federation for the exchange parameters calculations (theme "Electron" No. AAAA-A18-118020190098-5).S.S.S., A.K.P., and K.G.S. thank IRCC and the Department of Physics, IIT Bombay, for X-ray diffraction and magnetization facilities. S.S.S. acknowledges UGC-DAE CSR, Indore, for financial support under the Collaborative Research Scheme (CSR-IC-256/2017-18/1337). V.G. acknowledges UGC-DAE CSR, Indore, for the support. A.K.M. thanks CSIR, India, for SRF [File No.: 09/926(0011)2K18]. K.G.S. acknowledges financial support through Indo-Russian project: DST/INT/RFBR/IDIR/P-01/2016. The theoretical studies are supported by the Russian Science Foundation (Project No. 22-42-02021) for the electronic structure calculations and Ministry of Science and Higher Education of the Russian Federation for the exchange parameters calculations (theme “Electron” No. AAAA-A18-118020190098-5)

Robotic natural orifice specimen extraction surgery (NOSES) for anterior resection

Minimally invasive colorectal surgery is currently well-accepted, with open techniques being reserved for very difficult cases. Laparoscopic colectomy has been proven to have lower mortality, complication, and ostomy rates; a shorter median length of stay; and lower overall costs when compared to its open counterpart. This trend is seen in both benign and malignant indications. Natural orifice specimen extraction surgery (NOSES) in colorectal surgery was first described in the early 1990s. Three recent meta-analyses comparing transabdominal extraction against NOSES concluded that NOSES was superior in terms of overall postoperative complications, recovery of gastrointestinal function, postoperative pain, aesthetics, and hospital stay. However, NOSES was associated with a longer operative time. Herein, we present our technique of robotic NOSES anterior resection using the da Vinci Xi platform in diverticular disease and sigmoid colon cancers

Cancer stem-like cells from head and neck cancers are chemosensitized by the Wnt antagonist, sFRP4, by inducing apoptosis, decreasing stemness, drug resistance and epithelial to mesenchymal transition

Cancer stem cells (CSCs) of head and neck squamous cell carcinoma (HNSCC) are defined by high self-renewal and drug refractory potential. Involvement of Wnt/ß-catenin signaling has been implicated in rapidly cycling cells such as CSCs, and inhibition of the Wnt/ß-catenin pathway is a novel approach to target CSCs from HNSCC. In this study, we found that an antagonist of FrzB/Wnt, the secreted frizzled-related protein 4 (sFRP4), inhibited the growth of CSCs from two HNSCC cell lines, Hep2 and KB. We enriched the CD44+ CSC population, and grew them in spheroid cultures. sFRP4 decreased the proliferation and increased the sensitivity of spheroids to a commonly used drug in HNSCC, namely cisplatin. Self-renewal in sphere formation assays decreased upon sFRP4 treatment, and the effect was reverted by the addition of Wnt3a. sFRP4 treatment of spheroids also decreased ß-catenin, confirming its action through the Wnt/ß-catenin signaling pathway. Quantitative PCR demonstrated a clear decrease of the stemness markers CD44 and ALDH, and an increase in CD24 and drug-resistance markers ABCG2 and ABCC4. Furthermore, we found that after sFRP4 treatment, there was a reversal in the expression of epithelial to mesenchymal (EMT) markers with the restoration of the epithelial marker E-cadherin, and depletion of EMT-specific markers twist, snail and N-cadherin. This is the first report demonstrating that the naturally occurring Wnt inhibitor, sFRP4, can be a potential drug to destroy CSC-enriched spheroids from HNSCCs. The repression of EMT and the decrease in stemness profile further strengthen the use of sFRP4 as a potent therapeutic against CSC

Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD