Discovery of a first-in-class PROTAC degrader of histone lysine demethylase KDM4.

Targeting histone lysine demethylase 4 (KDM4) has emerged as a promising approach for cancer therapy. Despite significant progress in developing KDM4 inhibitors, many of these compounds demonstrate poor selectivity or limited cellular efficacy, and none have received approval for marketing. In this study, we designed and synthesized a series of novel KDM4-targeted proteolysis targeting chimeras (PROTAC) degraders, as exemplified by compound 11 (RDN8011).

Design, synthesis and biological evaluation of dual CDK9/PARP inhibitors for the treatment of cancer.

Combination of CDK9 and PARP inhibitors has demonstrated synergistic anticancer activity in ovarian cancer and triple-negative breast cancer (TNBC). In this study, we report the design and discovery of a series of dual CDK9/PARP inhibitors by incorporating pharmacophores targeting CDK9 and PARP. Notably, compounds 31, 34, and 36 exhibited potent and well-balanced inhibitory activity against CDK9 and PARP1, with IC values in the nanomolar range.

DNASE1L3-mediated PANoptosis enhances the efficacy of combination therapy for advanced hepatocellular carcinoma.

The introduction of combination therapy utilizing tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors for advanced hepatocellular carcinoma (HCC) has significantly altered the management of affected patients. However, the absence of predictive biomarkers to identify those who would derive the greatest benefit from this combination therapy underscores the necessity for further enhancements in its efficacy. In this study, we performed a proteomic analysis on surgical specimens from patients who either responded to or did not respond to combination therapy with sorafenib and programmed death-1 (PD-1) monoclonal antibody (mAb).

STIM1 promotes acquired resistance to sorafenib by attenuating ferroptosis in hepatocellular carcinoma.

Dysregulated calcium (Ca) signaling pathways are associated with tumor cell death and drug resistance. In non-excitable cells, such as hepatocellular carcinoma (HCC) cells, the primary pathway for Ca influx is through stromal interaction molecule 1 (STIM1)-mediated store-operated calcium entry (SOCE). Previous studies have demonstrated the involvement of STIM1-mediated SOCE in processes such as genesis, metastasis, and stem cell self-renewal of HCC.

Decoding the Molecular Mechanisms of BRAF -Induced Nevi Formation.

Melanocytes derived from neural crest cells harbor the BRAF mutation, which is the predominant driver of nevus formation in humans. This mutation leads to malignant cell proliferation and subsequent cell cycle arrest, culminating in oncogene-induced senescence and nevus development. Nevertheless, emerging evidence has highlighted the heterogeneity of cellular senescence markers in BRAF -induced senescent melanocytes.

Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma.

Background: While anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in patients with lung adenocarcinoma may hinder the efficacy of anti-PD-1 monotherapy.

Methods: Here, we delved into the patterns of lipid metabolism in patients with The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and their correlation with the immune microenvironment's cellular infiltration characteristics of the tumor.

GPAT3 is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma.

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), but acquired resistance during the treatment greatly limits its clinical efficiency. Lipid metabolic disorder plays an important role in hepatocarcinogenesis. However, whether and how lipid metabolic reprogramming regulates sorafenib resistance of HCC cells remains vague.

Unveiling the bifunctional roles of Cetyltrimethylammonium bromide in construction of NbCT@MoSe heterojunction for fast potassium storage.

Exploring robust electrode materials which could permit fast and reversible insertion/extraction of large K is a crucial challenge for potassium-ion batteries (PIBs). Smart interfacial design could facilitate electron/ion transport as well as assure the integrity of electrode. Herein, Cetyltrimethylammonium bromide (CTAB) was found to play bifunctional roles in construction of NbCT@MoSe heterostructure.

Comparison of consistency in acute stroke: Automated ASPECT score software tools and manual consensus scores.

Purpose: The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a standardized semi-quantitative scoring system. It is widely used to assess the extent of acute ischemic stroke (AIS). We evaluated the consistency of three automatic software packages with the overall and region-specific manual ASPECTS scores of AIS patients.

A new active bone-conduction implant: surgical experiences and audiological outcomes in patients with bilateral congenital microtia.

Purpose: First-generation bone bridges (BBs) have demonstrated favorable safety and audiological benefits in patients with conductive hearing loss. However, studies on the effects of second-generation BBs are limited, especially among children. In this study, we aimed to explore the surgical and audiological effects of second-generation BBs in patients with bilateral congenital microtia.

Stromal interaction molecule 1/microtubule-associated protein 1A/1B-light chain 3B complex induces metastasis of hepatocellular carcinoma by promoting autophagy.

Metastasis is the leading cause of death in hepatocellular carcinoma (HCC) patients, and autophagy plays a crucial role in this process by orchestrating epithelial-mesenchymal transition (EMT). Stromal interaction molecule 1 (STIM1), a central regulator of store-operated calcium entry (SOCE) in nonexcitable cells, is involved in the development and spread of HCC. However, the impact of STIM1 on autophagy regulation during HCC metastasis remains unclear.

VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature.

V-domain Ig suppressor of T cell activation (VISTA), encoded by the human VSIR gene, is a B7 family checkpoint homologous to the programmed death-Ligand 1 sequence. In gynecologic malignancies, VISTA is abnormally expressed and regulates the tumor immune microenvironment, causing a high upregulation of VISTA expression in T-cells and myeloid cells in the tumor microenvironment and promoting tumor proliferation, progression, and immune tolerance. Here, we review the research progress of VISTA in ovarian, cervical, and endometrial cancers through its structure and immunomodulatory mechanism.

Searching for desirable bodies: How recruiters value physically exertive extracurricular activities for graduate hiring at elite professional firms in China.

The field of research in evaluating and applying Bourdieu's theories has seen growing interests in studying how the formation and effect of cultural capital vary in different contexts and fields. While existing studies have increasingly focussed on evaluating the role of cultural capital in creating educational inequalities in the Chinese context, little is known about how activities and taste are valued in the Chinese labour market. Drawing on semi-structured interviews with 73 recruiters in elite professional firms in China, this article presents a study on how recruiters interpret physically exertive extracurricular activities (ECAs) for graduate hiring.

STIM1 in tumor cell death: angel or devil?

Stromal interaction molecule 1 (STIM1) is involved in mediating the store-operated Ca entry (SOCE), driving the influx of the intracellular second messenger calcium ion (Ca), which is closely associated with tumor cell proliferation, metastasis, apoptosis, autophagy, metabolism and immune processes. STIM1 is not only regulated at the transcriptional level by NF-κB and HIF-1, but also post-transcriptionally modified by miRNAs and degraded by ubiquitination. Recent studies have shown that STIM1 or Ca signaling can regulate apoptosis, autophagy, pyroptosis, and ferroptosis in tumor cells and act discrepantly in different cancers.

Development and validation of a core competence instrument for clinical nursing teachers: A mixed-methods study.

Background: Competence-based education (CBE) highlights the important position of clinical nursing teachers and stipulates additional requirements for them. However, research on the core competence of clinical nursing teachers remains lacking, which has hindered their development and the cultivation of nursing students.

Objectives: Developing and verifying a core competence instrument to evaluate clinical nursing teachers' competence in clinical settings and provide empirical guidance for their development.

Architecting carbon-coated MoCT/MoSe heterostructures enables robust potassium storage.

Herein, carbon-coated MoSe decorated MoCT MXene heterostructures (MoSe/MoCT@C) have been fabricated. MoCT works as a dual-function electron/ion conductor, which not only provides high conductivity and mechanical strength, but also prevents the severe self-aggregation of few layered MoSe nanosheets. The high reversible capacities of 405 mA h g at 100 mA g after 150 cycles and 258 mA h g at 2000 mA g after 400 cycles could be achieved for a potassium-ion battery.

Role of early hearing aid experience in speech recognition in patients with bilateral congenital microtia following Bonebridge implantation: a retrospective cohort study.

Purpose: To identify audiological and demographic variables that predict speech recognition abilities in patients with bilateral microtia who underwent Bonebridge (BB) implantation.

Methods: Fifty patients with bilateral microtia and bilateral conductive hearing loss (CHL) who underwent BB implantation were included. Demographic data, preoperative hearing aid use experience, and audiological outcomes (including pure-tone hearing threshold, sound field hearing threshold [SFHT], and speech recognition ability) for each participant were obtained.

Clinicopathological correlations of peritoneal endometriosis and deep infiltrating endometriosis.

Objective: The present study aims to investigate the clinical and histopathological features of peritoneal endometriosis (PEM) and deep infiltrating endometriosis (DIE).

Methods: A total of 100 patients with PEM and DIE admitted to Dalian Women and Children's Hospital/Dalian Women and Children's Medical Center between October 2018 and December 2021 were selected as the study subjects. One hundred and thirty-one PEM specimens and 37 DIE were collected, 22 cases of these patients' eutopic endometrium were used as control (15 in PEM, seven in DIE).

Vehicle crash simulations for safety: Introduction of connected and automated vehicles on the roadways.

Traffic accidents are one main cause of human fatalities in modern society. With the fast development of connected and autonomous vehicles (CAVs), there comes both challenges and opportunities in improving traffic safety on the roads. While on-road tests are limited due to their high cost and hardware requirements, simulation has been widely used to study traffic safety.

Mycorrhizae Enhance Soybean Plant Growth and Aluminum Stress Tolerance by Shaping the Microbiome Assembly in an Acidic Soil.

Strongly acidic soils are characterized by high aluminum (Al) toxicity and low phosphorus (P) availability, which suppress legume plant growth and nodule development. Arbuscular mycorrhizal fungi (AMF) stimulate rhizobia and enhance plant P uptake. However, it is unclear how this symbiotic soybean-AMF-rhizobial trio promotes soybean growth in acidic soils.

Optimal Choice for Improving the Hearing in Children with Unilateral Microtia and Atresia: Softband or Adhesive Adapter?

Introduction: A nonsurgical bone conduction hearing aid (BCHA) is a well-established treatment for children with congenital unilateral microtia and atresia (UMA). To date, limited studies have evaluated the audiological characteristics of the different wearing modes in the same nonsurgical BCHA.

Methods: Eighteen patients with UMA aged 5-24 years were included.

Case study of cervical cancer prevention in two sub-Saharan African countries: Rwanda and Sierra Leone.

Background: Cervical cancer is a public health issue of global concern. It is a preventable disease but continues to threaten the lives of women, especially in developing countries in sub-Saharan Africa.

Methods: We selected two African countries in sub-Saharan Africa (the Republic of Rwanda and the Republic of Sierra Leone) to show a good example of cervical cancer prevention and constrains hindering countries from effectively implementing cervical cancer programs.

Acceptance of clinical artificial intelligence among physicians and medical students: A systematic review with cross-sectional survey.

Background: Artificial intelligence (AI) needs to be accepted and understood by physicians and medical students, but few have systematically assessed their attitudes. We investigated clinical AI acceptance among physicians and medical students around the world to provide implementation guidance.

Materials And Methods: We conducted a two-stage study, involving a foundational systematic review of physician and medical student acceptance of clinical AI.

Characteristics of sound localization in children with unilateral microtia and atresia and predictors of localization improvement when using a bone conduction device.

This study aimed to determine the characteristics of sound localization in children with unilateral microtia and atresia (UMA) and the influence of a non-surgical bone conduction device (BCD). Hearing benefits were evaluated by the word recognition score (WRS), speech reception threshold, the international outcome inventory for hearing aids (IOI-HA), and the Speech, Spatial, and Qualities of Hearing Test for Parent (SSQ-P). Sound localization was measured using broadband noise stimuli randomly played from seven loudspeakers at different stimulus levels [65, 70, and 75 dB sound pressure levels (SPLs)].