Cervical squamous cell carcinoma outcomes across continents: A retrospective study.

OBJECTIVE: To assess the influence of geographies and race on the survival outcomes in patients diagnosed with cervical squamous cell carcinoma (CSCC) across three continents. METHODS: This multicontinental retrospective study was conducted in 8 hospitals across Asia, Europe, and North America (NA). Clinicopathologic data of 595 patients with presumed early stages of CSCC, treated surgically, with curative intent was collected. Descriptive analysis and Cox regression models were produced. RESULTS: A total of 595 patients, consisting of 445 (74.8 %) white, 75 (12.6 %) Blacks, and 75 (12.6 %) Asian patients were included. Geographical distribution comprised 69 % of patients from NA, 22 % from Europe, and 9 % from Asia. The median age at diagnosis was 46 years. The median overall survival (OS) and relapse-free survival (RFS) were 22.09 years and 21.19 years, respectively. Patient characteristics varied significantly across geographical regions, except for consensus tumor grade. Patients in Europe from middle-income countries with limited CC screening had a substantially higher risk of death than those in NA (HR, 1.79; 95 % CI, 1.13 to 2.79; p = 0.015). Patients from single center in Japan had higher risk of relapse than those from the four heterogeneous NA centers (sub-distribution hazard ratio, 2.19; 95 % CI, 1.22 to 3.95; p = 0.009), although OS did not differ significantly. Race remained statistically insignificant for survival outcomes across the three continents but seemed to influence survival outcomes in NA centers. CONCLUSION: Our study highlights impact of geographies and races on CSCC survival outcomes, emphasizing the need of considering these factors when developing targeted interventions against CSCC.

RCC1 regulation of subcellular protein localization via Ran GTPase drives pancreatic ductal adenocarcinoma growth.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with limited therapeutic options. Here, we evaluated the role of regulator of chromosome condensation 1 (RCC1) in PDAC. RCC1 functions as a guanine exchange factor for GTP-binding nuclear protein Ran (Ran) GTPase and is involved in nucleocytoplasmic transport. RCC1 RNA expression is elevated in PDAC tissues compared to normal pancreatic tissues and correlates with poor prognosis. RCC1 silencing by RNAi and CRISPR-Cas9 knockout (KO) results in reduced proliferation in 2-D and 3-D cell cultures. RCC1 knockdown (KD) reduced migration and clonogenicity, enhanced apoptosis, and altered cell cycle progression in human PDAC and murine cells from LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) tumors. Mechanistically, RCC1 KO shows widespread transcriptomic alterations including regulation of PTK7, a co-receptor of the Wnt signaling pathway. RCC1 KD disrupted subcellular Ran localization and the Ran gradient. Nuclear and cytosolic proteomics revealed altered subcellular proteome localization in Rcc1 KD KPC-tumor-derived cells and several altered metabolic biosynthesis pathways. In vivo, RCC1 KO cells show reduced tumor growth potential when injected as sub-cutaneous xenografts. Finally, RCC1 KD sensitized PDAC cells to gemcitabine chemotherapy treatment. This study reveals the role of RCC1 in pancreatic cancer as a novel molecular vulnerability that could be exploited to enhance therapeutic response.

The long-chain polyfluorinated alkyl substance perfluorohexane sulfonate (PFHxS) promotes bone marrow adipogenesis.

Per- and polyfluoroalkyl substances (PFAS) bioaccumulate in different organ systems, including bone. While existing research highlights the adverse impact of PFAS on bone density, a critical gap remains in understanding the specific effects on the bone marrow microenvironment, especially the bone marrow adipose tissue (BMAT). Changes in BMAT have been linked to various health consequences, such as the development of osteoporosis and the progression of metastatic tumors in bone. Studies presented herein demonstrate that exposure to a mixture of five environmentally relevant PFAS compounds promotes marrow adipogenesis in vitro and in vivo. We show that among the components of the mixture, PFHxS, an alternative to PFOS, has the highest propensity to accumulate in bone and effectively promote marrow adipogenesis. Utilizing RNAseq approaches, we identified the peroxisome proliferator-activated receptor (PPAR) signaling as a top pathway modulated by PFHxS exposure. Furthermore, we provide results suggesting the activation and involvement of PPAR-gamma (PPARγ) in PFHxS-mediated bone marrow adipogenesis, especially in combination with high-fat diet. In conclusion, our findings demonstrate the potential impact of elevated PFHxS levels, particularly in occupational settings, on bone health, and specifically bone marrow adiposity. This study contributes new insights into the health risks of PFHxS exposure, urging further research on the relationship between environmental factors, diet, and adipose tissue dynamics.

Statewide Linkage Study of Salmonella Infection and Colorectal Cancer Incidence in Michigan, United States.

Objective: Nontyphoidal Salmonella infection is one of the most common foodborne illnesses, and its oncogenic potential has been documented in animal models. The primary goal of this study was to examine whether individuals who were exposed to enteric Salmonella infection are more likely to develop colorectal cancer (CRC) than the general population through the linkage of 2 statewide public health surveillance databases. Materials and Methods: We designed a 2-stage probabilistic linkage, starting with 17,587 records of enteric salmonellosis reported to Michigan Department of Health and Human Services between 1992 and 2020. These records did not include unique identifiers (such as Social Security number [SSN]). The initial linkage to LexisNexis address history was conducted to obtain information to calculate each person's time in Michigan as well as SSN for the second linkage. The linkage to the state cancer registry was performed to obtain the observed number of CRC cases, while the expected number of CRC cases was calculated according to corresponding state CRC incidence by age, sex, and calendar year. Results: Ninety-three percent of the initially identified salmonellosis records were sent to LexisNexis linkage, which returned address history, death, and SSN for 97% of the records. Further linkage to the statewide cancer registry identified 98 incident CRC cases. Overall, the observed-to-expected (O/E) ratio was not different from unity (0.833; 95% CI, 0.627-1.003). Conclusions: While the new linkage strategy was found effective and should be applicable to other health conditions, we cannot rule out bias due to incomplete or underreporting of the infection in estimating the risk of CRC.

BRCA Status Dictates Wnt Responsiveness in Epithelial Ovarian Cancer.

The association of BRCA1 and BRCA2 mutations with increased risk for developing epithelial ovarian cancer is well established. However, the observed clinical differences, particularly the improved therapy response and patient survival in BRCA2-mutant patients, are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 functions in ovarian cancer. Transcriptomic and pathway analyses comparing BRCA1-mutant, BRCA2-mutant, and homologous recombination wild-type ovarian tumors showed differential regulation of the Wnt/ß-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type, BRCA1-null, and BRCA2-null mouse ovarian cancer cells, we observed preferential activation of canonical Wnt/ß-catenin signaling in BRCA1/2 wild-type ovarian cancer cells, whereas noncanonical Wnt/ß-catenin signaling was preferentially activated in the BRCA1-null ovarian cancer cells. Interestingly, BRCA2-null mouse ovarian cancer cells demonstrated a unique response to Wnt3A with the preferential upregulation of the Wnt signaling inhibitor Axin2. In addition, decreased phosphorylation and enhanced stability of ß-catenin were observed in BRCA2-null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3ß. These findings open venues for the translation of these molecular observations into modalities that can impact patient survival. SIGNIFICANCE: We show that BRCA1 and BRCA2 mutation statuses differentially impact the regulation of the Wnt/ß-catenin signaling pathway, a major effector of cancer initiation and progression. Our findings provide a better understanding of molecular mechanisms that promote the known differential clinical profile in these patient populations.

Role of Mitochondrial and Cytosolic Folylpolyglutamate Synthetase in One-Carbon Metabolism and Antitumor Efficacy of Mitochondrial-Targeted Antifolates.

Folate-dependent one-carbon (C1) metabolism encompasses distinct cytosolic and mitochondrial pathways connected by an interchange among serine, glycine, and formate. In both the cytosol and mitochondria, folates exist as polyglutamates, with polyglutamylation catalyzed by folylpolyglutamate synthetase (FPGS), including cytosolic and mitochondrial isoforms. Serine is metabolized by serine hydroxymethyltransferase (SHMT)2 in the mitochondria and generates glycine and C1 units for cellular biosynthesis in the cytosol. AGF347 is a novel pyrrolo[3,2-day]pyrimidine antifolate that targets SHMT2 in the mitochondria and SHMT1 and de novo purine biosynthesis in the cytosol. FPGS is expressed in primary pancreatic cancer specimens, and FPGS levels correlate with in vitro efficacies of AGF347 toward human pancreatic cancer cells. MIA PaCa-2 pancreatic cancer cells with CRISPR knockout of FPGS were engineered to express doxycycline-inducible FPGS exclusively in the cytosol (cFPGS) or in both the cytosol and mitochondria (mFPGS). Folate and AGF347 accumulations increased in both the cytosol and mitochondria with increased mFPGS but were restricted to the cytosol with cFPGS. AGF347-Glu5 inhibited SHMT2 ∼19-fold greater than AGF347 By metabolomics analysis, mFPGS stimulated the C1 flux from serine in the mitochondria and de novo purine and dTTP synthesis far greater than cFPGS. mFPGS enhanced in vitro inhibition of MIA PaCa-2 cell proliferation by AGF347 (∼30-fold) more than cFPGS (∼4.9-fold). Similar results were seen with other pyrrolo[3,2-d]pyrimidine antifolates (AGF291, AGF320); however, elevated mFPGS adversely impacted inhibition by the nonclassical SHMT2/SHMT1 inhibitor SHIN1. These results suggest a critical role of mFPGS levels in determining antitumor efficacies of mitochondrial-targeted pyrrolo[3,2-d]pyrimidine antifolates for pancreatic cancer. SIGNIFICANCE STATEMENT: AGF347 is a novel pyrrolo[3,2-d]pyrimidine antifolate that targets serine hydroxymethyltransferase (SHMT)2 in the mitochondria and SHMT1 and de novo purine biosynthesis in the cytosol. AGF347 accumulation increases with folylpolyglutamate synthetase (FPGS) levels in both the cytosol and mitochondria. Increased mitochondrial FPGS stimulated one-carbon metabolic fluxes in the cytosol and mitochondria and substantially enhanced in vitro inhibition of pancreatic cancer cells by AGF347. Mitochondrial FPGS levels play important roles in determining the antitumor efficacies of pyrrolo[3,2-d]pyrimidine antifolates for pancreatic cancer.

Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of combined CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma.

Outcomes for adult patients with a high-grade glioma continue to be dismal and new treatment paradigms are urgently needed. To optimize the opportunity for discovery, we performed a phase 0/1 dose-escalation clinical trial that investigated tumor pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics following combined ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) treatment in recurrent high-grade glioma. Patients with a recurrent high-grade glioma (n = 24) harboring 1) CDKN2A / B deletion or CDK4 / 6 amplification, 2) PTEN loss or PIK3CA mutations, and 3) wild-type retinoblastoma protein (Rb) were enrolled. Patients received neoadjuvant ribociclib and everolimus treatment and no dose-limiting toxicities were observed. The median unbound ribociclib concentrations in Gadolinium non-enhancing tumor regions were 170 nM (range, 65 - 1770 nM) and 634 nM (range, 68 - 2345 nM) in patients receiving 5 days treatment at the daily dose of 400 and 600 mg, respectively. Unbound everolimus concentrations were below the limit of detection (< 0.1 nM) in both enhancing and non-enhancing tumor regions at all dose levels. We identified a significant decrease in MIB1 positive cells suggesting ribociclib-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) based comparisons of 17 IDH-wild-type on-trial recurrences to 31 IDH-wild-type standard of care treated recurrences data demonstrated a significantly lower fraction of cycling and neural progenitor-like (NPC-like) malignant cell populations. We validated the CDK4/6 inhibitor-directed malignant cell state shifts using three patient-derived cell lines. The presented clinical trial highlights the value of integrating pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics to assess treatment effects in phase 0/1 surgical tissues, including malignant cell state shifts. ClinicalTrials.gov identifier: NCT03834740 .

Lipid Wizard: Analysis Software for Comprehensive Two-Dimensional Liquid Chromatography-Mass Spectrometry-Based Lipid Profiling.

Lipids play a significant role in life activities and participate in the biological system through different pathways. Although comprehensive two-dimensional liquid chromatography-mass spectrometry (2DLC-MS) has been developed to profile lipid abundance changes, lipid identification and quantification from 2DLC-MS data remain a challenge. We created Lipid Wizard, open-source software for lipid assignment and isotopic peak stripping of the 2DLC-MS data. Lipid Wizard takes the peak list deconvoluted from the 2DLC-MS data as input and assigns each isotopic peak to the lipids recorded in the LIPID MAPS database by precursor ion m/z matching. The matched lipids are then filtered by the first-dimension retention time (1D RT), followed by the second-dimension retention time (2D RT), where the 2D RT of each lipid is predicted using an equivalent carbon number (ECN) model. The remaining assigned lipids are used for isotopic peak stripping via an iterative linear regression. The performance of Lipid Wizard was tested using a set of lipid standards and then applied to study the lipid changes in the livers of mice (fat-1) fed with alcohol.

Mitochondrial and Cytosolic One-Carbon Metabolism Is a Targetable Metabolic Vulnerability in Cisplatin-Resistant Ovarian Cancer.

One-carbon (C1) metabolism is compartmentalized between the cytosol and mitochondria with the mitochondrial C1 pathway as the major source of glycine and C1 units for cellular biosynthesis. Expression of mitochondrial C1 genes including SLC25A32, serine hydroxymethyl transferase (SHMT) 2, 5,10-methylene tetrahydrofolate dehydrogenase 2, and 5,10-methylene tetrahydrofolate dehydrogenase 1-like was significantly elevated in primary epithelial ovarian cancer (EOC) specimens compared with normal ovaries. 5-Substituted pyrrolo[3,2-d]pyrimidine antifolates (AGF347, AGF359, AGF362) inhibited proliferation of cisplatin-sensitive (A2780, CaOV3, IGROV1) and cisplatin-resistant (A2780-E80, SKOV3) EOC cells. In SKOV3 and A2780-E80 cells, colony formation was inhibited. AGF347 induced apoptosis in SKOV3 cells. In IGROV1 cells, AGF347 was transported by folate receptor (FR) α. AGF347 was also transported into IGROV1 and SKOV3 cells by the proton-coupled folate transporter (SLC46A1) and the reduced folate carrier (SLC19A1). AGF347 accumulated to high levels in the cytosol and mitochondria of SKOV3 cells. By targeted metabolomics with [2,3,3-2H]L-serine, AGF347, AGF359, and AGF362 inhibited SHMT2 in the mitochondria. In the cytosol, SHMT1 and de novo purine biosynthesis (i.e., glycinamide ribonucleotide formyltransferase, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase) were targeted; AGF359 also inhibited thymidylate synthase. Antifolate treatments of SKOV3 cells depleted cellular glycine, mitochondrial NADH and glutathione, and showed synergistic in vitro inhibition toward SKOV3 and A2780-E80 cells when combined with cisplatin. In vivo studies with subcutaneous SKOV3 EOC xenografts in SCID mice confirmed significant antitumor efficacy of AGF347. Collectively, our studies demonstrate a unique metabolic vulnerability in EOC involving mitochondrial and cytosolic C1 metabolism, which offers a promising new platform for therapy.

Human epidermal growth factor receptor-2 (HER2) expression in FIGO3 high-grade endometrial endometrioid carcinoma: Clinicopathologic characteristics and future directions.

OBJECTIVES: To study the expression of HER2 in high-grade FIGO3 endometrial endometroid carcinoma (EEC) and to correlate our findings with the clinicopathologic characteristics of this tumor. METHODS: HER2 expression by immunohistochemistry (IHC) was performed on 10% formalin-fixed paraffin embedded tissue on cases diagnosed as FIGO3 EEC. HER2 expression was interpreted as negative (0), low (1+ and 2+) or positive (3+) using similar criteria as in the breast. HER2 amplification by Fluorescence in situ hybridization (FISH) was performed on cases interpreted as 2+ and 3+ by IHC. RESULTS: One hundred and forty-three FIGO3 EEC were identified. Of these, 70 (49%) cases were HER2 negative (IHC 0), and 73 (51%) cases expressed/amplified HER2 by IHC and/or FISH. Of the 73 cases expressing or amplifying HER2, 59 cases were IHC 1+, 12 cases were IHC 2+, and 2 cases were IHC 3+. FISH testing was performed in 12 cases. Only one of the two HER2 IHC 3+ cases showed HER2 gene amplification by FISH and the other 11 cases were not amplified. The 5-year overall survival (OS) rate for HER2 IHC 1+ cases was 92.20% (95% CI: 83.97-100.00), and the 5-year OS rate for HER2 IHC 2+/3+ cases was 89.50% (95% CI: 56.41-100.00). CONCLUSION: Our findings indicate that about one half of FIGO3 EEC variably expresses HER2 and with the emerging concept of "HER2 low", anti-HER2 agents may be explored as potential therapeutic options in these patients, for possible survival benefits.

Panobinostat sensitizes AraC-resistant AML cells to the combination of azacitidine and venetoclax.

The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML.

Mechanistic Modeling of Intrathecal Chemotherapy Pharmacokinetics in the Human Central Nervous System.

PURPOSE: The pharmacokinetics of intrathecally administered antibody or small-molecule drugs in the human central nervous system (CNS) remains poorly understood. This study aimed to provide mechanistic and quantitative perspectives on the CNS pharmacokinetics of intrathecal chemotherapy, by using a physiologically based pharmacokinetic (PBPK) modeling approach. EXPERIMENTAL DESIGN: A novel CNS PBPK model platform was developed and verified, which accounted for the human CNS general anatomy and physiologic processes governing drug distribution and disposition. The model was used to predict CNS pharmacokinetics of antibody (trastuzumab) and small-molecule drugs (methotrexate, abemaciclib, tucatinib) following intraventricular injection or intraventricular 24-hour infusion, and to assess the key determinants of drug penetration into the deep brain parenchyma. RESULTS: Intraventricularly administered antibody and small-molecule drugs exhibited distinct temporal and spatial distribution and disposition in human CNS. Both antibody and small-molecule drugs achieved supratherapeutic or therapeutic concentrations in the cerebrospinal fluid (CSF) compartments and adjacent brain tissue. While intrathecal small-molecule drugs penetrated the deep brain parenchyma to a negligible extent, intrathecal antibodies may achieve therapeutic concentrations in the deep brain parenchyma. Intraventricular 24-hour infusion enabled prolonged CNS exposure to therapeutically relevant concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. CONCLUSIONS: CNS PBPK modeling, in line with available clinical efficacy data, confirms the therapeutic value of intrathecal chemotherapy with antibody or small-molecule drugs for treating neoplastic meningitis and warrants further clinical investigation of intrathecal antibody drugs to treat brain parenchyma tumors. Compared with intraventricular injection, intraventricular 24-hour infusion may mitigate neurotoxicity while retaining potential efficacy.

Retinal Disease Diagnosis Using Deep Learning on Ultra-Wide-Field Fundus Images.

Ultra-wide-field fundus imaging (UFI) provides comprehensive visualization of crucial eye components, including the optic disk, fovea, and macula. This in-depth view facilitates doctors in accurately diagnosing diseases and recommending suitable treatments. This study investigated the application of various deep learning models for detecting eye diseases using UFI. We developed an automated system that processes and enhances a dataset of 4697 images. Our approach involves brightness and contrast enhancement, followed by applying feature extraction, data augmentation and image classification, integrated with convolutional neural networks. These networks utilize layer-wise feature extraction and transfer learning from pre-trained models to accurately represent and analyze medical images. Among the five evaluated models, including ResNet152, Vision Transformer, InceptionResNetV2, RegNet and ConVNext, ResNet152 is the most effective, achieving a testing area under the curve (AUC) score of 96.47% (with a 95% confidence interval (CI) of 0.931-0.974). Additionally, the paper presents visualizations of the model's predictions, including confidence scores and heatmaps that highlight the model's focal points-particularly where lesions due to damage are evident. By streamlining the diagnosis process and providing intricate prediction details without human intervention, our system serves as a pivotal tool for ophthalmologists. This research underscores the compatibility and potential of utilizing ultra-wide-field images in conjunction with deep learning.

Ocular Involvement and Treatment Pattern in Korean Patients with Marfan Syndrome: A Population-Based Study.

PURPOSE: This study aimed to investigate the incidence and prevalence of, and treatment patterns for ocular complications in Korean patients with Marfan syndrome. METHODS: Incidence and prevalence of Marfan syndrome was calculated from 2010 to 2018, based on data from the Korean National Health Insurance Service (KNHIS). Diagnosis codes (for cataract, ectopia lentis, retinal detachment, etc.) and surgery reimbursement codes (lensectomy, phacoemulsification, buckling, vitrectomy, etc.) in the patients with Marfan syndrome were retrieved by complete enumeration of the data. RESULTS: The annual prevalence of Marfan syndrome adjusted by age and sex was gradually increased from 2.44 per 100,000 in 2010 to 4.36 per 100,000 in 2018. The age group of 10-19 years showed the highest prevalence. The prevalence of ectopia lentis was 21.7%, of whom 43.0% underwent surgeries. Surgery for RD was performed in 253 (14.1%) of 2044 patients during the study period. CONCLUSION: Although the most prevalent ophthalmologic manifestation was ectopia lentis, total prevalence rate of RD was more than 10% in the study period; thus, regular fundus examination is recommended for the patients with Marfan syndrome.

The impact of physical activity changes on exercise capacity and health-related quality of life in young patients with CHD: a 3-year follow-up study.

OBJECTIVE: This study examined the relationship between changes in physical activity and their impact on exercise capacity and health-related quality of life over a 3-year span in patients with CHD. METHODS: We evaluated 99 young patients with CHD, aged 13-18 years at the outset. Physical activity, health-related quality of life, and exercise capacity were assessed via questionnaires and peak oxygen uptake measurements at baseline and after 3 years; changes in measures were estimated between the two time points and categorised into quartiles. Participants were stratified according to achieved (active) or not-achieved (inactive) recommended levels of physical activity (≥150 minutes/week) at both time points. RESULTS: Despite increases in physical activity, exercise capacity, and health-related quality of life over 3 years, the changes were not statistically significant (all p > 0.05). However, a positive association was found between physical activity changes and exercise capacity (ß = 0.250, p = 0.040) and health-related quality of life improvements (ß = 0.380, p < 0.001). Those with the most pronounced physical activity increase showed notable exercise capacity (p < 0.001) and health-related quality of life increases (p < 0.001) compared with patients with the largest decline in physical activity. The active-inactive category demonstrated a notable decline in exercise capacity compared to the active-active group, while the inactive-active group showed health-related quality of life improvements. CONCLUSIONS: Over 3 years, increased physical activity was consistently linked to increases in exercise capacity and health-related quality of life in patients with CHD, highlighting the potential of physical activity augmentation as an intervention strategy.

Molecular analysis of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in KPC pancreatic cancer mouse model.

BACKGROUND: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin-bound (nab)-paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient-derived tumours, and had promising activity in a phase I study. METHODS: Here, we investigated the impact of selinexor-gemcitabine-nab-paclitaxel (Sel-GemPac) combination on LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx1-Cre (KPC) mouse model utilising digital spatial profiling (DSP) and single nuclear RNA sequencing (snRNAseq). RESULTS: Sel-GemPac synergistically inhibited the growth of the KPC tumour-derived cell line. The Sel-GemPac combination reduced the 2D colony formation and 3D spheroid formation. In the KPC mouse model, at a sub-maximum tolerated dose (sub-MTD) , Sel-GemPac enhanced the survival of treated mice compared to controls (p < .05). Immunohistochemical analysis of residual KPC tumours showed re-organisation of tumour stromal architecture, suppression of proliferation and nuclear retention of tumour suppressors, such as Forkhead Box O3a (FOXO3a). DSP revealed the downregulation of tumour promoting genes such as chitinase-like protein 3 (CHIL3/CHI3L3/YM1) and multiple pathways including phosphatidylinositol 3'-kinase-Akt (PI3K-AKT) signalling. The snRNAseq demonstrated a significant loss of cellular clusters in the Sel-GemPac-treated mice tumours including the CD44+ stem cell population. CONCLUSION: Taken together, these results demonstrate that the Sel-GemPac treatment caused broad perturbation of PDAC-supporting signalling networks in the KPC mouse model. HIGHLIGHTS: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin-bound (nab)-paclitaxel (GemPac). Exporter protein exportin 1 (XPO1) inhibitor selinexor (Sel) with GemPac synergistically inhibited the growth of LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mouse derived cell line and enhanced the survival of mice. Digital spatial profiling shows that Sel-GemPac causes broad perturbation of PDAC-supporting signalling in the KPC model.

Association between knee osteoarthritis and mortality: a serial propensity score-matched cohort study.

BACKGROUND/AIMS: The association between symptomatic knee osteoarthritis (OA) and higher cardiovascular disease (CVD) mortality is established; however, findings from studies that utilized regression analysis were limited, attributed to the strong association between OA and metabolic risk factors. This study aimed to evaluate the association between knee OA and mortality through propensity score matching. METHODS: This was a cohort study including Korean National Health and Nutrition Examination Survey (2010-2013) participants aged ≥ 50 years. By linking the survey data to cause of death data (through 2019) from Statistics Korea, mortality and cause-specific mortality data were obtained. Radiographic knee OA (ROA) was defined as bilateral Kellgren-Lawrence grade ≥ 2. Propensity score matching (1:1) was conducted between asymptomatic ROA, knee pain, and symptomatic ROA groups and normal groups, balancing the confounding factors. Time to death was analyzed using Cox proportional hazard modeling. RESULTS: A higher CVD mortality was observed in the symptomatic ROA group, but not in others; the risk estimates were asymptomatic ROA (hazard ratio [HR] 1.12; 95% confidence interval [CI] 0.77-1.65), knee pain (HR 0.61; 95% CI 0.27-1.38), and symptomatic ROA (HR 1.39; 95% CI 0.89-2.17). No association was found between the all-cause/cancer mortality and other groups. CONCLUSION: When propensity score matching controls metabolic risk factor imbalances, the association between symptomatic knee OA and higher CVD mortality was weaker compared to results of prior studies that used regression adjustment. The results may be more precise estimates of the total risk of knee OA for mortality in Koreans.

The role of the immune response and inflammatory pathways in TNF-related apoptosis-inducing ligand (TRAIL) resistance in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, and the majority of TNBC lacks targeted therapies. Previous studies have shown that TNBC cells are highly sensitive to TNF-related apoptosis-inducing ligand (TRAIL), making it a potentially viable treatment option for TNBC. However, the development of TRAIL resistance limits its potential for clinical use, and the underlying mechanisms are not fully understood. To better understand the mechanism of resistance to TRAIL, we performed RNA sequencing to identify the candidates that are responsible for resistance to TRAIL in two previously established TRAIL-resistant MDA231 and SUM159 cells. This approach led us to identify differentially expressed genes (DEGs) and pathways in TRAIL-resistant MDA231 and SUM159 cells compared to their TRAIL-sensitive counterparts. We showed that several DEGs and pathways were associated with inflammation in TRAIL-resistant cells, including IL-1α and IL6. By downregulating IL-1α and IL6 expression, we showed that TRAIL sensitivity can be significantly restored in TRAIL-resistant cells. Therefore, this study identifies a mechanism by which the inflammation pathway promotes TRAIL resistance, which could be targeted for enhancing TRAIL-based therapies in TNBC cells.

Multi-Scale Learning with Sparse Residual Network for Explainable Multi-Disease Diagnosis in OCT Images.

In recent decades, medical imaging techniques have revolutionized the field of disease diagnosis, enabling healthcare professionals to noninvasively observe the internal structures of the human body. Among these techniques, optical coherence tomography (OCT) has emerged as a powerful and versatile tool that allows high-resolution, non-invasive, and real-time imaging of biological tissues. Deep learning algorithms have been successfully employed to detect and classify various retinal diseases in OCT images, enabling early diagnosis and treatment planning. However, existing deep learning algorithms are primarily designed for single-disease diagnosis, which limits their practical application in clinical settings where OCT images often contain symptoms of multiple diseases. In this paper, we propose an effective approach for multi-disease diagnosis in OCT images using a multi-scale learning (MSL) method and a sparse residual network (SRN). Specifically, the MSL method extracts and fuses useful features from images of different sizes to enhance the discriminative capability of a classifier and make the disease predictions interpretable. The SRN is a minimal residual network, where convolutional layers with large kernel sizes are replaced with multiple convolutional layers that have smaller kernel sizes, thereby reducing model complexity while achieving a performance similar to that of existing convolutional neural networks. The proposed multi-scale sparse residual network significantly outperforms existing methods, exhibiting 97.40% accuracy, 95.38% sensitivity, and 98.25% specificity. Experimental results show the potential of our method to improve explainable diagnosis systems for various eye diseases via visual discrimination.