Mendelian randomization analyses for PCOS: evidence, opportunities, and challenges.

Identifying etiological risk factors is significant for preventing and treating patients with polycystic ovary syndrome (PCOS). Through genetic variation, Mendelian randomization (MR) assesses causal associations between PCOS risk and related exposure factors. This emerging technology has provided evidence of causal associations of anti-Müllerian hormone (AMH) levels, sex hormone-binding globulin (SHBG) levels, menopause age, adiposity, insulin resistance (IR), depression, breast cancer, ovarian cancer, obsessive-compulsive disorder (OCD), and forced vital capacity (FVC) with PCOS, while lacking associations of type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), stroke, anxiety disorder (AD), schizophrenia (SCZ), bipolar disorder (BIP), and offspring birth weight with PCOS. In this review, we briefly introduce the concept and methodology of MR in terms of the opportunities and challenges in this field based on recent results obtained from MR analyses involving PCOS.

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.

circUBE3C modulates myoblast development by binding to miR-191 and upregulating the expression of p27.

Noncoding RNAs, including miRNAs (microRNAs) and circRNAs (circular RNA), are crucial regulators of myoblast proliferation and differentiation during muscle development. However, the specific roles and molecular mechanisms of circRNAs in muscle development remain poorly understood. Based on the existing circRNA-miRNA-mRNA network, our study focuses on circUBE3C, exploring its differential expression in fetal and adult muscle tissue of the cattle and investigating its impact on myoblast proliferation, apoptosis, and differentiation. The functional analysis of overexpression plasmids and siRNAs (small interfering RNAs) targeting circUBE3C was comprehensively evaluated by employing an array of advanced assays, encompassing CCK-8 (cell counting kit-8), EdU (5-ethynyl-20-deoxyuridine), flow cytometry, western blot analysis, and RT-qPCR. In vivo investigations indicated that overexpression of circUBE3C impedes the process of skeletal muscle regeneration. Mechanistically, we demonstrated that circUBE3C interacts with miR-191 and alleviates the suppression of p27 through cytoplasmic separation, bioinformatics prediction, dual-luciferase reporter assay, and RIP (RNA immunoprecipitation). Our findings indicate that the novel circRNA circUBE3C competitively binds to miR-191, thereby inhibiting proliferation and promoting apoptosis in bovine primary myoblasts and unveiling a regulatory pathway in bovine skeletal muscle development. These findings expand our understanding of circRNA functions in mammals and provide a basis for further exploration of their role in myogenesis and muscle diseases.

Activation of the PI3K/AKT signaling pathway by ARNTL2 enhances cellular glycolysis and sensitizes pancreatic adenocarcinoma to erlotinib.

BACKGROUND: Pancreatic adenocarcinoma (PC) is an aggressive malignancy with limited treatment options. The poor prognosis primarily stems from late-stage diagnosis and when the disease has become therapeutically challenging. There is an urgent need to identify specific biomarkers for cancer subtyping and early detection to enhance both morbidity and mortality outcomes. The addition of the EGFR tyrosine kinase inhibitor (TKI), erlotinib, to gemcitabine chemotherapy for the first-line treatment of patients with advanced pancreatic cancer slightly improved outcomes. However, restricted clinical benefits may be linked to the absence of well-characterized criteria for stratification and dependable biomarkers for the prediction of treatment effectiveness. METHODS AND RESULTS: We examined the levels of various cancer hallmarks and identified glycolysis as the primary risk factor for overall survival in PC. Subsequently, we developed a glycolysis-related score (GRS) model to accurately distinguish PC patients with high GRS. Through in silico screening of 4398 compounds, we discovered that erlotinib had the strongest therapeutic benefits for high-GRS PC patients. Furthermore, we identified ARNTL2 as a novel prognostic biomarker and a predictive factor for erlotinib treatment responsiveness in patients with PC. Inhibition of ARNTL2 expression reduced the therapeutic efficacy, whereas increased expression of ARNTL2 improved PC cell sensitivity to erlotinib. Validation in vivo using patient-derived xenografts (PDX-PC) with varying ARNTL2 expression levels demonstrated that erlotinib monotherapy effectively halted tumor progression in PDX-PC models with high ARNTL2 expression. In contrast, PDX-PC models lacking ARNTL2 did not respond favorably to erlotinib treatment. Mechanistically, we demonstrated that the ARNTL2/E2F1 axis-mediated cellular glycolysis sensitizes PC cells to erlotinib treatment by activating the PI3K/AKT signaling pathway. CONCLUSIONS: Our investigations have identified ARNTL2 as a novel prognostic biomarker and predictive indicator of sensitivity. These results will help to identify erlotinib-responsive cases of PC and improve treatment outcomes. These findings contribute to the advancement of precision oncology, enabling more accurate and targeted therapeutic interventions.

SRGN amplifies microglia-mediated neuroinflammation and exacerbates ischemic brain injury.

BACKGROUND: Microglia is the major contributor of post-stroke neuroinflammation cascade and the crucial cellular target for the treatment of ischemic stroke. Currently, the endogenous mechanism underlying microglial activation following ischemic stroke remains elusive. Serglycin (SRGN) is a proteoglycan expressed in immune cells. Up to now, the role of SRGN on microglial activation and ischemic stroke is largely unexplored. METHODS: Srgn knockout (KO), Cd44-KO and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAO) to mimic ischemic stroke. Exogenous SRGN supplementation was achieved by stereotactic injection of recombinant mouse SRGN (rSRGN). Cerebral infarction was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Neurological functions were evaluated by the modified neurological severity score (mNSS) and grip strength. Microglial activation was detected by Iba1 immunostaining, morphological analysis and cytokines' production. Neuronal death was examined by MAP2 immunostaining and FJB staining. RESULTS: The expression of SRGN and its receptor CD44 was significantly elevated in the ischemic mouse brains, especially in microglia. In addition, lipopolysaccharide (LPS) induced SRGN upregulation in microglia in vitro. rSRGN worsened ischemic brain injury in mice and amplified post-stroke neuroinflammation, while gene knockout of Srgn exerted reverse impacts. rSRGN promoted microglial proinflammatory activation both in vivo and in vitro, whereas Srgn-deficiency alleviated microglia-mediated inflammatory response. Moreover, the genetic deletion of Cd44 partially rescued rSRGN-induced excessed neuroinflammation and ischemic brain injury in mice. Mechanistically, SRGN boosted the activation of NF-κB signal, and increased glycolysis in microglia. CONCLUSION: SRGN acts as a novel therapeutic target in microglia-boosted proinflammatory response following ischemic stroke.

Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study.

Bruton tyrosine kinase (BTK) inhibitor is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Zanubrutinib, a highly selective BTK inhibitor, is approved for patients with MCL who have received ≥1 prior therapy. We report the long-term safety and efficacy results from the multicenter, open-label, phase 2 registration trial of zanubrutinib. Patients (n = 86) received oral zanubrutinib 160 mg twice daily. The primary endpoint was the overall response rate (ORR), assessed per Lugano 2014. After a median follow-up of 35.3 months, the ORR was 83.7%, with 77.9% achieving complete response (CR); the median duration of response was not reached. Median progression-free survival (PFS) was 33.0 months (95% confidence interval [CI], 19.4-NE). The 36-month PFS and overall survival (OS) rates were 47.6% (95% CI, 36.2-58.1) and 74.8% (95% CI, 63.7-83.0), respectively. The safety profile was largely unchanged with extended follow-up. Most common (≥20%) all-grade adverse events (AEs) were neutrophil count decreased (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), white blood cell count decreased (33.7%), and platelet count decreased (32.6%); most were grade 1/2 events. Most common (≥10%) grade ≥3 AEs were neutrophil count decreased (18.6%) and pneumonia (12.8%). Rates of infection, neutropenia, and bleeding were highest in the first 6 months of therapy and decreased thereafter. No cases of atrial fibrillation/flutter, grade ≥3 cardiac AEs, second primary malignancies, or tumor lysis syndrome were reported. After extended follow-up, zanubrutinib demonstrated durable responses and a favorable safety profile in R/R MCL. The trial is registered at ClinicalTrials.gov as NCT03206970.

Phase I study of the Syk inhibitor sovleplenib in relapsed or refractory mature B-cell tumors.

Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with anti-tumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/ refractory mature B-cell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase II dose (RP2D) (clinicaltrials gov. Identifier: NCT02857998). Overall, 134 Chinese patients were enrolled (dose escalation, N=27; dose expansion, N=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d.), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d.. The primary efficacy end point of independent review committee-assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% confidence interval: 37.5- 64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the dose-expansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased dose-proportionally with ascending dose levels from 200-800 mg, without observed saturation. Sovleplenib showed anti-tumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.

Genetic insights into the relationship between immune cell characteristics and ischemic stroke: A bidirectional Mendelian randomization study.

BACKGROUND AND PURPOSE: Ischemic stroke, a major contributor to global disability and mortality, is underpinned by intricate pathophysiological mechanisms, notably neuroinflammation and immune cell dynamics. Prior research has identified a nuanced and often paradoxical link between immune cell phenotypes and ischemic stroke susceptibility. The aim of this study was to elucidate the potential causal links between the median fluorescence intensity (MFI) and morphological parameters (MP) of 731 immune cell types and ischemic stroke risk. METHODS: By analyzing extensive genetic datasets, we conducted comprehensive Mendelian randomization (MR) analyses to discern the genetic correlations between diverse immune cell attributes (MFI and MP) and ischemic stroke risk. RESULTS: Our study identified key immune cell signatures linked to ischemic stroke risk. Both B cells and T cells, among other immune cell types, have a bidirectional influence on stroke risk. Notably, the regulatory T-cell phenotype demonstrates significant neuroprotective properties, with all odds ratio (OR) values and confidence intervals (CIs) being less than 1. Furthermore, CD39 phenotype immune cells, particularly CD39+ CD8+ T cells (inverse variance weighting [IVW] OR 0.92, 95% CI 0.87-0.97; p = 0.002) and CD39+ activated CD4 regulatory T cells (IVW OR 0.93, 95% CI 0.90-0.97; p < 0.001), show notable neuroprotection against ischemic stroke. CONCLUSION: This investigation provides new genetic insights into the interplay between various immune cells and ischemic stroke, underscoring the complex role of immune processes in stroke pathogenesis. These findings lay a foundation for future research, which may confirm and expand upon these links, potentially leading to innovative immune-targeted therapies for stroke prevention and management.

Inflammatory cell death PANoptosis is induced by the anti-cancer curaxin CBL0137 via eliciting the assembly of ZBP1-associated PANoptosome.

OBJECTIVE: PANoptosis, a new form of regulated cell death, concomitantly manifests hallmarks for pyroptosis, apoptosis, and necroptosis. It has been usually observed in macrophages, a class of widely distributed innate immune cells in various tissues, upon pathogenic infections. The second-generation curaxin, CBL0137, can trigger necroptosis and apoptosis in cancer-associated fibroblasts. This study aimed to explore whether CBL0137 induces PANoptosis in macrophages in vitro and in mouse tissues in vivo. METHODS: Bone marrow-derived macrophages and J774A.1 cells were treated with CBL0137 or its combination with LPS for indicated time periods. Cell death was assayed by propidium iodide staining and immunoblotting. Immunofluorescence microscopy was used to detect cellular protein distribution. Mice were administered with CBL0137 plus LPS and their serum and tissues were collected for biochemical and histopathological analyses, respectively. RESULTS: The results showed that CBL0137 alone or in combination with LPS induced time- and dose-dependent cell death in macrophages, which was inhibited by a combination of multiple forms of cell death inhibitors but not each alone. This cell death was independent of NLRP3 expression. CBL0137 or CBL0137 + LPS-induced cell death was characterized by simultaneously increased hallmarks for pyroptosis, apoptosis and necroptosis, indicating that this is PANoptosis. Induction of PANoptosis was associated with Z-DNA formation in the nucleus and likely assembly of PANoptosome. ZBP1 was critical in mediating CBL0137 + LPS-induced cell death likely by sensing Z-DNA. Moreover, intraperitoneal administration of CBL0137 plus LPS induced systemic inflammatory responses and caused multi-organ (including the liver, kidney and lung) injury in mice due to induction of PANoptosis in these organs. CONCLUSIONS: CBL0137 alone or plus inflammatory stimulation induces PANoptosis both in vitro and in vivo, which is associated with systemic inflammatory responses in mice.

Application of CRISPR-cas-based technology for the identification of tuberculosis, drug discovery and vaccine development.

Tuberculosis (TB), which caused by Mycobacterium tuberculosis, is the leading cause of death from a single infectious agent and continues to be a major public health burden for the global community. Despite being the only globally licenced prophylactic vaccine, Bacillus Calmette-Guérin (BCG) has multiple deficiencies, and effective diagnostic and therapeutic options are limited. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas (CRISPR-associated proteins) is an adaptive immune system that is found in bacteria and has great potential for the development of novel antituberculosis drugs and vaccines. In addition, CRISPR-Cas is currently recognized as a prospective tool for the development of therapies for TB infection with potential diagnostic and therapeutic value, and CRISPR-Cas may become a viable tool for eliminating TB in the future. Herein, we systematically summarize the current applications of CRISPR-Cas-based technology for TB detection and its potential roles in drug discovery and vaccine development.

Rare correlation of somatic PRKACA mutations with pregnancy-associated aldosterone- and cortisol-producing adenomas: a case report and literature review.

BACKGROUND: Somatic mutations have been observed to induce aldosterone-producing adenomas (APAs). These may be accelerated during pregnancy. Somatic PRKACA mutations are common in cortisol-producing adenomas (CPAs). However, their role in APAs, particularly aldosterone- and cortisol-producing adenomas (A/CPAs), is not well understood. This study aims to investigate the association between PRKACA mutations and the accelerated development of A/CPAs during pregnancy. CASE PRESENTATION: A patient with primary aldosteronism (PA) associated with severe Cushing's syndrome (CS) underwent surgical resection of an adrenal tumor one year after delivery. Pathologic examination revealed an adrenocortical adenoma characterized primarily by zona glomerulosa hyperplasia. Somatic mutation analysis revealed the presence of the somatic PRKACA mutation, which was validated as a deleterious mutation by various computational databases. Immunohistochemical results showed positive staining for cytochrome P450 family 11 subfamily B member 1 (CYP11B1), cytochrome P450 family 11 subfamily B member 2 (CYP11B2), and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). Our study included a review of 20 previously documented cases of aldosterone- and cortisol-producing adenomas (A/CPAs), two of which were concurrently positive for both CYP11B1 and CYP11B2, consistent with our findings. CONCLUSION: Somatic mutations in PRKACA may correlate with the upregulation of LHCGR, which synergistically drives the accelerated growth of co-secretion tumors during pregnancy, thereby exacerbating disease progression.

Global epidemiology and genetic diversity of mcr-positive Klebsiella pneumoniae: A systematic review and genomic analysis.

The rapid increase of mcr-positive Klebsiella pneumoniae (K. pneumoniae) has received considerable attention and poses a major public health concern. Here, we systematically analyzed the global distribution of mcr-positive K. pneumoniae isolates based on published articles as well as publicly available genomes. Combining strain information from 78 articles and 673 K. pneumoniae genomes, a total of 1000 mcr-positive K. pneumoniae isolates were identified. We found that mcr-positive K. pneumoniae has disseminated widely worldwide, especially in Asia, with a higher diversity of sequence types (STs). These isolates were disseminated in 57 countries and were associated with 12 different hosts. Most of the isolates were found in China and were isolated from human sources. Moreover, MLST analysis showed that ST15 and ST11 accounted for the majority of mcr-positive K. pneumoniae, which deserve sustained attention in further surveillance programs. mcr-1 and mcr-9 were the dominant mcr variants in mcr-positive K. pneumoniae. Furthermore, a Genome-wide association study (GWAS) demonstrated that mcr-1- and mcr-9-producing genomes exhibited different antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs), thereby indicating a distinct evolutionary path. Notably, the phylogenetic analysis suggested that certain mcr-positive K. pneumoniae genomes from various geographical areas and hosts harbored a high degree of genetic similarities (<20 SNPs), suggesting frequent cross-region and cross-host clonal transmission. Overall, our results emphasize the significance of monitoring and exploring the transmission and evolution of mcr-positive K. pneumoniae in the context of "One health".

Analysis of erythrocyte and iron study data among plateletpheresis donors in Hangzhou, China.

BACKGROUND: The purpose of this study is to obtain the iron parameters level of blood donors and the population who need to pay attention to iron parameters level in this area. METHODS: A total of 993 plateletpheresis donors were included in this study, including 798 males and 195 females. The results of erythrocyte and iron parameters of blood donors were compared and analyzed in different groups according to the gender, age and number of blood donations. RESULT: The proportion of men and women with low serum ferritin (SF) levels was 10.8 % and 27.7 %, respectively. The mean levels of serum iron (SI), SF, transferrin saturation (Tfs), hemoglobin (Hb) and hematocrit (HCT) of male blood donors decreased with the increase of age groups, but there was no significant statistical difference between the results of female blood donors. The level of SI, SF, Tfs, Hb and HCT of male donors decreased with the increase of blood donations in the past year, while TRF and TIBC increased. The level of Hb, HCT and SF of female donors showed no significant downward trend, while the levels of TRF increased with increasing donations in the past year, excluding first-time donors. The SI of female donors trended down, and TIBC trended up with increasing donations. CONCLUSION: Blood collection institutions need to focus on iron parameters levels in older and frequent male donors, and young fertile female donors.

Lipid alterations play a role in the integration of PD-1/PD-L1 inhibitors and anlotinib for the treatment of advanced non-small-cell lung cancer.

BACKGROUND: Studies have shown that integrating anlotinib with programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors enhances survival rates among progressive non-small-cell lung cancer (NSCLC) patients lacking driver mutations. However, not all individuals experience clinical benefits from this therapy. As a result, it is critical to investigate the factors that contribute to the inconsistent response of patients. Recent investigations have emphasized the importance of lipid metabolic reprogramming in the development and progression of NSCLC. METHODS: The objective of this investigation was to examine the correlation between lipid variations and observed treatment outcomes in advanced NSCLC patients who were administered PD-1/PD-L1 inhibitors alongside anlotinib. A cohort composed of 30 individuals diagnosed with advanced NSCLC without any driver mutations was divided into three distinct groups based on the clinical response to the combination treatment, namely, a group exhibiting partial responses, a group manifesting progressive disease, and a group demonstrating stable disease. The lipid composition of patients in these groups was assessed both before and after treatment. RESULTS: Significant differences in lipid composition among the three groups were observed. Further analysis revealed 19 differential lipids, including 2 phosphatidylglycerols and 17 phosphoinositides. CONCLUSION: This preliminary study aimed to explore the specific impact of anlotinib in combination with PD-1/PD-L1 inhibitors on lipid metabolism in patients with advanced NSCLC. By investigating the effects of using both anlotinib and PD-1/PD-L1 inhibitors, this study enhances our understanding of lipid metabolism in lung cancer treatment. The findings from this research provide valuable insights into potential therapeutic approaches and the identification of new therapeutic biomarkers.

Identification and assessment of new PIM2 inhibitors for treating hematologic cancers: A combined approach of energy-based virtual screening and machine learning evaluation.

PIM2, part of the PIM kinase family along with PIM1 and PIM3, is often overexpressed in hematologic cancers, fueling tumor growth. Despite its significance, there are no approved drugs targeting it. In response to this challenge, we devised a thorough virtual screening workflow for discovering novel PIM2 inhibitors. Our process includes molecular docking and diverse scoring methods like molecular mechanics generalized born surface area, XGBOOST, and DeepDock to rank potential inhibitors by binding affinities and interaction potential. Ten compounds were selected and subjected to an adequate evaluation of their biological activity. Compound 2 emerged as the most potent inhibitor with an IC50 of approximately 135.7 nM. It also displayed significant activity against various hematological cancers, including acute myeloid leukemia, mantle cell lymphoma, and anaplastic large cell lymphoma (ALCL). Molecular dynamics simulations elucidated the binding mode of compound 2 with PIM2, offering insights for drug development. These results highlight the reliability and efficacy of our virtual screening workflow, promising new drugs for hematologic cancers, notably ALCL.

Global distribution and genetic characterization of blaOXA-positive plasmids in Escherichia coli.

In recent years, the emergence of blaOXA-encoding Escherichia coli (E. coli) poses a significant threat to human health. Here, we systematically analyzed the global geographic distribution and genetic characteristics of 328 blaOXA-positive E. coli plasmids based on NCBI database. Twelve blaOXA variants have been discovered, with blaOXA-1 (57.93%) being the most common, followed by blaOXA-10 (11.28%) and blaOXA-48 (10.67%). Our results suggested that blaOXA-positive E. coli plasmids were widespread in 40 countries, mainly in China, the United States, and Spain. MLST analysis showed that ST2, ST43, and ST471 were the top three host STs for blaOXA-positive plasmids, deserving continuing attention in future surveillance program. Network analysis revealed a correlation between different blaOXA variants and specific antibiotic resistance genes, such as blaOXA-1 and aac (6')-Ib-cr (95.79%), blaOXA-181 and qnrS1 (87.88%). The frequent detection of aminoglycosides-, carbapenems- and even colistin-related resistance genes in blaOXA-positive plasmids highlights their multidrug-resistant potential. Additionally, blaOXA-positive plasmids were further divided into eight clades, clade I-VIII. Each clade displayed specificity in replicon types and conjugative transfer elements. Different blaOXA variants were associated with specific plasmid lineages, such as blaOXA-1 and IncFII plasmids in clade II, and blaOXA-48 and IncL plasmids in clade I. Overall, our findings provide a comprehensive insight into blaOXA-positive plasmids in E. coli, highlighting the role of plasmids in blaOXA dissemination in E. coli.

Benefit from luteal phase progestin-primed ovarian stimulation with clomiphene citrate supplementation in young women with diminished ovarian reserve: a retrospective study. / åµæ³¡æœŸå’Œé»„ä½“æœŸé«˜å­•æ¿€ç´ çŠ¶æ€ä¿ƒæŽ’åµæ–¹æ¡ˆåœ¨å¹´è½»åµå·¢å‚¨å¤‡åŠŸèƒ½å‡é€€å¥³æ€§ä¸­çš„åº”ç”¨.

OBJECTIVES: To compare the pregnant outcomes of luteal phase progestin-primed ovarian stimulation (PPOS) protocol with clomiphene citrate supplementation (LPPOS+CC) and follicular phase PPOS+CC protocol (FPPOS+CC) in young women with diminished ovarian reserve (DOR). METHODS: A total of 483 women aged ≤35 years with DOR, who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)/embryo transfer (ET) with controlled ovarian stimulation using LPPOS+CC (n=257) or FPPOS+CC (n=226) protocols during June 2018 and December 2021 at the First Affiliated Hospital of Wenzhou Medical University, were included in this retrospective study. The baseline characteristics, ovarian stimulation, endocrinological indicators, clinical outcomes between the two groups, and pregnancy outcomes of women achieved at least one high-quality cleavage-stage embryo or good-morphology blastocyst between the two groups were compared. RESULTS: No statistically significant differences were identified between the groups with respect to number of oocytes retrieved, oocyte maturation rate, high-quality cleavage-stage embryo cycle rate, the percentage of women with profound pituitary suppression, preterm birth rate, and live birth rate (P>0.05). Compared to FPPOS+CC group, the duration of stimulation [11.0 (9.0,12.0) vs. 9.0 (8.0,11.0) d, P<0.01] was significantly longer in the LPPOS+CC group. The LH levels on the day of trigger [4.0 (2.7,5.3) vs. 5.1 (3.2,7.2) IU/L, P<0.01], the percentage of women with LH levels of >10 IU/L on the trigger day (3.13% vs. 10.67%, P<0.01), and the two pronucleate (2PN) rate of ICSI oocytes (72.16% vs. 79.56%, P<0.05) were significantly lower in the LPPOS+CC group than those in the FPPOS+CC group. The consumption of total gonadotropin [2213 (1650,2700) vs. 2000 (1575,2325) IU, P<0.01], the progesterone levels on the day of trigger [1.3 (0.8,2.9) vs. 0.9 (0.6,1.2) ng/mL, P<0.01], the clinical pregnancy rate [61.88% vs. 46.84%, P<0.01], and implantation rate [42.20% vs. 31.07%, P<0.01] in the LPPOS+CC group were significantly higher than those in the FPPOS+CC group. CONCLUSIONS: Compared to FPPOS+CC, the LPPOS+CC protocol appears to have better pregnancy outcomes for young women with DOR undergoing IVF-ICSI-ET.

Latest Advances in the Application of Humanized Mouse Model for Staphylococcus aureus.

Staphylococcus aureus (S. aureus) is an important pathogen for humans and can cause a wide range of diseases, from mild skin infections, severe osteomyelitis to fatal pneumonia, sepsis, and septicemia. The mouse models have greatly facilitated the development of S. aureus studies. However, due to the substantial differences in immune system between mice and humans, the conventional mouse studies are not predictive of success in humans, in which case humanized mice may overcome this limitation to some extent. Humanized mice can be used to study the human-specific virulence factors produced by S. aureus and the mechanisms by which S. aureus interacts with humans. This review outlined the latest advances in humanized mouse models used in S. aureus studies.

Abundant Neutrophils-initiated Acute Myocardial Injury Following Coxsackievirus A6 Infection.

Coxsackievirus (CV) A6 is currently considered as a predominant pathogen of hand, foot, and mouth disease (HFMD), and is occasionally linked to myocardial injury. We first established a mouse model of CVA6-induced myocardial injury. Next, we analyzed the immune cell phenotypes CVA6-infected mice hearts by FACS, and found that CVA6 led to massive neutrophils infiltration, suggesting their potential link with the occurrence of myocardial injury. We further used either αGr-1 or αLy6G antibody to deplete neutrophils, and found that neutrophil-depleted animals showed decreased cardiac enzymes, lower degree pathology in hearts, and reduced inflammatory cytokine production compared to isotype controls. Finally, we confirmed the involvement of neutrophils in myocardial injury of clinical patients with severe HFMD. Overall, our study suggests that excessive neutrophils contribute to myocardial injury caused by CVA6 infection, which provides new insight into myocardial injury during the development of HFMD severity and the outcome of immune cell-mediated therapies.

Genomic Insights into CRISPR-Harboring Plasmids in the Klebsiella Genus: Distribution, Backbone Structures, Antibiotic Resistance, and Virulence Determinant Profiles.

CRISPR systems are often encoded by many prokaryotes as adaptive defense against mobile genetic elements (MGEs), but several MGEs also recruit CRISPR components to perform additional biological functions. Type IV-A systems are identified in Klebsiella plasmids, yet the distribution, characterization, and role of these plasmids carrying CRISPR systems in the whole Klebsiella genus remain unclear. Here, we performed large-scale comparative analysis of these plasmids using publicly available plasmid genomes. CRISPR-harboring plasmids were mainly distributed in Klebsiella pneumoniae (9.09%), covering 19.23% of sequence types, but sparse in Klebsiella species outside Klebsiella pneumoniae (3.92%). Plasmid genome comparison reiterated that these plasmids often carried the cointegrates of IncFIB and IncHI1B replicons, occasionally linked to other replicons, such as IncFIA, IncFII, IncR, IncQ, and IncU. Comparative genome analysis showed that CRISPR-carrying Klebsiella plasmids shared a conserved pNDM-MAR-like conjugation module as their backbones and served as an important vector for the accretion of antibiotic resistance genes (ARGs) and even virulence genes (VGs). Moreover, compared with CRISPR-negative IncFIB/IncHIB plasmids, CRISPR-positive IncFIB/IncHIB plasmids displayed high divergences in terms of ARGs, VGs, GC content, plasmid length, and backbone structures, suggesting their divergent evolutionary paths. The network analysis revealed that CRISPR-positive plasmids yielded fierce competitions with other plasmid types, especially conjugative plasmids, thereby affecting the dynamics of plasmid transmission. Overall, our study provides valuable insights into the role of CRISPR-positive plasmids in the spread of ARGs and VGs in Klebsiella genus.