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PURPOSE: AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics, and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory hematologic malignancies. PATIENTS AND METHODS: In the monotherapy cohort (n = 61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, during a 3-week cycle. In the combination cohort (n = 17), patients with acute myeloid leukemia and myelodysplastic syndrome received escalating doses of AZD5991 and venetoclax during either a 3- or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma pharmacokinetics and antitumor activity. RESULTS: The most common (≥30%) adverse events were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred because of adverse events: cardiac arrest, sepsis, tumor lysis syndrome, and acute respiratory failure; only tumor lysis syndrome was related to AZD5991. Dose-limiting toxicities occurred in five patients. Three patients with myelodysplastic syndrome achieved an objective response: one marrow complete remission without hematologic improvement, one partial remission with AZD5991 monotherapy, and one marrow complete remission with AZD5991 + venetoclax. Asymptomatic elevations of troponin I or T were observed in eight (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after Cycle 1. No associations were found between elevated troponin and cardiovascular risk factors. CONCLUSIONS: Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate.

This study investigates the underlying mechanisms of hydrogen peroxide (H₂O₂) sensing using a composite material of bismuth oxide and bismuth oxyselenide (Bi2OxSey). The antagonistic effect of tungsten (W)-doping on the electrochemical behavior was also examined. Undoped, 2 mol%, 4 mol%, and 6 mol% W-doped Bi2OxSey nanostructures were synthesized using a one-pot solution phase method involving selenium powder and hydrazine hydrate. W-doping induced a morphological transformation from nanosheets to spherical nanoparticles and amorphization of the bismuth oxyselenide phase. Electrochemical sensing measurements were conducted using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). H₂O₂ detection was achieved over a wide concentration range of 0.02 to 410 µM. In-depth CV analysis revealed the complex interplay of oxidation-reduction processes within the bismuth oxide and Bi2O2Se components of the composite material. W-doping exhibited an antagonistic effect, significantly reducing sensitivity. Among the studied samples, undoped Bi2OxSeγ demonstrated a high sensitivity of 83 μA μM⁻1 cm⁻2 for the CV oxidation peak at 0 V, while 6 mol% W-Bi2OxSey became completely insensitive to H2O2. Interestingly, DPV analysis showed a reversal of sensitivity trends with 2 and 4 mol% W-doping. The applicability of these samples for real-world analysis, including rainwater and urine, was also demonstrated.

PURPOSE: Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL. PATIENTS AND METHODS: Final results of the phase I study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion [Days 1, 3, 5 (Cycle 1); weekly infusions starting Day 8, Cycle 1] was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. RESULTS: Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in 1 patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n = 17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders. CONCLUSIONS: Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.

Foodborne illnesses caused by Salmonella represent a global one health challenge, with biofilm-forming strains exhibiting enhanced public health risks due to their ability to persist due to resistance to antimicrobial agents, disinfectants, and environmental stresses. While food-safety and public health investigation primarily focus on Salmonella identification and source tracing, they often overlook the biofilm-forming capacity of isolates, limiting their predictive value for risks posed by biofilm producing Salmonella. This study assessed fourier transform infrared (FTIR) biotyping for rapid serotype-independent differentiatial detection of biofilm-positive (BFP) from biofilm-negative (BFN) Salmonella. A total of 270 Salmonella strains representing 12 common serotypes were classified using three conventional biofilm assays (congo red and coomassie brilliant blue agar test, calcofluor test, and tube test) into true BFP (n = 80), true BFN (n = 64), and uncertain (n = 59) biofilm producers. Biofilm production for each group was also assessed with a microtiter plate assay. FTIR biotyping was applied to a subset of 115 strains (61 BFP, 54 BFN). Using spectral windows of 1180–1050 cm−1 and 1400–1200 cm−1, FTIR biotyping accurately differentiated BFP from BFN strains with 93.4 % sensitivity, 83.3 % specificity, and 88.6 % overall accuracy. FTIR biotyping differentiated 59 strains with uncertain biofilm status into BFN (n = 45) and BFP (n = 14). FTIR biotyping provides a rapid, sensitive and specific method for detection of biofilm-forming Salmonella strains. Incorporating FTIR biotyping for biofilm detection in current Salmonella surveillance and source-tracing protocols can enhance food safety risk assessments and improve Salmonella outbreak prevention.

In this paper, the existing Susceptible-Infected-Recovered-Deceased (SIRD) compartmental epidemiologic process model is modified for forecasting the coronavirus effect in India. The data from India was studied for weekly fatalities, weekly infected, weekly recovered, new cases, infected and recovered individuals, Reproductive Number [Formula: see text], recovery rate, death rate, and coefficient of transmission from 30 January 2020 to 31 July 2021. SARS Coronavirus 2 (SARS-CoV-2) is the Covid strain that causes Covid sickness (COVID-19), a respiratory ailment that triggered the outbreak of COVID-19 at the beginning of December 2019. We aim to provide a hybrid SIRD model for predicting the COVID-19 outbreak. In the proposed method, to improve the exploration ability of the Grey Wolf Optimizer (GWO) or to avoid stagnation in the swarm, a modified Grey Wolf Optimization Algorithm is used to optimize the initial value of Infected individuals. The modified SIRD model is further applied to get the predicted values. The data is examined on weekly basis to prevent noise. Depending on the fact, that the precise mode of transmission is highly dependent on how and when different precautions such as isolation, confinement, and other preventative measures were implemented, we put together our projections concerning satisfactory speculations based on genuine realities. The experimental results show the various trends observed in the pandemic in terms of number of peaks, increasing trend, decreasing trend, and continuous trend for infected individuals, weekly change in number of cases, weekly deaths, weekly infected, and weekly recoeverd cases of Covid-19. The proposed modified SIRD model could be a valuable tool for assessing the impact of government measures on COVID-19 outbreak.

Acute Myeloid Leukaemia (AML) is a malignant disorder of the bone marrow in which there is maturational arrest in blood cell progenitors, resulting in the failure of normal haematopoiesis. Acute Promyelocytic Leukaemia (APML) is a subtype of AML with a defined clinical course and a biology that is distinct from other forms of AML. Morphologically, the most common form of APML shows the presence of heavily granulated cells with folded and twisted nuclei in the bone marrow. Biologically, the cytogenetic changes define the syndrome, and molecular changes in the chromosomes play a critical role in leukaemogenesis. The occurrence of APML in the paediatric population is very rare, accounting for

According to the Humane Society, 25 to 40 percent of pet dogs in the United States are adopted from animal shelters. Shelter dogs can harbor bacterial, viral, fungal, and protozoal pathogens, posing risks to canine and human health. These bacterial pathogens may also carry antibiotic resistance genes (ARGs), serving as a reservoir for antimicrobial resistance (AMR) transmission. This study aimed to utilize whole metagenome sequencing (WMS) to screen for microbial pathogens and assess the resistome in healthy shelter dogs. Fecal samples from 58 healthy shelter dogs across 10 shelters in Kentucky, Tennessee, and Virginia were analyzed using WMS. Genomic DNA was extracted, and bioinformatics analyses were performed to identify pathogens and ARGs. The WMS detected 53 potentially zoonotic or known pathogens including thirty-eight bacterial species, two protozoa, five yeast species, one nematode, four molds, and three viruses. A total of 4560 ARGs signatures representing 182 unique genes across 14 antibiotic classes were detected. Tetracycline resistance genes were most abundant (49%), while β-lactam resistance genes showed the highest diversity with 75 unique ARGs. ARGs were predominantly detected in commensal bacteria; however, nearly half (18/38, 47.4%) of known bacterial pathogens detected in this study carried ARGs for resistance to one or more antibiotic classes. This study provides evidence that healthy shelter dogs carry a diverse range of zoonotic and antibiotic-resistant pathogens, posing a transmission risk through fecal shedding. These findings highlight the value of WMS for pathogen detection and AMR surveillance, informing therapeutic and prophylactic strategies to mitigate the transmission of pathogens among shelter dog populations and the risk associated with zoonoses.

Abstract Association between measurable residual disease (MRD) and survival outcomes in chronic lymphocytic leukemia (CLL) has often been reported. However, limited quantitative analyses over large datasets have been undertaken to establish the predictive power of MRD. Here, we provide a comprehensive assessment of published MRD data to explore the utility of MRD in the prediction of progression‐free survival (PFS). We undertook two independent analyses, which leveraged available published data to address two complimentary questions. In the first, data from eight clinical trials was modeled via a meta‐regression approach, showing that median PFS can be predicted from undetectable MRD rates at 3–6 months of post‐treatment. The resulting model can be used to predict the probability of technical success of a planned clinical trial in chemotherapy. In the second, we investigated the evidence for predicting PFS from competing MRD metrics, for example baseline value and instantaneous MRD value, via a joint modeling approach. Using data from four small studies, we found strong evidence that including MRD metrics in joint models improves predictions of PFS compared with not including them. This analysis suggests that incorporating MRD is likely to better inform individual progression predictions. It is therefore proposed that systematic MRD collection should be accompanied by modeling to generate algorithms that inform patients' progression.

The growth and survival of individual trees determine the physical structure of a forest with important consequences for forest function. However, given the diversity of tree species and forest biomes, quantifying the multitude of demographic strategies within and across forests and the way that they translate into forest structure and function remains a significant challenge. Here, we quantify the demographic rates of 1961 tree species from temperate and tropical forests and evaluate how demographic diversity (DD) and demographic composition (DC) differ across forests, and how these differences in demography relate to species richness, aboveground biomass (AGB), and carbon residence time. We find wide variation in DD and DC across forest plots, patterns that are not explained by species richness or climate variables alone. There is no evidence that DD has an effect on either AGB or carbon residence time. Rather, the DC of forests, specifically the relative abundance of large statured species, predicted both biomass and carbon residence time. Our results demonstrate the distinct DCs of globally distributed forests, reflecting biogeography, recent history, and current plot conditions. Linking the DC of forests to resilience or vulnerability to climate change, will improve the precision and accuracy of predictions of future forest composition, structure, and function.

The development of high-performance hydrogen peroxide (H2O2) sensors is critical for various applications, including environmental monitoring, industrial processes, and biomedical diagnostics. This study explores the development of efficient and selective H2O2 sensors based on bismuth oxide/bismuth oxyselenide (Bi2O3/Bi2O2Se) nanocomposites. The Bi2O3/Bi2O2Se nanocomposites were synthesized using a simple solution-processing method at room temperature, resulting in a unique heterostructure with remarkable electrochemical characteristics for H2O2 detection. Characterization techniques, including powder X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM), confirmed the successful formation of the nanocomposites and their structural integrity. The synthesis time was varied to obtain the composites with different Se contents. The end goal was to obtain phase pure Bi2O2Se. Electrochemical measurements revealed that the Bi2O3/Bi2O2Se composite formed under optimal synthesis conditions displayed high sensitivity (75.7 µA µM−1 cm−2) and excellent selectivity towards H2O2 detection, along with a wide linear detection range (0–15 µM). The superior performance is attributed to the synergistic effect between Bi2O3 and Bi2O2Se, enhancing electron transfer and creating more active sites for H2O2 oxidation. These findings suggest that Bi2O3/Bi2O2Se nanocomposites hold great potential as advanced H2O2 sensors for practical applications.

Background: Ovary is the most common site of non-neoplastic and neoplastic lesions, can appear at any age, and is the leading cause of hospitalization and surgery. The ovary is made up of totipotent sex cells and multipotent mesenchymal cells. As a result, when it becomes neoplastic, almost any type of tumor can develop. Aims and Objectives: The aim of the study was to find out the histopathological findings of ovarian lesions. Materials and Methods: The present study was carried out in the Department of Pathology, Pacific Institute of Medical Sciences, Udaipur, from April 2021 to September 2022 and includes 102 cases of ovarian lesions. Histopathology department received the specimens in formalin filled container and performed routine grossing and H and E staining procedure. Results: The incidence of neoplastic ovarian lesion was 40.2%. Majority of non-neoplastic lesion of ovary was follicular cyst (42.6%) followed by simple cyst (36.1%). Surface epithelial tumor was diagnosed in majority of ovarian tumors (73.2%) followed by germ cell tumor (22.0%). The majority histopathological benign tumor type was serous cystadenoma (43.9%) and malignant was high-grade serous carcinoma (14.63%). Conclusion: The incidence rate increased with age, with the greatest number of new cases being diagnosed beyond 4th and 5th decade. In our study, the youngest patient was of 2 year and oldest was of more than 60 years. However, histopathological study of ovarian tumors is still considered as a gold standard method, our observations and results proved to be valuable base line information regarding frequency and pattern of ovarian tumors.

Abstract Rho-associated coiled-coil containing protein kinase 1 (ROCK1) intracellular cell signaling pathway regulates cell morphology, polarity, and cytoskeletal remodeling. We observed the activation of ROCK1/myosin light chain (MLC2) signaling pathway in buffalopox virus (BPXV) infected Vero cells. ROCK1 depletion by siRNA and specific small molecule chemical inhibitors (Thiazovivin and Y27632) resulted in a reduced BPXV replication, as evidenced by reductions in viral mRNA/protein synthesis, genome copy numbers and progeny virus particles. Further, we demonstrated that ROCK1 inhibition promotes deadenylation of viral mRNA (mRNA decay), mediated via inhibiting interaction with PABP [(poly(A)-binding protein] and enhancing the expression of CCR4-NOT (a multi-protein complex that plays an important role in deadenylation of mRNA). In addition, ROCK1/MLC2 mediated cell contraction, and perinuclear accumulation of p-MLC2 was shown to positively correlate with viral mRNA/protein synthesis. Finally, it was demonstrated that the long-term sequential passage (P = 50) of BPXV in the presence of Thiazovivin does not select for any drug-resistant virus variants. In conclusion, ROCK1/MLC2 cell signaling pathway facilitates BPXV replication by preventing viral mRNA decay and that the inhibitors targeting this pathway may have novel therapeutic effects against buffalopox.

In this study, the status of T cell-dependent cytokine gene expressions in the acute phase (3-day post-infection and 5-day post-infection) of infection with vaccine virus strains of New castle disease virus (NDV) (R2B and Lasota), Avian infectious bronchitis virus (AIBV) (Massachusetts H120), and Infectious Bursal Disease virus (IBDV) in SPF chicken of seven day age was evaluated. The birds were divided into four groups, each having six birds. Each group of birds was inoculated with the prescribed dose of different vaccines at 7 days of age. Blood was collected before inoculation (uninfected), at the 3rd and 5th day post-inoculation. Presence of virus in peripheral blood confirmed by real-time reverse-transcription PCR assay and quantitation of cytokine was performed in peripheral blood by real time PCR assay. It was observed that the infection with different vaccine strains of viruses in poultry modulates cytokine expression in order to elicit antiviral immune responses. AIBV and NDV viruses markedly up-regulate IL- 2, IL-12, p40, IL-4, IL-5, and IL-13 whereas, IBDV induces prolonged up-regulation of IFN-γ, IL-10 genes.