Prostate cancer (PCa) is a leading malignancy in men, and understanding its molecular mechanisms is crucial for advancing therapeutic strategies. Ubiquitination, a key post-translational modification, regulates protein degradation and signaling, playing a vital role in cancer progression. This study focuses on HECTD4, a HECT-type E3 ubiquitin ligase, to identify its ubiquitination targets and understand its role in PCa.

HECTD4 knockdown was performed in LNCaP, PC-3, and DU145 PCa cell lines. A combination of semi-quantitative PCR and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify proteins with altered expression and ubiquitination profiles. Gene ontology analysis, pathway analysis, and a proliferation assay were conducted to explore the biological significance of HECTD4.

We identified 1,605 downregulated and 1,736 upregulated proteins upon HECTD4 knockdown. Key proteins involved in tumor suppression and cell cycle regulation, such as NUSAP1, CDK6, and MED13L, were ubiquitinated by HECTD4. Functional annotations revealed that these targets are associated with critical pathways, including phosphoinositide 3-kinase (PI3K)-AKT, Ras-mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR), as well as immune infiltration, drug response, and survival analysis.

HECTD4 regulates protein stability and activation through ubiquitination, impacting cell cycle progression, tumor suppression, and immune response in PCa. These findings suggest that HECTD4 is a promising therapeutic target, with potential applications in drug development aimed at disrupting oncogenic signaling and enhancing treatment efficacy.

The immunological synapse (IS) is a nanoscale platform that coordinates T cell activation, cytoskeletal polarization, Ca²⁺ signaling, and the directed secretion of lytic granules. In cancers, an acidic tumor microenvironment (TME; extracellular pH_e ~ 6.4-6.8) imposes a biophysical and metabolic stress that could destabilize this interface. Experimental studies indicate that even modest acidification could significantly reduce integrin-dependent adhesion strength, delay actin clearance at the synapse, and suppress store-operated Ca²⁺ entry, thereby leading to marked decreases in cytokine production and cytotoxic granule release. In parallel, tumor cells often maintain relative intracellular alkalinity by enhancing proton export via transporters such as NHE1, MCT1/4, and CAIX, thereby reinforcing cortical actin "shielding," metabolic resilience, and resistance to perforin-mediated killing. These asymmetric pH adaptations may therefore establish a hidden checkpoint at the IS that favors tumor survival. We synthesize current evidence on pH-dependent regulation of actin dynamics, integrin activation, mitochondrial function, and Ca²⁺ channels (Orai1/STIM1); highlight key methodological gaps, including the lack of approaches combining real-time intra- and extracellular pH and Ca²⁺ imaging; and discuss enabling technologies such as microfluidic platforms, genetically encoded pH sensors, and multiparametric single-cell assays. Finally, we outline therapeutic strategies aimed at modulating pH (buffers, inhibitors of NHE1, MCTs, V-ATPases, or CAIX) or engineering pH-resistant effector cells and consider how these approaches could synergize with immune checkpoint blockade, CAR-T cells, and bispecific antibodies. Viewing acidosis as a druggable checkpoint reframes the IS as a bidirectional, pH-tuned system and suggests testable paths to restore antitumor immunity.

Gallbladder cancer (GBC) is the most common and aggressive type of tumor occurring in the biliary system. Several studies have indicated the possible functions of circular RNAs (circRNAs) in GBC tumorigenesis. This research aimed to explore the roles of a novel circRNA, circ-ZEB1 (hsa_circ_0093509), in GBC. The expressions of circ-ZEB1, miR-144-3p, and ZEB2 in GBC cells were detected using RT-qPCR or western blot. The subcellular localization of circ-ZEB1 in GBC cells was determined. The function of circ-ZEB1, miR-144-3p, and ZEB2 in GBC cells was assessed by using CCK-8, EdU staining, colony formation, or Transwell assays. The relationship among miR-144-3p and corresponding targets, circ-ZEB1 and ZEB2, was confirmed. Additionally, xenograft experiments were conducted to assess the role of circ-ZEB1 in tumor growth in vivo. circ-ZEB1 was predominantly found in the cytoplasmic region of GBC cells and was upregulated in the GBC cell lines. Suppression of circ-ZEB1 reduced the proliferation and migration of GBC-SD and SGC-996 cells. Knockdown of circ-ZEB1 attenuates tumor growth in vivo. Mechanistically, circ-ZEB1 sponged miR-144-3p, which targeted ZEB2. Additionally, inhibition of miR-144-3p rescues the effects of circ-ZEB1 or ZEB2 knockdown. These results clarified a vital role of the circ-ZEB1/miR-144-3p/ZEB2 axis in GBC advancement, and may serve as a novel therapeutic target for GBC treatment.

Cancer stemness is a major therapeutic challenge in oncology. This study investigated the functional role and molecular mechanism of cell division cycle-associated 8 (CDCA8) in non-small cell lung cancer (NSCLC) stem cells. In this study, NSCLC and paracancerous tissues were collected. The lung adenocarcinoma cell line A549 and the lung squamous cell carcinoma cell line NCI-H520 were used. The stem-like cell population in A549 and NCI-H520 was isolated by CD44+ fluorescence-activated cell sorting. Gene expression was detected by quantitative real-time PCR, western blotting, and immunohistochemical staining. Cell stemness was assessed by biomarker (SOX and NANOG) expression detection, colony formation assay, and sphere-formation assay. Cell migration and invasion ability were determined by the Transwell experiment. Our results showed that CDCA8 expression was higher in NSCLC tissues than in paracancerous tissues. CDCA8 overexpression enhanced stemness properties, as evidenced by increased biomarker expression and colony formation, larger sphere size, and enhanced migratory/invasive capacity. Conversely, CDCA8 knockdown had the opposite effect. Mechanistically, we identified Y-box binding protein 1 (YBX1) as a direct binding protein of CDCA8 mRNA that positively regulated CDCA8 expression. YBX1 overexpression had a similar effect to CDCA8. Furthermore, recovery experiments revealed that the stemness-promoting effect of YBX1 was reversed by CDCA8 knockdown. These findings were further validated in xenograft models, confirming that the YBX1/CDCA8 axis promoted tumorigenesis in vivo. Collectively, our study reveals that YBX1 enhances cell stemness and metastasis of NSCLC by promoting CDCA8 expression. Our findings established a new mechanism that maintains NSCLC stemness and may provide novel biomarkers.

Bronchopulmonary dysplasia (BPD) is the most common pulmonary complication in preterm neonates. Emerging evidence links red blood cell (RBC) transfusions to increased BPD risk.

We conducted a retrospective cohort study of all infants of extremely low birth weight (ELBW) admitted to our NICU from January 2021 to December 2023. Infants enrolled within 7 days of birth were followed until 36 weeks' postmenstrual age (PMA) or until discharge or death-whichever came first. We extracted data on RBC transfusions, baseline characteristics and BPD diagnosis from validated electronic health records. To minimise confounding, we applied propensity score matching (PSM), overlap weighting (OW), multivariable logistic regression (adjusted for prespecified covariates), and restricted cubic spline (RCS) regression to assess nonlinear dose-response relationships.

Among 746 very low birth weight (VLBW) infants, BPD incidence was 35.2% (263/746). Before PSM, BPD occurred in 48.3% (224/464) of transfused infants vs 13.8% (39/282) of non-transfused infants (unadjusted OR=5.81; 95% CI: 3.96 to 8.53; p<0.001). After PSM (173 matched pairs), BPD remained significantly higher in the transfused group (39.3% vs 19.6%; adjusted OR=2.97; 95% CI: 1.76 to 5.04; p<0.001). OW yielded consistent results (OR=2.53; 95% CI: 1.64 to 3.91; p<0.001). In transfused infants (n=464), RCS regression showed a nonlinear association between timing of first transfusion and BPD risk (p=0.03). Neither total transfusion count nor blood storage duration correlated with BPD.

RBC transfusions are linked to a greater risk of BPD in preterm infants, with the timing of the initial transfusion having a nonlinear effect on the development of BPD. These findings highlight the need for further investigation into optimal transfusion strategies to mitigate BPD risk in this vulnerable population.

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) may cause stress-induced transient acute cardiac dysfunction through myocardial stunning, in the form of exacerbation-triggered Takotsubo syndrome (referred to as Takotsubo stunning). Although prior studies suggest an association between AECOPD and transient cardiac dysfunction, existing evidence is limited to retrospective cohorts, case reports and expert consensus. Therefore, the incidence and clinical impact of Takotsubo stunning with acute heart failure (AHF) during AECOPD remain unknown and may be overlooked due to overlapping clinical symptoms. Cardiac Assessment and Takotsubo-stunning among COPD-exacerbations in-Hospital (CATCH study) aims to determine the incidence of Takotsubo stunning during AECOPD and to evaluate its clinical implication.

CATCH is a prospective observational cohort study enrolling adults (≥18 years) admitted for AECOPD at Sahlgrenska University Hospital (Gothenburg, Sweden). Participants with chronic left ventricular systolic dysfunction (left ventricular ejection fraction <50%), pre-existing chronic regional wall motion abnormalities (RWMA) or prior type 1 myocardial infarction are excluded. Following informed consent, participants undergo echocardiographic screening for RWMA and/or systolic left ventricular dysfunction. Screening-positive patients have follow-up echocardiography at 24 hours (±6) and 30 days (±48 hours). Those with reversible dysfunction constitute the CATCH case group, while screening-negative participants serve as controls. Additional assessments include ECG, chest X-ray, N-terminal pro-B-type natriuretic peptide blood analysis and COPD severity. Primary outcomes include the incidence of reversible RWMA or left ventricular dysfunction (proxy for Takotsubo stunning) and in-hospital clinical signs of AHF (Killip class >1). A sample size of 150 patients is required for detecting AHF differences (α=0.05, 80% power).

The study received ethical approval from the Swedish Ethical Review Authority. All participants provided written informed consent. Results will be disseminated through peer-reviewed journals and scientific meetings.

The CATCH study is registered at ClinicalTrials.gov (NCT06597331). The reference number for ethical approval is 2024-02071-01 (with addenda 2024-05448-02 and 2025-05861-02).

Acute exacerbations (AEs) drive disease progression and healthcare burden in chronic obstructive pulmonary disease (COPD). Although prior AE history is the strongest predictor of future events, it cannot guide risk assessment in AE-naïve patients, highlighting the need for new prediction tools.

In this retrospective multicentre cohort study, we enrolled training and validation cohorts from five hospitals. Baseline demographics, symptom scores, spirometry, blood eosinophils and comorbidities were extracted from electronic records. Multivariable logistic regression was used to identify predictors and convert into score-based models.

The training and validation cohorts included 310 and 86 AE-naïve patients with COPD, respectively. Independent predictors of 1-year AEs included coexisting asthma, modified Medical Research Council score ≥2, blood eosinophils ≥2%, per cent predicted forced expiratory volume in 1 s <50% and cardiovascular comorbidities (ie, heart failure and ischaemic cerebrovascular events). Three models were developed with areas under receiver operating characteristic curves of 0.727 to 0.750 and 0.717 to 0.728 in the training and validation cohorts, respectively. At the optimal cutoffs, the sensitivity ranged from 76.7% to 88.2% and specificity from 42.0% to 65.7%. Risk stratification separated patients into low-risk, intermediate-risk and high-risk groups in validation cohort, with increasing AE rates (0.10, 0.43 and 0.86 events/year, respectively; P for trend=0.0047).

By incorporating baseline AE history, the externally validated, score-based prediction models provide a practical tool to estimate 1-year AE risk in patients with COPD.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by fibrothrombotic pulmonary vascular obstruction and associated small-vessel vasculopathy resulting in a progressive increase in pulmonary vascular resistance and right heart failure. Pulmonary thromboendarterectomy is the first-line treatment for surgically accessible disease. However, many patients are ineligible because of surgically inaccessible distal disease, medical comorbidities, or symptomatic residual disease after pulmonary thromboendarterectomy. Balloon pulmonary angioplasty (BPA) has emerged as a very effective therapeutic option in these patients. This statement from the BPA-CTEPH Alliance reviews the role of BPA in CTEPH, describing patient selection, procedural techniques, periprocedural management, complications, and training requirements. This U.S.-focused document provides practical guidance for establishing a BPA program within a multidisciplinary CTEPH center. Technical refinement and improved patient selection have significantly enhanced the safety and efficacy of BPA. Contemporary evidence suggests that BPA is associated with significant improvements in pulmonary vascular resistance, mean pulmonary artery pressure, functional class, and quality of life. There is a considerable learning curve associated with BPA, and complication rates, once prohibitive, have substantially decreased with operator experience and with adjunct medical therapy. BPA has become a critical component of multimodality management of CTEPH, with durable hemodynamic and clinical benefits. Continued research, with a particular focus on randomized controlled trials in the United States, is crucial to defining long-term outcomes and expanding access to this lifesaving therapy.

Sarcoidosis is a heterogeneous granulomatous disease with highly variable clinical trajectories, yet no validated biomarkers exist to distinguish progressive sarcoidosis (P-sarcoidosis) from non-progressive disease (NP-sarcoidosis). This lack of tractable biomarkers limits early risk stratification and impedes therapeutic decision-making. Preliminary data from our group suggest that P-sarcoidosis and NP-sarcoidosis may be differentiated by blood-derived and peripheral blood mononuclear cell (PBMC)-derived molecular signatures, as well as ex vivo granuloma biogenesis in response to putative disease-causing antigens. This protocol describes a multi-omic study aimed at identifying mechanistically grounded, clinically translatable biomarkers that distinguish P-sarcoidosis from NP-sarcoidosis.

We will perform an integrative proteomic and transcriptomic analysis across three biological compartments: ex vivo granuloma model, PBMCs and plasma. Participants with clinically adjudicated P-sarcoidosis or NP-sarcoidosis will provide blood samples for multi-omic profiling. P-sarcoidosis versus NP-sarcoidosis phenotype will be assessed based on changes in spirometry, diffusing capacity for carbon monoxide, chest radiography and need for treatment for pulmonary symptoms. Patient-reported outcomes will also be recorded. Data-driven computational approaches will be used to identify molecular pathways associated with granuloma formation and disease persistence and to develop a classifier that distinguishes P-sarcoidosis from NP-sarcoidosis. Rigorous internal validation, feature-selection procedures and statistical controls for high-dimensional data will be applied. Candidate biomarkers emerging from multi-compartment integration will be prioritised based on biological coherence, reproducibility and clinical feasibility.

The study protocol has been approved by the Biomedical Research Alliance of New York, serving as a single Institutional Review Board (IRB) for the project (IRB # 23-02-503), as well as at National Jewish Health (IRB# HS-4091), University of Minnesota (STUDY00020121/SITE00002051) and The Ohio State University (IRB# 2023X0140). All participants will provide informed consent prior to enrolment. Results will be disseminated through peer-reviewed publications, scientific conferences and presentations to patients and advocacy groups. De-identified datasets and analytic workflows will be shared in accordance with institutional policies and data-sharing agreements.

Cataract surgery is the most frequently performed surgery worldwide, crucial for restoring sight in millions. The COVID-19 pandemic and an aging population have increased barriers to timely surgery. Missed preoperative instructions and poor adherence to postoperative care contribute to surgery cancellations, delays, and potential complications. Mobile digital health interventions could enhance adherence and reduce cancellations.

This study assessed the effectiveness of the Sharp Health Companion smartphone app, built on the CareKit health platform, compared with printed instructions. The aim was to evaluate its impact on medication adherence, surgery delays and cancellations, visual outcomes, and patient experience among older adults undergoing cataract surgery.

In this randomized controlled trial, 200 patients aged 41-87 (mean 69, SD 8.2) years were enrolled at a high-volume ophthalmology practice between December 2022 and January 2024. Most participants (145/200, 73%) were 65 years or older. Patients were randomized to group 1 (printed instructions with phone reminders, n=104) or group 2 (Sharp Health Companion app supplemented with backup printed instructions, n=96). Both groups received identical perioperative instructions and medications. Data included demographics, visual acuity, medication adherence (self-reported by paper checklist or Sharp Health Companion app care-card checklist and eye medication bottle weights), surgery cancellations and delays, and satisfaction surveys administered preoperatively, on postoperative day 1, and at 30 days.

Sharp Health Companion app users had fewer same-day surgery delays (1/96, 1%) than those receiving printed instructions (10/104, 10%; P=.01), while cancellation rates were similar (P=.33). Patient-reported preparedness for surgery was high and comparable between groups on postoperative day 1 (group 1: mean 9.56, SD 1.19; group 2: 9.77, SD 0.73; P=.16). Preparedness for recovery at postoperative month 1 was similarly high (mean 9.92, SD 0.37 vs mean 9.85, SD 0.47; P=.28). At 30 days postoperatively, visual acuity improvement was similar (mean 0.14, SD 0.17 vs mean 0.11, SD 0.13 logarithm of the minimum angle of resolution; P=.13), and complications were rare (iritis 2/98, 2% vs 1/87,1%; cystoid macular edema 1/98, 1% vs 1/87, 1%). Self-reported medication adherence favored printed instruction users (66/68, 97% vs 47/64, 73%; P<.001), whereas objective antibiotic-drop adherence favored app users (mean 5.36, SD 1.17 g vs mean 5.67, SD 1.00 g; P=.046).

The Sharp Health Companion app reduced same-day surgery delays and improved patient experience while supporting objective medication adherence in predominantly older adults undergoing cataract surgery. These findings suggest mobile health interventions can enhance perioperative care and efficiency, even in populations less familiar with technology.

ClinicalTrials.gov NCT07028359; https://clinicaltrials.gov/ct2/show/NCT07028359.