Octyl gallate has potent anti-inflammasome activity by directly binding to NLRP3 LRR domain.

The NOD-, LRR-, and Pyrin domain-containing protein 3 (NLRP3) inflammasome plays key roles in regulating inflammation. Numerous studies show that the abnormal activation of NLRP3 associates with the initiation and progression of various diseases. Hence, the NLRP3 inflammasome may be a promising therapeutic target for these diseases. Octyl gallate (OG) is a small molecule with antioxidant, antimicrobial, antifungal, and anti-inflammatory activities; however, the mechanism underlying its anti-inflammatory activity is still unclear. Here, we developed a screening system for NLRP3-inflammasome inhibitors. A total of 3287 small molecules were screened for inhibitors of nigericin-induced NLRP3 oligomerization. OG was identified as a novel inhibitor. We show that OG directly targets the LRR domain of NLRP3 and thereby blocks the inflammatory cascade of the NLRP3 inflammasome. This contrasts with the mode-of-action of other direct NLRP3 inhibitors, which all bind to the NACHT domain of NLRP3. Interestingly, OG also inhibits the priming step by downregulating the Raf-MEK1/2-ERK1/2 axis. Thus, OG inhibits the NLRP3 inflammasome by two distinct mechanisms. Importantly, OG injection ameliorated the inflammation in mouse models of foot gout and sepsis. Our study identifies OG as a potential therapeutic agent for NLRP3-associated diseases.

Phylogenetic analysis of swine influenza A (H1N2) viruses isolated in Jinju City, Republic of Korea.

Genomic sequences of the swine influenza A (H1N2) viruses "A/Swine/South Korea/GN-1/2018" and "A/Swine/South Korea/GNJJ/2020" sampled from Jinju City, Republic of Korea, are reported here. The sequences of these viruses were 99% similar. These included eight genes from each of the H3N2pM, A(H1N1)2009pdm, and North American swine lineages.

Assessment of Equine Influenza Virus Status in the Republic of Korea from 2020 to 2022.

Equine influenza virus (EIV) causes acute respiratory disease in horses and belongs to the influenza A virus family Orthomyxoviridae, genus Orthomyxovirus. This virus may have severe financial implications for the horse industry owing to its highly contagious nature and rapid transmission. In the Republic of Korea, vaccination against EIV has been practiced with the active involvement of the Korea Racing Authority since 1974. In this study, we monitored the viral RNA for EIV using PCR, as well as the antibody levels against 'A/equine/South Africa/4/03 (H3N8, clade 1)', from 2020 to 2022. EIV was not detected using RT-PCR. The seropositivity rates detected using a hemagglutination inhibition assay were 90.3% in 2020, 96.7% in 2021, and 91.8% in 2022. The geometric mean of antibody titer (GMT) was 83.4 in 2020, 135.7 in 2021, and 95.6 in 2022. Yearlings and two-year-olds in training exhibited lower positive rates (59.1% in 2020, 38.9% in 2021, and 44.1% in 2022) than the average. These younger horses may require more attention for vaccination and vaccine responses against EIV. Continuous surveillance of EIV should be performed to monitor the prevalence and spread of this disease.

First Detection of Influenza D Virus Infection in Cattle and Pigs in the Republic of Korea.

Influenza D virus (IDV) belongs to the Orthomyxoviridae family, which also include the influenza A, B and C virus genera. IDV was first detected and isolated in 2011 in the United States from pigs with respiratory illness. IDV circulates in mammals, including pigs, cattle, camelids, horses and small ruminants. Despite the broad host range, cattle are thought to be the natural reservoir of IDV. This virus plays a role as a causative agent of the bovine respiratory disease complex (BRDC). IDV has been identified in North America, Europe, Asia and Africa. However, there has been no information on the presence of IDV in the Republic of Korea (ROK). In this study, we investigated the presence of viral RNA and seroprevalence to IDV among cattle and pigs in the ROK in 2022. Viral RNA was surveyed by the collection and testing of 999 cattle and 2391 pig nasal swabs and lung tissues using a real-time RT-PCR assay. IDV seroprevalence was investigated by testing 742 cattle and 1627 pig sera using a hemagglutination inhibition (HI) assay. The viral RNA positive rate was 1.4% in cattle, but no viral RNA was detected in pigs. Phylogenetic analysis of the hemagglutinin-esterase-fusion (HEF) gene was further conducted for a selection of samples. All sequences belonged to the D/Yamagata/2019 lineage. The seropositivity rates were 54.7% in cattle and 1.4% in pigs. The geometric mean of the antibody titer (GMT) was 68.3 in cattle and 48.5 in pigs. This is the first report on the detection of viral RNA and antibodies to IDV in the ROK.

European Committee on Antimicrobial Susceptibility Testing-Recommended Rapid Antimicrobial Susceptibility Testing of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus From Positive Blood Culture Bottles.

Background: Early diagnosis and treatment are important for a good prognosis of bloodstream infections. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommends rapid antimicrobial susceptibility testing (RAST) based on the disk diffusion methodology for 4, 6, and 8 hours of incubation. We evaluated EUCAST-RAST of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus from positive blood culture bottles. Methods: Twenty strains of E. coli, K. pneumoniae, and S. aureus were tested using EUCAST-RAST. Ten antimicrobial agents against E. coli and K. pneumoniae and four agents against S. aureus were tested. The diameter of the inhibition zone (mm) was compared with the minimal inhibitory concentration (µg/mL) obtained using the Sensititre AST system (TREK Diagnostic Systems, East Grinstead, UK). Results: For E. coli, the percentage of total categorical agreement (CA) was 69.5% at 4 hours, and 87% at 8 hours. For K. pneumoniae, the total CA was 89% at 4 hours, and 95.5% at 6 hours. For S. aureus, the total CA was 100% after 4 hours. Discrepancies were observed mainly for E. coli with ß-lactam antimicrobial agents, and the numbers of errors decreased over time. Conclusions: EUCAST-RAST for K. pneumoniae and S. aureus met the United States Food and Drug Administration criteria at 6 and 4 hours, respectively, whereas that for E. coli did not meet the criteria for up to 8 hours. RAST can shorten the turn-around testing time by more than one day; therefore, if applied accurately according to laboratory conditions, antimicrobial agent results can be reported faster.

Expanding roles of centrosome abnormalities in cancers.

Centrosome abnormalities are hallmarks of human cancers. Structural and numerical centrosome abnormalities correlate with tumor aggressiveness and poor prognosis, implicating that centrosome abnormalities could be a cause of tumorigenesis. Since Boveri made his pioneering recognition of the potential causal link between centrosome abnormalities and cancer more than a century ago, there has been significant progress in the field. Here, we review recent advances in the understanding of the causes and consequences of centrosome abnormalities and their connection to cancers. Centrosome abnormalities can drive the initiation and progression of cancers in multiple ways. For example, they can generate chromosome instability through abnormal mitosis, accelerating cancer genome evolution. Remarkably, it is becoming clear that the mechanisms by which centrosome abnormalities promote several steps of tumorigenesis are far beyond what Boveri had initially envisioned. We highlight various cancer-promoting mechanisms exerted by cells with centrosome abnormalities and how these cells possessing oncogenic potential can be monitored. [BMB Reports 2023; 56(4): 216-224].

Changes in the Mean of and Variance in Psychological Disease Incidences before and during the COVID-19 Pandemic in the Korean Adult Population.

The coronavirus disease 2019 (COVID-19) pandemic has been suggested to increase the risk of depression and anxiety disorders. This study expanded upon previous findings by estimating the changes in medical visits for various psychological disorders during the COVID-19 pandemic compared to before COVID-19. The entire Korean population ≥ 20 years old (~42.3 million) was included. The first COVID-19 case in Korea was reported on 20 January 2020. Thus, the period from January 2018 through to February 2020 was classified as "before COVID-19", and the period from March 2020 through to May 2021 was classified as "during COVID-19". Monthly medical visits due to the following 13 psychological disorders were evaluated: depressive disorder, bipolar disorder, primary insomnia, schizophrenia, panic disorder, hypochondriasis, posttraumatic stress disorder (PTSD), anxiety disorder, anorexia nervosa, addephagia, alcoholism, nicotine dependency, and gambling addiction were evaluated. The differences in the number of medical visits and the variance of diseases before and during the COVID-19 pandemic were analyzed using the Mann−Whitney U test and Levene's test. Subgroup analyses were conducted according to age and sex. The frequencies of medical visits for depressive disorder, bipolar disorder, primary insomnia, panic disorder, hypochondriasis, PTSD, anxiety disorder, anorexia nervosa, addephagia, and gambling addiction were higher during COVID-19 than before COVID-19 (all p < 0.001). However, the frequencies of medical visits for schizophrenia, alcoholism, and nicotine dependency were lower during the COVID-19 pandemic than before the COVID-19 pandemic (all p < 0.001). The psychological disorders with a higher frequency of medical visits during COVID-19 were consistent in all age and sex subgroups. In the old age group, the number of medical visits due to schizophrenia was also higher during COVID-19 than before COVID-19 (p < 0.001). Many psychological disorders, including depressive disorder, bipolar disorder, primary insomnia, panic disorder, hypochondriasis, PTSD, anxiety disorder, anorexia nervosa, addephagia, and gambling addiction, had a higher number of related medical visits, while disorders such as schizophrenia, alcoholism, and nicotine dependency had a lower number of related medical visits during COVID-19 among Korean adults.

Physical Activity Is Associated with a Lower Risk of Osteoporotic Fractures in Osteoporosis: A Longitudinal Study.

The purpose of our study was to examine the occurrence of osteoporotic fractures (fxs) according to the level of physical activity (PA) among osteoporosis using the Korean National Health Insurance Service (NHIS) customized database. From NHIS data from 2009 to 2017, osteoporosis was selected as requested. PA was classified into 'high PA' (n = 58,620), 'moderate PA' (n = 58,620), and 'low PA' (n = 58,620) and were matched in a 1:1:1 ratio by gender, age, income within the household unit, and region of residence. A stratified Cox proportional hazard model was used to calculate hazard ratios (HRs) for each type of fx comparing PA groups. The 'low PA' group was the reference group. For vertebral fx, the adjusted HR (95% confidence intervals (CIs)) was 0.27 (0.26-0.28) for the 'high PA' group and 0.43 (0.42-0.44) for the 'moderate PA' group. For hip fx, the adjusted HR (95% CIs) was 0.37 (0.34-0.40) for the 'high PA' group and 0.51 (0.47-0.55) for the 'moderate PA' group. For distal radius fx, the adjusted HR (95% CIs) was 0.32 (0.30-0.33) for the 'high PA' group and 0.46 (0.45-0.48) for the 'moderate PA' group. The results of this study suggest that a higher intensity of PA is associated with a lower risk of osteoporotic fxs, including vertebral fx, hip fx, and distal radius fx.

Association between Proton Pump Inhibitor Use and Parkinson's Disease in a Korean Population.

Few studies have shown an increased risk of Parkinson's disease (PD) with the use of proton pump inhibitors (PPIs), and the pathophysiological mechanism for this association has not been unveiled. This study examined the relationship between PPI use and PD in a Korean population. We investigated 3026 PD patients and 12,104 controls who were matched by age, sex, income, and region of residence at a ratio of 1:4 in the Korean National Health Insurance Service, National Sample Cohort between 2002 and 2015. We estimated the associations between current and past use of PPIs and PD using odds ratios (ORs) and 95% confidence intervals (CIs) in a conditional/unconditional logistic regression after adjusting for probable confounders. Compared with PPI nonusers, both current users and past users had significantly greater odds of having PD, with ORs of 1.63 (95% CI = 1.44−1.84) and 1.12 (95% CI = 1.01−1.25), respectively. A significant association with PD was observed in individuals who used PPIs for 30−90 days and ≥90 days (OR = 1.26 and 1.64, 95% CI = 1.12−1.43 and 1.43−1.89) but not among those who used PPIs for <30 days. Both current and past use of PPIs associated with a higher probability of PD in the Korean population. Our study provides evidence regarding the association between PPI exposure and PD, but further investigation and possible explanations are warranted.

Physical Activity, Sunshine Duration, and Osteoporotic Fractures: A Nested Case-Control Study.

This study examined the associations between the occurrence of osteoporotic fractures in detailed sites and combined physical activity (PA) and sunshine duration (SD). Data from the Korean National Health Insurance Service-National Health Screening Cohort for 7-year periods and from the Korea Meteorological Administration were used. Osteoporotic fractures (n = 12,103), including vertebral fractures, hip fractures, and distal radius fractures, and matched controls (n = 24,206) were selected in 1:2 ratios by age, sex, income, and region of residence. PA was classified as moderate- to high-intensity PA (High PA) and low-intensity PA (Low PA). SD was classified as Short SD (<6.1 h) and Long SD (≥6.1 h). Conditional logistic regression was used to calculate the odds ratios (ORs) with 95%-confidence intervals (CIs) of the combined PA and SD groups for the occurrence of each osteoporotic fracture. Compared to 'Low PA + Short SD', the adjusted ORs (95% CIs) for vertebral fracture in 'High PA + Short SD' and 'High PA + Long SD' were 0.83 (0.76-0.91) and 0.84 (0.77-0.92), respectively. Hip/distal radius fractures were not associated with the combined PA and SD group. We suggest that a higher intensity of PA is inversely associated with the risk of vertebral fracture.

A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors.

INTRODUCTION: This integrated analysis of a phase 1/2 study (NCT03046992) evaluated the efficacy and safety of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), in patients with advanced EGFR T790M-positive NSCLC after previous EGFR TKI therapy. METHODS: Adults with EGFR mutation-positive NSCLC that progressed after prior EGFR-directed TKIs received once daily oral lazertinib 240 mg continuously until disease progression. Prior TKIs to treat T790M-positive NSCLC were prohibited. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included progression-free survival, overall survival, and intracranial ORR. RESULTS: A total of 78 patients received lazertinib 240 mg at 17 centers in South Korea. Among patients with T790M-positive tumors at baseline (N = 76), one (1.3%) had a complete response and 41 (53.9%) had partial responses, giving an ORR of 55.3% (95% confidence interval [CI]: 44.1-66.4). Median progression-free survival was 11.1 months (95% CI: 5.5-16.4). Median overall survival was not reached (median follow-up = 22.0 mo). In patients with measurable intracranial lesions (n = 7), one (14.3%) had a complete intracranial response and five (71.4%) had partial responses, giving an intracranial ORR of 85.7% (95% CI: 59.8%-100.0%). The most common treatment-emergent adverse events were rash (37.2%), pruritus (34.6%), and paresthesia (33.3%); most were mild to moderate in severity. Serious drug-related adverse events occurred in three patients (gastritis, pneumonia, pneumonitis). The major mechanism of resistance was EGFR T790M loss. CONCLUSIONS: Lazertinib 240 mg/d has a manageable safety profile with durable antitumor efficacy, including brain metastases, in patients with advanced T790M-positive NSCLC after previous EGFR TKI therapy.

Smoking-associated Downregulation of FILIP1L Enhances Lung Adenocarcinoma Progression Through Mucin Production, Inflammation, and Fibrosis.

Lung adenocarcinoma (LUAD) is the major subtype in lung cancer, and cigarette smoking is essentially linked to its pathogenesis. We show that downregulation of Filamin A interacting protein 1-like (FILIP1L) is a driver of LUAD progression. Cigarette smoking causes its downregulation by promoter methylation in LUAD. Loss of FILIP1L increases xenograft growth, and, in lung-specific knockout mice, induces lung adenoma formation and mucin secretion. In syngeneic allograft tumors, reduction of FILIP1L and subsequent increase in its binding partner, prefoldin 1 (PFDN1) increases mucin secretion, proliferation, inflammation, and fibrosis. Importantly, from the RNA-sequencing analysis of these tumors, reduction of FILIP1L is associated with upregulated Wnt/ß-catenin signaling, which has been implicated in proliferation of cancer cells as well as inflammation and fibrosis within the tumor microenvironment. Overall, these findings suggest that down-regulation of FILIP1L is clinically relevant in LUAD, and warrant further efforts to evaluate pharmacologic regimens that either directly or indirectly restore FILIP1L-mediated gene regulation for the treatment of these neoplasms. Significance: This study identifies FILIP1L as a tumor suppressor in LUADs and demonstrates that downregulation of FILIP1L is a clinically relevant event in the pathogenesis and clinical course of these neoplasms.

Extracellular Vesicle Molecular Signatures Characterize Metastatic Dynamicity in Ovarian Cancer.

BACKGROUND: Late-stage diagnosis of ovarian cancer, a disease that originates in the ovaries and spreads to the peritoneal cavity, lowers 5-year survival rate from 90% to 30%. Early screening tools that can: i) detect with high specificity and sensitivity before conventional tools such as transvaginal ultrasound and CA-125, ii) use non-invasive sampling methods and iii) longitudinally significantly increase survival rates in ovarian cancer are needed. Studies that employ blood-based screening tools using circulating tumor-cells, -DNA, and most recently tumor-derived small extracellular vesicles (sEVs) have shown promise in non-invasive detection of cancer before standard of care. Our findings in this study show the promise of a sEV-derived signature as a non-invasive longitudinal screening tool in ovarian cancer. METHODS: Human serum samples as well as plasma and ascites from a mouse model of ovarian cancer were collected at various disease stages. Small extracellular vesicles (sEVs) were extracted using a commercially available kit. RNA was isolated from lysed sEVs, and quantitative RT-PCR was performed to identify specific metastatic gene expression. CONCLUSION: This paper highlights the potential of sEVs in monitoring ovarian cancer progression and metastatic development. We identified a 7-gene panel in sEVs derived from plasma, serum, and ascites that overlapped with an established metastatic ovarian carcinoma signature. We found the 7-gene panel to be differentially expressed with tumor development and metastatic spread in a mouse model of ovarian cancer. The most notable finding was a significant change in the ascites-derived sEV gene signature that overlapped with that of the plasma-derived sEV signature at varying stages of disease progression. While there were quantifiable changes in genes from the 7-gene panel in serum-derived sEVs from ovarian cancer patients, we were unable to establish a definitive signature due to low sample number. Taken together our findings show that differential expression of metastatic genes derived from circulating sEVs present a minimally invasive screening tool for ovarian cancer detection and longitudinal monitoring of molecular changes associated with progression and metastatic spread.

High WHSC1L1 Expression Reduces Survival Rates in Operated Breast Cancer Patients with Decreased CD8+ T Cells: Machine Learning Approach.

Nuclear receptor-binding SET domain protein (NSD), a histone methyltransferase, is known to play an important role in cancer pathogenesis. The WHSC1L1 (Wolf-Hirschhorn syndrome candidate 1-like 1) gene, encoding NSD3, is highly expressed in breast cancer, but its role in the development of breast cancer is still unknown. The purpose of this study was to analyze the survival rates and immune responses of breast cancer patients with high WHSC1L1 expression and to validate the results using gradient boosting machine (GBM) in breast cancer. We investigated the clinicopathologic parameters, proportions of immune cells, pathway networks and in vitro drug responses according to WHSC1L1 expression in 456, 1500 and 776 breast cancer patients from the Hanyang University Guri Hospital, METABRIC and TCGA, respectively. High WHSC1L1 expression was associated with poor prognosis, decreased CD8+ T cells and high CD274 expression (encoding PD-L1). In the pathway networks, WHSC1L1 was indirectly linked to the regulation of the lymphocyte apoptotic process. The GBM model with WHSC1L1 showed improved prognostic performance compared with the model without WHSC1L1. We found that VX-11e, CZC24832, LY2109761, oxaliplatin and erlotinib were effective in inhibiting breast cancer cell lines with high WHSC1L1 expression. High WHSC1L1 expression could play potential roles in the progression of breast cancer and targeting WHSC1L1 could be a potential strategy for the treatment of breast cancer.

FILIP1L Loss Is a Driver of Aggressive Mucinous Colorectal Adenocarcinoma and Mediates Cytokinesis Defects through PFDN1.

Aneuploid mucinous colorectal adenocarcinoma (MAC) is an aggressive subtype of colorectal cancer with poor prognosis. The tumorigenic mechanisms in aneuploid MAC are currently unknown. Here we show that downregulation of Filamin A-interacting protein 1-like (FILIP1L) is a driver of MAC. Loss of FILIP1L increased xenograft growth, and, in colon-specific knockout mice, induced colonic epithelial hyperplasia and mucin secretion. The molecular chaperone prefoldin 1 (PFDN1) was identified as a novel binding partner of FILIP1L at the centrosomes throughout mitosis. FILIP1L was required for proper centrosomal localization of PFDN1 and regulated proteasome-dependent degradation of PFDN1. Importantly, increased PFDN1, caused by downregulation of FILIP1L, drove multinucleation and cytokinesis defects in vitro and in vivo, which were confirmed by time-lapse imaging and 3D cultures of normal epithelial cells. Overall, these findings suggest that downregulation of FILIP1L and subsequent upregulation of PFDN1 is a driver of the unique neoplastic characteristics in aggressive aneuploid MAC. SIGNIFICANCE: This study identifies FILIP1L as a tumor suppressor in mucinous colon cancer and demonstrates that FILIP1L loss results in aberrant stabilization of a centrosome-associated chaperone protein to drive aneuploidy and disease progression.

Characterization and Application of a Recombinant Exolytic GH50A ß-Agarase from Cellvibrio sp. KY-GH-1 for Enzymatic Production of Neoagarobiose from Agarose.

Neoagarobiose (NA2) is the repeating disaccharide unit of agarose and possesses various promising biological activities. To identify an efficient exolytic ß-agarase required for NA2 production from agarose, the GH50A ß-agarase gene from agar-degrading Cellvibrio sp. KY-GH-1 was overexpressed as a recombinant His-tagged protein using the Escherichia coli expression system. GH50A ß-agarase that consists of 797 amino acids was able to produce predominantly NA2 from agarose at an optimal temperature and pH of 35 °C and 7.5, respectively. The enzyme was stable up to 35 °C and within a pH range of 7.0-9.0. The K m, V max, K cat, and K cat/K m values of the enzyme were 26.5 mg/mL, 16.9 U/mg, 25.2 s-1, and 1.2 × 105 s-1 M-1, respectively. The copresence of 5 mM MnSO4 and 10 mM tris(2-carboxyethyl)phosphine (TCEP) resulted in a 2.5-fold enhancement of the enzyme activity. For NA2 production, neoagaro-oligosaccharides (NAOSs) containing NA4-NA18 were preferred over agarose or agaro-oligosaccharides (AOSs) as substrates. NA2 was produced along with minor amounts of agarotriose (A3) after treatment of AOS with the enzyme, indicating that the exolytic digestion of AOS by the enzyme was initiated by releasing A3 from nonreducing ends. Enzymatic hydrolysis of 0.4% agarose (100 mL) using GH50A ß-agarase (20 µg/mL) for 4 h under optimal reaction conditions (5 mM MnSO4, 10 mM TCEP, 35 °C, 20 mM Tris-HCl, and pH 7.5) and purification of NA2 from hydrolysis products by Bio-Gel P-2 column chromatography resulted in the recovery of 216 mg of NA2 (∼54% yield from agarose). Altogether, these results suggest that the recombinant GH50A ß-agarase is useful to convert agarose to NA2.

Small but mighty: the causes and consequences of micronucleus rupture.

Micronuclei are small DNA-containing nuclear structures that are spatially isolated from the main nucleus. They are frequently found in pathologies, including cancer. It was recently shown that these nuclear structures are not only biomarkers of disease but also play an active role in tumor biology. Many consequences of micronucleus formation on tumor biology are dependent on the frequent and irreversible rupture of their nuclear envelopes, which results in the exposure of their DNA contents to the cytoplasm. In this review, we discuss models of defective nuclear envelope deposition on missegregated chromosomes that lead to nuclear envelope rupture. Furthermore, we expound upon the various downstream consequences of micronucleus nuclear envelope rupture on cells. These consequences include a massive DNA rearrangement phenomenon called chromothripsis and activation of the cGAS-STING innate immune signaling pathway, which can be a double-edged sword with tumorigenesis and tumor prevention functions. Although micronuclei are small structures, the impact they have on cells and their microenvironment is quite large.

Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer.

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.

Higher Acid-Base Imbalance Associated with Respiratory Failure Could Decrease the Survival of Patients with Scrub Typhus during Intensive Care Unit Stay: A Gene Set Enrichment Analysis.

Ninety percent of patients with scrub typhus (SC) with vasculitis-like syndrome recover after mild symptoms; however, 10% can suffer serious complications, such as acute respiratory failure (ARF) and admission to the intensive care unit (ICU). Predictors for the progression of SC have not yet been established, and conventional scoring systems for ICU patients are insufficient to predict severity. We aimed to identify simple and robust indicators to predict aggressive behaviors of SC. We evaluated 91 patients with SC and 81 non-SC patients who were admitted to the ICU, and 32 cases from the public functional genomics data repository for gene expression analysis. We analyzed the relationships between several predictors and clinicopathological characteristics in patients with SC. We performed gene set enrichment analysis (GSEA) to identify SC-specific gene sets. The acid-base imbalance (ABI), measured 24 h before serious complications, was higher in patients with SC than in non-SC patients. A high ABI was associated with an increased incidence of ARF, leading to mechanical ventilation and worse survival. GSEA revealed that SC correlated to gene sets reflecting inflammation/apoptotic response and airway inflammation. ABI can be used to indicate ARF in patients with SC and assist with early detection.

TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer.

Perturbed epigenomic programs play key roles in tumorigenesis, and chromatin modulators are candidate therapeutic targets in various human cancer types. To define singular and shared dependencies on DNA and histone modifiers and transcription factors in poorly differentiated adult and pediatric cancers, we conducted a targeted shRNA screen across 59 cell lines of 6 cancer types. Here, we describe the TRPS1 transcription factor as a strong breast cancer-specific hit, owing largely to lineage-restricted expression. Knockdown of TRPS1 resulted in perturbed mitosis, apoptosis, and reduced tumor growth. Integrated analysis of TRPS1 transcriptional targets, chromatin binding, and protein interactions revealed that TRPS1 is associated with the NuRD repressor complex. These findings uncover a transcriptional network that is essential for breast cancer cell survival and propagation.