Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Extracellular vesicle biomarkers for cognitive impairment in Parkinson's disease.

Besides motor symptoms, many individuals with Parkinson's disease develop cognitive impairment perhaps due to coexisting α-synuclein and Alzheimer's disease pathologies and impaired brain insulin signalling. Discovering biomarkers for cognitive impairment in Parkinson's disease could help clarify the underlying pathogenic processes and improve Parkinson's disease diagnosis and prognosis. This study used plasma samples from 273 participants: 103 Parkinson's disease individuals with normal cognition, 121 Parkinson's disease individuals with cognitive impairment (81 with mild cognitive impairment, 40 with dementia) and 49 age- and sex-matched controls. Plasma extracellular vesicles enriched for neuronal origin were immunocaptured by targeting the L1 cell adhesion molecule, then biomarkers were quantified using immunoassays. α-Synuclein was lower in Parkinson's disease compared to control individuals (P = 0.004) and in cognitively impaired Parkinson's disease individuals compared to Parkinson's disease with normal cognition (P < 0.001) and control (P < 0.001) individuals. Amyloid-ß42 did not differ between groups. Phosphorylated tau (T181) was higher in Parkinson's disease than control individuals (P = 0.003) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and controls (P < 0.001). Total tau was not different between groups. Tyrosine-phosphorylated insulin receptor substrate-1 was lower in Parkinson's disease compared to control individuals (P = 0.03) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and controls (P = 0.01), and also decreased with increasing motor symptom severity (P = 0.005); serine312-phosphorylated insulin receptor substrate-1 was not different between groups. Mechanistic target of rapamycin was not different between groups, whereas phosphorylated mechanistic target of rapamycin trended lower in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.05). The ratio of α-synuclein to phosphorylated tau181 was lower in Parkinson's disease compared to controls (P = 0.001), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and decreased with increasing motor symptom severity (P < 0.001). The ratio of insulin receptor substrate-1 phosphorylated serine312 to insulin receptor substrate-1 phosphorylated tyrosine was higher in Parkinson's disease compared to control individuals (P = 0.01), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and increased with increasing motor symptom severity (P = 0.003). α-Synuclein, phosphorylated tau181 and insulin receptor substrate-1 phosphorylated tyrosine contributed in diagnostic classification between groups. These findings suggest that both α-synuclein and tau pathologies and impaired insulin signalling underlie Parkinson's disease with cognitive impairment. Plasma neuronal extracellular vesicles biomarkers may inform cognitive prognosis in Parkinson's disease.

Clinico-immunological evaluation of use of omega-3 fatty acids as nutraceutical approach in management of patients with chronic periodontitis: A randomized clinical trial.

Background: Subgingival bacterial colonization and biofilm formation are known to be the main etiology of periodontal disease progression. This biofilm elicits host response and the interaction between host defence mechanisms with plaque microorganisms and their products results in periodontal disease. Host modulatory therapy (HMT) is a form of treatment of periodontitis that focuses on treatment of the host in the host-bacteria interaction. Omega-3 fatty acids have emerged as a potential HMT agent to treat inflammation associated with periodontal disease. Methods: A total of 60 cases of chronic periodontitis were allocated into two groups; the test group (n = 30) were treated with scaling and root planing (SRP) and given a dietary supplementation of omega-3 fatty acid while the control group were treated with SRP alone. Clinical parameters carried out were plaque index (PI), gingival bleeding index (GBI), pocket probing depth (PPD) and clinical attachment level (CAL) and immunological parameter included interleukin-1ß level in saliva at baseline, 3 months and 6 months after therapy. Results: At 6 months, both the groups showed significant improvements with regards to all clinical and immunological parameters compared to baseline (all p < 0.05). However, test group presented with more favourable statistically significant results. Conclusion: The use of omega-3 fatty acid as nutraceutical agent to conventional method acted as beneficial therapeutic measures and effective in patients with chronic periodontitis when compared with SRP alone.

Identification of Clinically Relevant Brain Endothelial Cell Biomarkers in Plasma.

BACKGROUND: Proteins expressed by brain endothelial cells (BECs), the primary cell type of the blood-brain barrier, may serve as sensitive plasma biomarkers for neurological and neurovascular conditions, including cerebral small vessel disease. METHODS: Using data from the BLSA (Baltimore Longitudinal Study of Aging; n=886; 2009-2020), BEC-enriched proteins were identified among 7268 plasma proteins (measured with SomaScanv4.1) using an automated annotation algorithm that filtered endothelial cell transcripts followed by cross-referencing with BEC-specific transcripts reported in single-cell RNA-sequencing studies. To identify BEC-enriched proteins in plasma most relevant to the maintenance of neurological and neurovascular health, we selected proteins significantly associated with 3T magnetic resonance imaging-defined white matter lesion volumes. We then examined how these candidate BEC biomarkers related to white matter lesion volumes, cerebral microhemorrhages, and lacunar infarcts in the ARIC study (Atherosclerosis Risk in Communities; US multisite; 1990-2017). Finally, we determined whether these candidate BEC biomarkers, when measured during midlife, were related to dementia risk over a 25-year follow-up period. RESULTS: Of the 28 proteins identified as BEC-enriched, 4 were significantly associated with white matter lesion volumes (CDH5 [cadherin 5], CD93 [cluster of differentiation 93], ICAM2 [intracellular adhesion molecule 2], GP1BB [glycoprotein 1b platelet subunit beta]), while another approached significance (RSPO3 [R-Spondin 3]). A composite score based on 3 of these BEC proteins accounted for 11% of variation in white matter lesion volumes in BLSA participants. We replicated the associations between the BEC composite score, CDH5, and RSPO3 with white matter lesion volumes in ARIC, and further demonstrated that the BEC composite score and RSPO3 were associated with the presence of ≥1 cerebral microhemorrhages. We also showed that the BEC composite score, CDH5, and RSPO3 were associated with 25-year dementia risk. CONCLUSIONS: In addition to identifying BEC proteins in plasma that relate to cerebral small vessel disease and dementia risk, we developed a composite score of plasma BEC proteins that may be used to estimate blood-brain barrier integrity and risk for adverse neurovascular outcomes.

Reversible Modulation of Aptamer-Ligand Binding in RNA Light-Up Aptamers Containing G-Quadruplex Using Chemical Stimuli.

Regulating a system in equilibrium transiently to out-of-equilibrium by using certain stimuli is the strategy used by natural biomolecules to function. Herein, we showed that the interaction of synthetic RNA aptamers, having a G-quadruplex core structure, with their corresponding ligands could be regulated from their equilibrium state to non-equilibrium state in a reversible manner using simple chemical stimuli (Ag+ and cysteine). The approach would be useful for designing aptamer regulators that work in a dynamic nucleic acid network, where a strict control on aptamer-ligand interaction is needed. In addition, to the best of our knowledge, this is the first report which shows that RNA G-quadruplexes can be disrupted by the addition of silver ions. This would be useful not only in designing RNA-based sensors or regulators but would also be useful for understanding the role of metal ions in RNA folding and catalysis.

Surface area change detection of snow/ice cover over Zemu Glacier of Sikkim Himalaya.

This study assessed the snow/ice surface area changes over the Zemu Glacier in the Eastern Himalayas. Zemu is considered to be the largest glacier in the Eastern Himalayas located in the Sikkim State of India. Change detection in the snow/ice surface areal extent of the Zemu Glacier was delineated from the year 1945 using US Army Map Service-Topographical Sheets and Landsat imageries available from 1987 to 2020. The results obtained solely focus on surface-change delineation using remote sensing satellite data and GIS software. Landsat imagery of the years 1987, 1997, 2009, 2018, and 2020 was used for snow and ice pixel extraction. Normalized Difference Snow Index (NDSI), Snow Cover Index (S3), and new band ratio index were used to extract the pure snow and ice pixels, fresh snow, and debris-covered snow/ice area and pixels mixed with shadow to demarcate the surface area changes. Manual delineation was required and undertaken for better results. A slope raster image was generated from Shuttle Radar Topography Mission (SRTM) digital elevation model (DEM) data to delineate the slope and hill shade. The results illustrate that the snow/ice surface covering the glacier had an area of 113.5 km2 in the year 1945 which was reduced to 78.31 km2 in the year 2020 indicating a total snow/ice surface area loss of 31% in 75 years. A loss of 11.45% was observed from 1945 to 1987 in the areal extent, while from 1987 to 2009, a decadal loss of approximately 7% was observed. The surface area loss of 8.46% from 2009 to 2018 led to infer the maximum loss of snow and ice over the glacier body at a rate of 0.94% per year. Between the years 2018 and 2020, the glacier lost 1.08% of its surface area. The Accumulation Area Ratio (AAR) considering the accumulation and ablation areas of the glacier indicated a gradual decline of the accumulation zone in the recent years. Global Land Ice Measurement from Space (GLIMS) program data with RGI version 6.0 was used as a reference to demarcate the areal extent of Zemu Glacier. The study gained above 80% of overall accuracy by generating a confusion matrix in ArcMap. The analysis of this seasonal snow/ice cover showed that there has been a drastic decline in the surface snow/ice cover area over the Zemu Glacier over the years 1987 to 2020 and NDSI; S3 analysis provided improved results to delineate snow/ice cover area over such steep terrain topography of Sikkim Himalaya.

Desymmetrisation of meso-2,4-Dimethyl-8-oxabicyclo[3.2.1]-oct-6-ene-3-ol and its Application in Natural Product Syntheses.

The compounds containing chiral centers and different functional groups serve as magnificent building blocks for the preparation of various natural products that are having immense biological activity. "Dimethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol" is one of the wonderful synthons to construct multiple stereo centers at a time during the asymmetric synthesis. In this account, we discuss our research efforts toward the synthesis of various simple and complex natural products from the past three decades (1995-2020) by using dimethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol as a synthon. Moreover, the synthetic utility of this starting material was investigated and well demonstrated. Further, we executed the desymmetrization of dimethyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-ol by hydroboration to get different chiral centers. After obtaining the stereocenters, we could manage either the fragment, formal or total synthesis of natural products, by simple protection and deprotection sequence followed by C-C bond formation steps.

A Systematic Review of Sodium Disorders in HHV-6 Encephalitis.

Human herpesvirus 6 (HHV-6) encephalitis has a high mortality rate. Among those who survive, ~80% develop some type of permanent neurologic disorder. Early diagnosis and treatment may help prevent long-term sequelae. There have been several case reports as well as retrospective and prospective studies associating HHV-6 encephalitis with some form of sodium imbalance, either hyponatremia or hypernatremia; however, the exact frequency post-HCT is unknown, with reports ranging from 30% to 100%. We performed a systematic review of the literature and found 34 cases of HHV-6 encephalitis reported in conjunction with sodium imbalance that documented the timing of that imbalance relative to the onset of encephalitis. Sodium imbalance occurred before or at the onset of HHV-6 encephalitis in all but 2 cases (94%). This finding supports previous suggestions that sodium imbalance can be considered an early indicator of the potential development or presence of HHV-6 encephalitis in at-risk patient populations.

Polarization independent enhancement of zeroth order diffracted second harmonic from multilayer gallium selenide on a silicon resonant metasurface.

We demonstrate polarization-independent resonant-enhancement of second harmonic generation (SHG) from multilayer Gallium Selenide (GaSe) on a silicon-based resonant metasurface. Two-dimensional hexagonal photonic lattice with circularly symmetric silicon meta-atoms are designed to achieve resonant field enhancement at the fundamental wavelength independent of the incident polarization direction. Such structures are however found to exhibit strong resonant field depolarization effects at the fundamental excitation fields resulting in modified nonlinear polarization components when compared to the native GaSe layer. Furthermore, the sub-wavelength metasurface designed to have resonances at the fundamental wavelengths act as a higher order diffraction grating at the second harmonic wavelength. Nonlinear wave propagation simulations show that the higher order diffracted SHG exhibit strong polarization dependent enhancement with characteristics very different from the native GaSe layer. In this context, polarization independent enhancement of the second harmonic signal is achieved only for the zeroth order diffracted component. Experimental study of second harmonic generation from the GaSe layer integrated with the silicon metasurface shows maximum nonlinear signal enhancement on-resonance with polarization dependence identical to the native GaSe layer by selectively detecting the zeroth-order diffracted component. This work shows that it is not sufficient to use symmetric meta-atoms in such 2D material integrated resonant metasurfaces for achieving polarization independent nonlinear optical enhancement. Depolarization of the resonant fields and higher-order diffraction at the nonlinear signal wavelength need to be considered as well.

Nesfatin-1 ameliorates type-2 diabetes-associated reproductive dysfunction in male mice.

PURPOSE: The present study was aimed to demonstrate the recuperative effect of nesfatin-1 on testicular dysfunction in the high-fat diet (HFD)/streptozotocin (STZ)-induced type-2 diabetes mellitus (T2DM) mice. METHOD AND RESULTS: Three experimental groups were formed: (1) vehicle control (VC), (2) T2DM mice, (3) T2DM + nesf-1. The mice with blood glucose level higher than 300 mg/dL following HFD and a single dose of STZ were used for the experiment. The T2DM mice showed increases in body mass, blood glucose and insulin levels, reductions in spermatogenesis and steroidogenesis, production of antioxidative enzymes, and disturbed lipid profile. These alterations were all ameliorated by administration of nesfatin-1 at 20 µg/Kg BW for 15 days. Nesfatin-1 treatment also increased the production of testosterone (T), improved insulin sensitivity, and effectively ameliorated the testicular aberrations, and increased spermatogenesis and steroidogenesis. In addition, nesfatin-1 treatment upregulated the PCNA and Bcl2 expression and inhibited the caspase-3 and prohibitin expression in T2DM mice. Nesfatin-1 increased insulin receptor (IR) and GLUT8 expressions, and lactate production, the changes that further substantiate the increase of energy influx to the testis. CONCLUSION: Altogether, the results suggest the ameliorative effect of nesfatin-1 against T2DM-associated testicular dysfunctions and improved insulin sensitivity along with promoting T production and fertility in T2DM mice.

Organocatalytic Reductive Propargylation: Scope and Applications.

An amino acid-catalyzed three-component reductive coupling protocol has been developed for the selective high-yielding synthesis of nearly fifty examples of propargylated cyclic/acyclic systems from the various propargyl aldehydes, cyclic/acyclic CH acids, and Hantzsch ester under ambient conditions. It is an economical, efficient, catalytic, metal-free protocol for the quick gram-scale synthesis of propargylated cyclic/acyclic compounds, and many of these coupling compounds were purified by a simple precipitation-filtration technique instead of column chromatography. Functionally rich propargylated cyclic-1,3-diketones were specifically transformed into dihydropyrans found in natural products and drugs through an annulative etherification reaction by using Lewis-acid (AgOTf) catalysis. Further, we developed the C-methylation reactions on propargylated cyclic-1,3-diketones, which are prolific synthons in natural products and medicinal chemistry.

A highly efficient Baby Spinach-based minimal modified sensor (BSMS) for nucleic acid analysis.

Molecular recognition between nucleic acids has proven to be a powerful tool for designing hybridization probes for the detection of DNA and RNA sequences. Most detection probes rely on the conjugation of small molecule dyes to nucleic acids for fluorescence output, which is not cost-effective and also limits their applications in vivo, as they are not genetically encodable. More affordable sensors devoid of any chemical labeling are needed that show high fluorescence output and are genetically encodable. Here, we have designed a label-free Baby Spinach-based minimal modified sensor (BSMS) for the analysis of nucleic acids. The minimal modification in the sensor design reduces the complexity of the design, and provides additional stabilization after binding the target nucleic acids, leading to a high fluorescence output. BSMS is able to detect both DNA and RNA of potentially any lengths and is based on a Baby Spinach aptamer that binds and enhances the fluorescence of a small molecule dye. BSMS shows specificity towards its analyte in the presence of other sequences and selectively differentiates between closely related sequences. BSMS comprises genetically encodable unmodified RNA and has been shown to function at ambient temperature, and thus is anticipated to provide nucleic acid monitoring in vivo.

Microscopic study of resonant third-harmonic generation from amorphous silicon nanodisk arrays.

A detailed microscopic study of third-harmonic generation (THG) from two-dimensional arrays of sub-wavelength spaced amorphous silicon nanodisks is reported. The arrays are designed to support broadband, minimally angle-sensitive resonances for the fundamental excitation wavelength in the 1500 nm region. This results in resonantly enhanced visible THG in the green spectral range with ∼500-fold enhancement on-resonance, compared to the unpatterned a-Si thin-film. THG multispectral microscopic imaging reveals individual nanodisks with enhanced nonlinear signal on-resonance. For increasing pump intensities, spatially dependent saturation effects are observed for the first time, to the best of our knowledge, in such dielectric nanostructure arrays with THG images showing a reversal of contrast.

A possible direct action of oxytocin on spermatogenesis and steroidogenesis in pre-pubertal mouse.

The aim of this study was to evaluate the effects of in vivo and in vitro treatments of oxytocin (OT) on the testis of pre-pubertal mice. The OT treatment produced significant changes in the spermatogenic and steroidogenic activity by increasing expression of OT-receptor in the testis of pre-pubertal mice. Treatment with OT showed increased proliferation of germ cells as indicated by increased number of spermatocytes and round spermatids. Dose-dependent increase in expression of PCNA, Bcl-2 and AR proteins was observed in the testis of OT-treated mice as compared with the control and further supports the role of OT in germ cell proliferation and survival. The pre-pubertal mice treated with increasing dose of OT showed significant increase in testosterone synthesis due to dose-dependent stimulatory effects on 3ß-HSD activity and increased expression of STAR, LH-receptor (LH-R) and gonadotrophin-releasing hormone receptor (GnRH-R) proteins in the testis. The in vitro study has confirmed in vivo finding showing direct action of OT on testicular steroidogenesis. Thus, OT stimulates testicular spermatogenesis and steroidogenesis by directly acting on testis in mice.

Disseminated CD8-positive, CD30-positive cutaneous lymphoproliferative eruption with overlapping features of mycosis fungoides and primary cutaneous anaplastic large cell lymphoma following remote solitary lesional presentation.

CD8-positive, CD30-positive cutaneous lymphoproliferative disorders constitute a rare subset of T-cell lymphoproliferative conditions, including variants of primary cutaneous anaplastic large cell lymphoma (ALCL), mycosis fungoides, lymphomatoid papulosis type D, cutaneous gamma-delta T-cell lymphoma and cutaneous peripheral T-cell lymphoma. These entities share overlapping clinical, histopathologic and immunophenotypic features, presenting both a clinical and pathological diagnostic challenge. Presented here is a 73-year-old man with a disseminated, indolent CD30+, CD8+ cutaneous lymphoproliferative disorder with overlapping clinical and histopathological features of both mycosis fungoides and primary cutaneous ALCL, as well as features of lymphomatoid papulosis. To our knowledge, this is the first case of a generalized CD8+, CD30+ eruption with features of both mycosis fungoides and primary cutaneous ALCL arising following an episode of solitary primary cutaneous CD8-positive ALCL.

Hypolipidemic mechanism of oryzanol components- ferulic acid and phytosterols.

UNLABELLED: The effect of oryzanol (well known hypolipidemic component in rice bran oil) and its chemical constituents- ferulic acid (FA) and phytosterols on hypolipidemia were investigated. METHODS AND RESULTS: Docking (in silico) studies showed that FA had a better binding ability with lipase while sterols bound well with HMG-CoA reductase. Further in vivo studies of feeding high fat (30%) to rats increased body weights, serum TC, TG, non-HDL-C and reduced HDL-C were observed, compared to normal diet fed group (ND). ORZ treated groups alleviated the lipid profile. Furthermore, increased organ weights, higher intestinal lipase activity, and liver lipid peroxidation was observed in the high-fat group (HF). These effects were ameliorated in oryzanol concentrate fed groups (ORZ). Higher fecal fat was found in ORZ groups, analysis of fecal matter by mass spectroscopy revealed the presence of FA. In vitro, a bile acid binding study supported the strong affinity of sterol towards bile acids. In conclusion, oryzanol in the intestine is cleaved into FA and sterol by intestinal lipase enzymes both lipase and HMG-CoA reductase activities were inhibited, respectively. These hydrolysates eliminated the bile acids, thus lowering lipid profiles.