BACKGROUND: Coronary atherectomy is used to treat severely calcified coronary artery lesions which are more frequent with increasing age, but its impact in older adults has not been sufficiently examined. METHODS: We compared adults ≥ 18 years old who underwent coronary atherectomy during inpatient PCI in 2016-2023 from the Vizient Clinical Data Base and compared outcomes in younger (< 65 years), youngest-old (65-74 years), middle-old (75-84 years), and oldest-old (≥ 85 years) adults. Primary outcome was in-hospital mortality, and secondary outcomes included postprocedural complications. RESULTS: Among 47,337 patients who underwent coronary atherectomy, 19,862 (42.0%) were younger adults and 27,475 (58.0%) were older adults, including 13,583 youngest-old, 10,206 middle-old, and 3,686 oldest-old adults. Compared with younger adults, youngest-old adults had higher mortality (adjusted odds ratio [aOR] = 1.37, P < 0.001), ischemic stroke (aOR = 1.35, P = 0.005), gastrointestinal hemorrhage (GIH) (aOR = 1.44, P < 0.001), acute kidney injury (AKI) (aOR = 1.43, P < 0.001), tamponade (aOR = 1.86, P < 0.001), and pericardiocentesis (aOR = 2.32, P < 0.001). Middle-old adults had higher mortality (aOR = 1.80, P < 0.001), GIH (aOR = 1.42, P = 0.002), AKI (aOR = 1.63, P < 0.001), tamponade (aOR = 2.52, P < 0.001), and pericardiocentesis (aOR = 3.13, P < 0.001). Oldest-old adults had the highest odds for mortality (aOR = 2.03, P < 0.001), GIH (aOR = 1.48, P = 0.016), AKI (aOR = 2.26, P < 0.001), tamponade (aOR = 3.86, P < 0.001), and pericardiocentesis (aOR = 4.21, P < 0.001). There was a significant interaction (P-interaction=0.035) between atherectomy and age groups with regard to the odds of in-hospital mortality. CONCLUSIONS In this large claims-based study, in-hospital mortality, GIH, AKI, tamponade, and pericardiocentesis were higher in older adults compared with younger adults, in a stepwise manner by age group.

Cancer is characterized by abnormal cell proliferation. Cyclins and cyclin-dependent kinases (CDKs) have been recognized as essential regulators of the intricate cell cycle, orchestrating DNA replication and transcription, RNA splicing, and protein synthesis. Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers, rendering cyclins and CDKs attractive therapeutic targets. Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use, fueling the development of CDK-targeted therapies. With this enthusiasm for finding novel CDK-targeting anti-cancer agents, there have also been exciting advances in the field of targeted protein degradation through innovative strategies, such as using proteolysis-targeting chimera, heat shock protein 90 (HSP90)‍-mediated targeting chimera, hydrophobic tag-based protein degradation, and molecular glue. With a focus on the translational potential of cyclin- and CDK-targeting strategies in cancer, this review presents the fundamental roles of cyclins and CDKs in cancer. Furthermore, it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs, detailing the underlying mechanisms of action for each approach. A comprehensive overview of the structure and activity of existing CDK degraders is also provided. By examining the structure‍‒‍activity relationships, target profiles, and biological effects of reported cyclin/CDK degraders, this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.
Humans ; Neoplasms/metabolism* ; Cyclin-Dependent Kinases/antagonists & inhibitors* ; Cyclins/metabolism* ; Proteolysis ; Antineoplastic Agents/pharmacology* ; Molecular Targeted Therapy ; Proteasome Endopeptidase Complex/metabolism* ; Animals

Tumor lineage plasticity (LP) is an emerging hallmark of cancer progression. Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids, we identified bromodomain protein BRD4 as a crucial player. Integrated ChIP-seq and RNA-seq analysis of tumors revealed, for the first time, that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis, axonogenesis, EMT and stem cells and key drivers such as POU3F2 (BRN2), ASCL1/2, NeuroD1, SOX2/9, RUNX1/2 and DLL3. Interestingly, BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1. Significantly, we demonstrated that BRD4 inhibitor AZD5153, currently at clinical development, possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer (NEPC) and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action (MOA) by AZD5153. Together, our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.

During the hyperacute phase of intracerebral hemorrhage (ICH), the mass effect and blood components mechanically lead to brain damage and neurotoxicity. Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake, culminating in ferroptosis in neurons. M6A (N6-methyladenosine) modification, the most prevalent mRNA modification, plays a critical role in various cell death pathways. The Fto (fat mass and obesity-associated protein) demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels. Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis. Applying nanopore direct RNA sequencing, we identified voltage-dependent anion channel 3 (Vdac3) as a potential target associated with ferroptosis. Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA. These findings elucidate the intricate interplay between Fto, Vdac3, m6A methylation, and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.
Ferroptosis/physiology* ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics* ; Animals ; Neurons/metabolism* ; Transferrin/pharmacology* ; Mice ; Methylation ; Mice, Inbred C57BL ; Adenosine/metabolism* ; RNA, Messenger/metabolism* ; Male ; Oxidative Stress/physiology*

Otitis media is an infection of the middle ear mainly caused by bacteria, and current treatments rely heavily on antibiotics. However, the emergence of antibiotic-resistant bacterial strains seriously affects their efficacy. In our study, we found that extracellular vesicles (EVs) derived from human natural killer cells (NKs) inhibit the proliferation of both standard and levofloxacin (LVX)-resistant strains of Staphylococcus aureus in a dose-dependent manner. Moreover, compared to LVX, EVs were more effective at reducing effusion and rescuing hearing thresholds in animal models. For LVX-sensitive strains, EVs were significantly more effective in terms of curative time but not curative rate. For LVX-resistant strains, EVs were significantly more effective in terms of both curative rate and curative time when applied alone or applied jointly with LVX. In summary, we found that NK EVs are highly effective in treating otitis media, providing an alternative approach for treating this common disease.
Killer Cells, Natural/metabolism* ; Exosomes/metabolism* ; Animals ; Humans ; Otitis Media/therapy* ; Staphylococcus aureus/drug effects* ; Disease Models, Animal ; Anti-Bacterial Agents/pharmacology* ; Levofloxacin/pharmacology*

Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.

Immigrants in the United States (U.S.) healthcare workforce face challenging working conditions. This study aimed to compare the working conditions of healthcare workers based on immigration status. Using National Health Interview Survey (NHIS) 2015 data, we compared the sociodemographic characteristics and working conditions between 374 non-U.S. born and 1,986 U.S. born healthcare workers. Multivariable logistic regression was used to examine associations between immigration status and selected working conditions. It was found that non-U.S. born and U.S. born healthcare workers differed in sociodemographic and occupational characteristics. After adjusting for sociodemographic covariates, non-U.S. born healthcare workers had higher odds of non-permanent contract work (aOR: 1.87, 95% CI [1.25, 2.79], p < 0.01) and lower odds of workplace harassment (aOR: 0.51, 95% CI [0.31, 0.83], p < 0.01), compared to U.S. born healthcare workers. Immigrant healthcare workers' occupational experiences should be further explored to improve organizational and psychosocial working conditions.

Immigrants in the United States (U.S.) healthcare workforce face challenging working conditions. This study aimed to compare the working conditions of healthcare workers based on immigration status. Using National Health Interview Survey (NHIS) 2015 data, we compared the sociodemographic characteristics and working conditions between 374 non-U.S. born and 1,986 U.S. born healthcare workers. Multivariable logistic regression was used to examine associations between immigration status and selected working conditions. It was found that non-U.S. born and U.S. born healthcare workers differed in sociodemographic and occupational characteristics. After adjusting for sociodemographic covariates, non-U.S. born healthcare workers had higher odds of non-permanent contract work (aOR: 1.87, 95% CI [1.25, 2.79], p < 0.01) and lower odds of workplace harassment (aOR: 0.51, 95% CI [0.31, 0.83], p < 0.01), compared to U.S. born healthcare workers. Immigrant healthcare workers' occupational experiences should be further explored to improve organizational and psychosocial working conditions.

Immigrants in the United States (U.S.) healthcare workforce face challenging working conditions. This study aimed to compare the working conditions of healthcare workers based on immigration status. Using National Health Interview Survey (NHIS) 2015 data, we compared the sociodemographic characteristics and working conditions between 374 non-U.S. born and 1,986 U.S. born healthcare workers. Multivariable logistic regression was used to examine associations between immigration status and selected working conditions. It was found that non-U.S. born and U.S. born healthcare workers differed in sociodemographic and occupational characteristics. After adjusting for sociodemographic covariates, non-U.S. born healthcare workers had higher odds of non-permanent contract work (aOR: 1.87, 95% CI [1.25, 2.79], p < 0.01) and lower odds of workplace harassment (aOR: 0.51, 95% CI [0.31, 0.83], p < 0.01), compared to U.S. born healthcare workers. Immigrant healthcare workers' occupational experiences should be further explored to improve organizational and psychosocial working conditions.

Immigrants in the United States (U.S.) healthcare workforce face challenging working conditions. This study aimed to compare the working conditions of healthcare workers based on immigration status. Using National Health Interview Survey (NHIS) 2015 data, we compared the sociodemographic characteristics and working conditions between 374 non-U.S. born and 1,986 U.S. born healthcare workers. Multivariable logistic regression was used to examine associations between immigration status and selected working conditions. It was found that non-U.S. born and U.S. born healthcare workers differed in sociodemographic and occupational characteristics. After adjusting for sociodemographic covariates, non-U.S. born healthcare workers had higher odds of non-permanent contract work (aOR: 1.87, 95% CI [1.25, 2.79], p < 0.01) and lower odds of workplace harassment (aOR: 0.51, 95% CI [0.31, 0.83], p < 0.01), compared to U.S. born healthcare workers. Immigrant healthcare workers' occupational experiences should be further explored to improve organizational and psychosocial working conditions.