Search

In this work, we investigate a predator–prey model with Crowley–Martin functional response and constant harvesting. The model is extended by incorporating two constant time delays, where the first delay(τ 1) is for density dependent feedback mechanism in the logistic growth of the prey and the second one is for gestation delay(τ 2) of the predator population. The dynamical behaviours such as positivity, boundedness, extinction criteria and existence, stability and bifurcations of the equilibria of the non-delay model are qualitatively discussed. The existence of periodic solutions via Hopf-bifurcation with respect to absence of delay, single delay and both delays are established. Finally, numerical simulations have been carried out to confirm our numerical results.

Aims: This study's objective was to determine how early-stage grass pea seedlings will respond to salinity and drought stress with iso-osmotic potential, emphasising ROS-scavenging enzymes. Study Design: Completely randomized design. Place and Duration of Study: Laboratory studies on the grass pea varieties BK-14 and Pratik were carried out in the academic years 2017–2018 and 2018–2019 at the Department of Plant Physiology, Bidhan Chandra Krishi Viswavidyalaya, Kalyani, Nadia, West Bengal, India. Methodology: Sodium chloride and PEG 6000 solutions with iso-osmotic potentials of -0.2, -0.4, and -0.8 MPa were used to study salinity's effects and drought stress. The experiment was conducted in sand culture using modified Hoagland solution under diffused light, at a temperature of 22°C and an approximate relative humidity (R.H.) of 80±1%. Results: Results indicated that drought stress was found to produce more adverse effects on seedling dry weight and lipid peroxidation in comparison with iso-osmotic potential of salinity stress. Variety BK-14 was found to be more tolerant than Pratik for seedling dry weight at the highest intensity of drought stress. The data further indicated that drought- induced more accumulation of phenol in the leaf as well than iso-osmotic salinity stress. The activities of four ROS scavenging enzymes (viz, superoxide dismutase, guaiacol peroxidase, ascorbate peroxidase and catalase) in leaves mostly showed a sigmoidal pattern of changes under varying levels of both stresses. Comparative analysis indicated that Pratik registered higher activities of two peroxidases, viz, GPOX and APX, under higher levels of drought stress while BK 14 registered higher activities under salinity stress. However, BK-14 was found to register a higher increase in SOD activity at the most intense level of salinity and drought stress as compared to Pratik. Conclusion: In the present experiment, it was discovered that BK-14 was generally more tolerant than Pratik for seedling growth under the utmost level of stress. This may be explained by the stronger antioxidative mechanism it exhibited in the present experiment under the conditions of the maximum stress, as generated by both enzymatic and non-enzymatic components.

Relative humidity (RH), an important climatic element influencing tree growth, is also crucial in assessing the General Circulation Models (GCMs) on global warming. However, in the absence of a relatively long record of RH in the Himalayan region, precise modelling of the climate change related processes and their impacts on this region are not well established. Here we present a new RH reconstruction for the pre-monsoon months (February–May) starting from 1800 C.E. using the tree-ring width data of subtropical Pinus roxburghii (chir-pine) from Pithoragarh, Western Himalaya, India. We found significant positive correlation between tree growth and pre-monsoon RH (n = 67, r = +0.569, p

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1–21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics.

Plant lectins, a natural source of glycans with a therapeutic potential may lead to the discovery of new targeted therapies. Glycans extracted from plant lectins are known to act as ligands for C-type lectin receptors (CLRs) that are primarily present on immune cells. Plant-derived glycosylated lectins offer diversity in their N-linked oligosaccharide structures that can serve as a unique source of homogenous and heterogenous glycans. Among the plant lectins-derived glycan motifs, Man9GlcNAc2Asn exhibits high-affinity interactions with CLRs that may resemble glycan motifs of pathogens. Thus, such glycan domains when presented along with antigens complexed with a nanocarrier of choice may bewilder the immune cells and direct antigen cross-presentation - a cytotoxic T lymphocyte immune response mediated by CD8+ T cells. Glycan structure analysis has attracted considerable interest as glycans are looked upon as better therapeutic alternatives than monoclonal antibodies due to their cost-effectiveness, reduced toxicity and side effects, and high specificity. Furthermore, this approach will be useful to understand whether the multivalent glycan presentation on the surface of nanocarriers can overcome the low-affinity lectin-ligand interaction and thereby modulation of CLR-dependent immune response. Besides this, understanding how the heterogeneity of glycan structure impacts the antigen cross-presentation is pivotal to develop alternative targeted therapies. In the present review, we discuss the findings on structural analysis of glycans from natural lectins performed using GlycanBuilder2 - a software tool based on a thorough literature review of natural lectins. Additionally, we discuss how multiple parameters like the orientation of glycan ligands, ligand density, simultaneous targeting of multiple CLRs and design of antigen delivery nanocarriers may influence the CLR targeting efficacy. Integrating this information will eventually set the ground for new generation immunotherapeutic vaccine design for the treatment of various human malignancies.

Background As per the Warburg effect, cancer cells are known to convert pyruvate into lactate. The accumulation of lactate is associated with metabolic and epigenetic reprogramming, which has newly been suggested to involve lactylation. However, the role of secreted lactate in modulating the tumor microenvironment through lactylation remains unclear. Specifically, there are gaps in our understanding of the enzyme responsible for converting lactate to lactyl-CoA and the nature of the enzyme that performs lactylation by utilizing lactyl-CoA as a substrate. It is worth noting that there are limited papers focused on metabolite profiling that detect lactate and lactyl-CoA levels intracellularly and extracellularly in the context of cancer cells. Methods Here, we have employed an in-house developed vertical tube gel electrophoresis (VTGE) and LC-HRMS assisted profiling of extracellular metabolites of breast cancer cells treated by anticancer compositions of cow urine DMSO fraction (CUDF) that was reported previously. Furthermore, we used molecular docking and molecular dynamics (MD) simulations to determine the potential enzyme that can convert lactate to lactyl-CoA. Next, the histone acetyltransferase p300 (HAT p300) enzyme (PDB ID: 6GYR) was evaluated as a potential enzyme that can bind to lactyl-CoA during the lactylation process. Results We collected evidence on the secretion of lactate in the extracellular conditioned medium of breast cancer cells treated by anticancer compositions. MD simulations data projected that acetyl-CoA synthetase could be a potential enzyme that may convert lactate into lactyl-CoA similar to a known substrate acetate. Furthermore, a specific and efficient binding (docking energy -9.6 kcal/mol) of lactyl-CoA with p300 HAT suggested that lactyl-CoA may serve as a substrate for lactylation similar to acetylation that uses acetyl-CoA as a substrate. Conclusion In conclusion, our data provide a hint on the missing link for the lactylation process due to lactate in terms of a potential enzyme that can convert lactate into lactyl-CoA. This study helped us to project the HAT p300 enzyme that may use lactyl-CoA as a substrate in the lactylation process of the tumor microenvironment.

Fusion genes were predicted by chimerascan + deFUSE, with BLAT validation.

Differential attack is a basic cryptanalysis method for block ciphers that exploits the high probability relations between the input and output differences. The existing work in quantum differential cryptanalysis of block ciphers is focused on resource estimation to recover the last round subkeys on the basis of relations constructed using classical methods. To find such relations using quantum computing, we propose a method to search the high probability differential and impossible differential characteristics. The method explores all possible input and output difference pairs using superposition of qubits. The proposed method is used to design the quantum circuit to search the differential characteristics for a toy cipher smallGIFT. We execute the quantum circuit on a quantum simulator to get differential and impossible characteristics. These characteristics are validated with the characteristics obtained using branch-and-bound based method. The differential characteristic is used to mount quantum key recovery attack using Grover's search. We provide the estimation of quantum resources to search the differential characteristics of lightweight block cipher GIFT-64 on a quantum computer.

Sarcomatoid metastatic renal cell carcinoma (mRCC) is associated with a poor prognosis, and the biology of the disease has been inadequately characterized. RNA sequencing (RNA-seq) was performed on adjacent benign, clear cell, and sarcomatoid components from clinical specimens with sarcomatoid mRCC. M phase and cell-cycle pathways were enriched in sarcomatoid versus adjacent clear cell components, suggesting greater cell proliferation. The expression of aurora kinase A (AURKA) was increased as part of these pathways, and its increased expression was validated by quantitative PCR (qPCR). Immunohistochemical (IHC) analysis revealed that AURKA levels were increased in sarcomatoid tissue compared with their benign or clear cell parts. The increase in AURKA correlated with increased mTOR pathway activity, as evidenced by increased expression of phosphorylated mTOR (S2448) and ribosomal protein S6K (T389). When AURKA was stably expressed in a RCC cell line (Renca), it resulted in increased expression and activity of mTOR, suggesting that overexpression of AURKA can activate the mTOR pathway. These results warrant the analysis of a larger clinical cohort and suggest that targeting AURKA and/or mTOR in patients with sarcomatoid mRCC should be explored.Implications: Comparative RNA-seq of adjacent sarcomatoid and clear cell histology of RCC indicates a proliferative phenotype and increased AURKA-dependent activation of mTOR signaling in sarcomatoid RCC, which could be targeted by available agents. Mol Cancer Res; 13(1); 130–7. ©2014 AACR.

Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non–clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation are limited. In this multicenter analysis, we explored the efficacy of PD-1/PD-L1 inhibitors in patients with nccRCC or sarcomatoid/rhabdoid differentiation. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate. Secondary endpoints include time-to-treatment failure (TTF), overall survival (OS), and biomarker correlates. Forty-three patients were included: papillary (n = 14; 33%), chromophobe (n = 10; 23%), unclassified (n = 9; 21%), translocation (n = 3; 7%), and ccRCC with sarcomatoid differentiation (n = 7, 16%). Of those 43 patients, 11 patients (26%) had sarcomatoid and/or rhabdoid differentiation (n = 7 with ccRCC; n = 4 nccRCC). Overall, 8 patients (19%) objectively responded, including 4 patients (13%) who received PD-1/PD-L1 monotherapy. Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (n = 3/7, 43%), translocation RCC (n = 1/3, 33%), and papillary RCC (n = 4/14, 29%). The median TTF was 4.0 months [95% confidence interval (CI), 2.8–5.5] and median OS was 12.9 months (95% CI, 7.4–not reached). No specific genomic alteration was associated with clinical benefit. Modest antitumor activity for PD-1/PD-L1–blocking agents was observed in some patients with nccRCC. Further prospective studies are warranted to investigate the efficacy of PD-1/PD-L1 blockade in this heterogeneous patient population. Cancer Immunol Res; 6(7); 758–65. ©2018 AACR.

Includes: Table 1S. Baseline patient and disease characteristics. Table 2S. Tumor mutation burden status. Table 3S. PDL1 expression data. Figure 1S. Overall survival for the total cohort.

Supplemtary figure and table legends

RNA-seq QC data (C=clear cell, S=sarcomatoid, B=benign).

Forward and reverse primers.

CONSORT diagram for the phase I/II trial of everolimus with and without BNC105P

Significantly different genes sarcomatoid vs. clear cell.

Master table of 82 mRCC patients with clinical and transcriptomic Nanostring data

PURPOSE Circulating tumor DNA (ctDNA) has been validated across multiple indications in the adjuvant and surveillance settings. We evaluated whether targeted digital sequencing (TARDIS) may distinguish a partial response (PR) from a complete response (CR) among patients with metastatic renal cell carcinoma (mRCC) receiving immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS Eligible patients had mRCC that yielded a PR or CR to ICI therapy. Peripheral blood was obtained at a single time point for ctDNA analysis. TARDIS was used for quantification of average variant allele fractions (VAFs). Our primary objective was to determine the association between VAFs and depth of response (PR v CR). A secondary objective was to determine whether VAFs were associated with disease progression. RESULTS Twelve patients were analyzed, nine of whom achieved a PR (75%). Patients received either nivolumab monotherapy (50%) or nivolumab plus ipilimumab (50%). ctDNA analysis incorporated an average of 30 patient-specific mutations (range, 19-35); average coverage depth was 103,342 reads per target. TARDIS quantified a significant difference in VAFs between PR and CR (median, 0.181% [IQR, 0.077%-0.420%] v 0.007% [IQR, 0.0%-0.028%], respectively [ P = .014]). Of the 12 patients in the series, six patients demonstrated radiographic progression subsequent to ctDNA assessment. Patients who progressed on subsequent scans had significantly higher ctDNA than those who maintained their response (median, 0.362% [IQR, 0.181%-2.71%] v 0.033% [IQR, 0.007%-0.077%], respectively [ P = .026]). CONCLUSION In this pilot study, TARDIS accurately differentiated PR from CR among patients with mRCC receiving immunotherapy, and also prospectively identified patients at risk for subsequent progression. Given these findings, we envision subsequent studies that validate these results and investigate the utility of this assay to discern appropriate candidates for discontinuation of immunotherapy.