Research progress of LpxC inhibitor on Gram-negative bacteria.

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a metalloprotein that utilizes zinc as a cofactor. LpxC plays a crucial role in catalyzing the synthesis of Lipid A, a major component of the outer membrane lipopolysaccharide in Gram-negative (G-) bacteria, and LpxC shares no common amino acid sequence with various mammalian enzyme proteins. LpxC is essential for the survival of Gram-negative bacteria, making it a promising target for the antibacterial drug development.

Prevalence of Homologous Recombination Repair Mutations and Association with Clinical Outcomes in Patients with Solid Tumors: A Study Using the AACR Project GENIE Dataset.

Background/objectives: Mutations in and/or (BRCAm) and other homologous recombination repair genes (HRRm) are associated with several cancers. We evaluated the prevalence and association with overall survival (OS) of somatic BRCAm and HRRm among patients with advanced solid tumors.

Methods: We used deidentified data from the AACR GENIE Biopharma Collaborative dataset derived from patients with tumors genotyped using next-generation sequencing between 1 January 2014 and 31 December 2017.

Discovery of novel PRMT1 inhibitors: a combined approach using AI classification model and traditional virtual screening.

Protein arginine methyltransferases (PRMTs) play crucial roles in gene regulation, signal transduction, mRNA splicing, DNA repair, cell differentiation, and embryonic development. Due to its significant impact, PRMTs is a target for the prevention and treatment of various diseases. Among the PRMT family, PRMT1 is the most abundant and ubiquitously expressed in the human body.

The numbers of biopsied cells in routine clinical process of preimplantation genetic testing (PGT) do not affect the pregnancy outcomes of embryos.

Study Question: Does the number of biopsied trophectoderm cells sampled for preimplantation genetic testing for monogenic disease (PGT-M) affect subsequent clinical outcomes for those selected embryos?

Summary Answer: The number of biopsied cells does not affect the pregnancy outcome of preimplantation genetically tested embryos.

What Is Known Already: The successful execution of PGT relies on the availability of a certain number of high-quality biopsied cells. Evidence in the literature has reported that blastocyst biopsies may have a negative impact on clinical outcomes.

Neoadjuvant anti-PD-1 alone or in combination with anti-TIGIT or an oncolytic virus in resectable stage IIIB-D melanoma: a phase 1/2 trial.

Neoadjuvant immunotherapies have shown antitumor activity in melanoma. Substudy 02C of the global, rolling-arm, phase 1/2, adaptive-design KEYMAKER-U02 trial is evaluating neoadjuvant pembrolizumab (anti-PD-1) alone or in combination, followed by adjuvant pembrolizumab, for stage IIIB-D melanoma. Here we report results from the first three arms: pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy.

Towards Effective Causal Partitioning by Edge Cutting of Adjoint Graph.

Causal partitioning is an effective approach for causal discovery based on the divide-and-conquer strategy. Up to now, various heuristic methods based on conditional independence (CI) tests have been proposed for causal partitioning. However, most of these methods fail to achieve satisfactory partitioning without violating d-separation, leading to poor inference performance.

The Prediction of LptA and LptC Protein-Protein Interactions and Virtual Screening for Potential Inhibitors.

Antibiotic resistance in Gram-negative bacteria remains one of the most pressing challenges to global public health. Blocking the transportation of lipopolysaccharides (LPS), a crucial component of the outer membrane of Gram-negative bacteria, is considered a promising strategy for drug discovery. In the transportation process of LPS, two components of the LPS transport (Lpt) complex, LptA and LptC, are responsible for shuttling LPS across the periplasm to the outer membrane, highlighting their potential as targets for antibacterial drug development.

CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial.

C-X-C motif chemokine receptor 2 (CXCR2) has a role in tumor progression, lineage plasticity, and reduction of immune checkpoint inhibitor efficacy. Preclinical evidence suggests potential benefit of CXCR2 inhibition in multiple solid tumors. In this phase 2 study (NCT03473925), adults with previously treated advanced or metastatic castration-resistant prostate cancer (CRPC), microsatellite-stable colorectal cancer (MSS CRC), or non-small-cell lung cancer (NSCLC) were randomized 1:1 to the CXCR2 antagonist navarixin 30 or 100 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks up to 35 cycles.

Biomarker Testing Journey Among Patients with Advanced Solid Tumors and Treatment Patterns by Homologous Recombination Repair Status: A Clinico-Genomic Database Study.

Introduction: Defects in the homologous recombination repair (HRR) pathway can include mutations in BRCA1 and BRCA2 (BRCAm) and other HRR genes (HRRm). These mutations are associated with a homologous recombination deficiency (HRD) phenotype. We evaluated testing journey and treatment patterns by BRCAm, HRRm, and HRD status in a real-world dataset.

Development of preimplantation genetic testing for monogenic diseases in China.

Preimplantation genetic testing for monogenic diseases (PGT-M) can effectively interrupt the transmission of genetic diseases from parents to the offspring before pregnancy. In China, there are over ten million individuals afflicted with monogenic disorders. This literature review summarizes the development of PGT-M in China for the past 24 years, covering the general steps such as the indications and contraindications, genetic and reproductive counselling, biopsy methods, detecting techniques and strategies during PGT-M application in China.

Association Between Homologous Recombination Repair Biomarkers and Survival in Patients With Solid Tumors.

Purpose: Mutations in and/or (BRCAm), other homologous recombination repair genes (HRRm), and homologous recombination deficiency (HRD) lead to an accumulation of genomic alterations that can drive tumorigenesis. The prognostic impact of these HRR pathway defects on overall survival (OS) in patients not receiving poly (ADP-ribose) polymerase inhibitors (PARPi) or immunotherapy is unclear. We evaluated the association of HRR biomarkers with OS in patients with advanced solid tumors receiving therapy excluding PARPi and immunotherapy.

The impact of digital finance on SMEs financialization: Evidence from thirty million Chinese enterprise registrations.

Based on the registration information of 30 million Chinese enterprises, this study innovatively constructs a financialization index based on the text information of enterprise business scope. Then, the impact of digital finance on small and medium-sized enterprise (SME) financialization is examined. Specifically, this study screens out SMEs involved in financial transactions by counting the keyword information in their business scope.

Discovery of 2,4-diphenyl-substituted thiazole derivatives as PRMT1 inhibitors and investigation of their anti-cervical cancer effects.

Cervical cancer is one of the most common cancers that affects middle-aged women and the discovery of new drugs to aid clinical management is needed. As an important member of the protein arginine methyltransferases (PRMTs) family, PRMT1 catalyzes the methylation of protein arginine, which can influence multiple biological processes of cancer cells, such as activating epithelial-mesenchymal transformation (EMT) and acquiring resistance to apoptosis. Therefore, PRMT1 can be considered as a potential drug target for cervical cancer.

A novel compound to overcome influenza drug resistance in endonuclease inhibitors.

Influenza is a seasonal respiratory illness that kills hundreds of thousands of people every year. Currently, neuraminidase inhibitors and endonuclease inhibitors are used in antiviral therapy. However, both drug types have encountered drug-resistant influenza strains in the human body.

Butein inhibits cancer cell growth by rescuing the wild-type thermal stability of mutant p53.

p53 is a transcription factor that activates the expression of various genes involved in the maintenance of genomic stability, and more than 50% of cancers harbor inactivating p53 mutations, which are indicative of highly aggressive cancer and poor prognosis. Pharmacological targeting of mutant p53 to restore the wild-type p53 tumor-suppressing function is a promising strategy for cancer therapy. In this study, we identified a small molecule, Butein, that reactivates mutant p53 activity in tumor cells harboring the R175H or R273H mutation.

Hybrid Metal-Organic Frameworks/Carbon Fibers Reinforcements for Additively Manufactured Composites.

Additively manufactured (AM) composites based on short carbon fibers possess strength and stiffness far less than their continuous fiber counterparts due to the fiber's small aspect ratio and inadequate interfaces with the epoxy matrix. This investigation presents a route for preparing hybrid reinforcements for AM that comprise short carbon fibers and nickel-based metal-organic frameworks (Ni-MOFs). The porous MOFs furnish the fibers with tremendous surface area.

Opto-magnetic resonance single-beam magnetometer driven by vector polarized light.

In this paper, we present an analysis of the amplitude variations of the opto-magnetic resonance absorption signals obtained in a single-beam magnetometer driven by radially or azimuthally polarized light (RPL/APL). It is shown that optically polarized atoms driven by cylindrical vector beams obtained only the alignment of atomic multipole moments but not the orientation, which is in good agreement with our simulation and experimental results. In comparison with the plane polarized pump light fields, cylindrical vector beams with much more complete electric vector polarization distribution in the transverse plane, make it unlikely to create the "emptying state " (no-atom populated) among the ground-state Zeeman sublevels for any possible orientation of the applied static magnetic field.

Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors.

Background: Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors.

Methods: Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab).

Phase 1b study of intravenous coxsackievirus A21 (V937) and ipilimumab for patients with metastatic uveal melanoma.

Purpose: No standard of care therapy exists for patients with metastatic uveal melanoma who are not HLA-A2:01 positive. The phase 1b, open-label CLEVER study (NCT03408587) evaluated V937 in combination with ipilimumab in patients with uveal melanoma.

Methods: Adults with advanced uveal melanoma and liver metastases received up to 8 cycles of intravenous V937 (1 × 10 TCID per infusion; infusions on days 1, 3, 5, and 8 [cycle 1], then every 3 weeks [Q3W] thereafter [cycles 2-8]) and 4 cycles of intravenous ipilimumab 3 mg/kg Q3W (beginning at cycle 1 day 8).

The Anti-Multidrug-Resistant Study on 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline Compounds.

As a major public health problem, the prevalence of () infections in hospitals due to the pathogen's multiple-antibiotic resistance has attracted extensive attention. We previously reported a series of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline (PQZ) compounds, which were designed by targeting dihydrofolate reductase (DHFR), and exhibited potent antibacterial activities. In the current study, based on our molecular-modeling study, it was proposed that PQZ compounds may function as potent DHFR (DHFR)-inhibitors as well, which inspired us to consider their anti- abilities.