Analysis Of Clinical Database Research Articles

The Anti-Metastatic Action of Oxyresveratrol via Suppression of Phosphoryl-ERK/-PKCα-Mediated Sp1/MMP1 Signaling in Human Renal Carcinoma Cells.

Oxyresveratrol (OxyR) exerts biological and pharmacological effects in a variety of tumor cells, including antioxidant action, antitumor activity, and proapoptotic effects. However, the regulation of targeted signaling pathways by OxyR and the mechanism underlying these effects in human renal cell carcinoma (RCC) have been less studied. We observed that OxyR at noncytotoxic doses did not affect the growth of human RCC cells or normal kidney HK2 cells. OxyR inhibited ACHN and Caki-1 cell migration and invasion through targeting matrix metalloproteinase 1 (MMP1) expression. Analysis of clinical databases showed that high MMP1 expression is associated with lower overall survival (OS) in these cancers (p < 0.01). OxyR significantly inhibited the mRNA and protein expression of Sp1. Furthermore, luciferase assay results showed that OxyR inhibited Sp1 transcriptional activity. Additionally, OxyR preferentially suppressed the activation of ERK and PKCα. Treatment with U0126 (MEK inhibitor) or G06976 (PKCα inhibitor) clearly decreased Sp1 and MMP1 expression and inhibited RCC cell migration and invasion. In conclusion, OxyR may be a potential antitumor therapy for the inhibition of migration and invasion by controlling p-ERK/Sp1 and p-PKCα/Sp1-mediated MMP1 expression in RCC.

Targeting MCL1 with Sanggenon C overcomes MCL1-driven adaptive chemoresistance via dysregulation of autophagy and endoplasmic reticulum stress in cervical cancer

BackgroundCervical cancer ranks as one of the most prevalent malignancies among women worldwide and poses a significant threat to health and quality of life. MCL1 is an antiapoptotic protein closely linked to tumorigenesis, drug-resistance and poor prognosis in various cancers. Sanggenon C, a natural flavonoid derived from Morus albal., exhibits multiple activities, including anti-oxidant, anti-inflammatory, antivirus, and antitumor properties. However, the molecular mechanisms by which Sanggenon C exerts antitumor effects on in cervical cancer remain unclear. PurposeTo investigate the oncogenic role of MCL1 and elucidate the antitumor activity of Sanggenon C, along with its molecular mechanisms, in cervical cancer. MethodsIn vitro, the effects of Sanggenon C on proliferation, the cell cycle, apoptosis, and autophagy were explored. Transcriptome sequencing was employed to analyze critical genes and pathways. The expression of genes or proteins was evaluated via immunofluorescence, qRT-PCR, immunohistochemistry, and Western blotting. To identify targets of Sanggenon C, various techniques such as clinical database analysis, molecular docking, cellular thermal shift assays, co-immunoprecipitation, and ubiquitination assays were utilized. Additionally, Xenograft mouse models were established to further investigate Sanggenon C as a novel MCL1 inhibitor and its anti-tumor activity in vivo. ResultsOur investigation reveals that Sanggenon C effectively inhibits cervical cancer cell proliferation both in vitro and in vivo. Furthermore, Sanggenon C induces endoplasmic reticulum stress and triggers protective autophagy via activation of the ATF4-DDIT3-TRIB3-AKT-MTOR signaling axis. Furthermore, Sanggenon C specifically targets MCL1 to exert its antitumor effects by modulating MCL1 protein stability through SYVN1-mediated ubiquitination. Notably, MCL1 overexpression attenuates the Sanggenon C-induced decrease in cell viability and apoptosis. Our study further characterizes the role of MCL1 in cisplatin resistance and identifies MCL1 as a promising target for Sanggenon C, which effectively inhibits proliferation and induces apoptosis in cisplatin-resistant cervical cancer cells. Importantly, combining Sanggenon C with an autophagy inhibitor represents a promising strategy to enhance therapeutic outcomes in cisplatin-resistant cervical cancer cells. ConclusionOur findings demonstrates that Sanggenon C induces endoplasmic reticulum stress and highlights the potential of targeting MCL1 to exploit vulnerabilities in drug-resistant cervical cancer cells. Sanggenon C emerges as a promising therapeutic agent against MCL1-driven adaptive chemoresistance through disruption of autophagy and endoplasmic reticulum stress in cervical cancer.

The Effects of Multidisciplinary Intensive Rehabilitation on Cognitive and Executive Functions in Parkinson's Disease: A Clinical Database Analysis.

Background/Objectives: This study is based on data collected from a medical health record review to assess whether multidisciplinary intensive rehabilitation treatment in Parkinson's disease (PD) patients can improve global cognitive functioning and executive functions. Methods: The data related to PD patients were extrapolated from a clinical database called "NeuroRehab". A total of 104 PD patients (51 males; 53 females) performed 6 weeks of multidisciplinary intensive rehabilitation treatment in clinical practice from January 2019 to May 2023. This training program was characterized by three daily sessions of 60 min of activities (muscle relaxation and stretching exercises, moderate physical aerobic exercise, and occupational therapy). The patients were classified and stratified according to disease severity (according to the Hoehn and Yahr scale), postural instability and gait difficulty (PIGD) or tremor-dominant (TD) subtypes, disease duration (DD), and the presence of dyskinesias. The effect of multidisciplinary intensive rehabilitation treatment on cognitive and executive functions was evaluated through the administration of cognitive tests, such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Frontal Assessment Battery (FAB). All the parameters were evaluated at the baseline (T0) and at the end of the rehabilitation program (T1). Results: The multidisciplinary intensive rehabilitation treatment significantly improved cognitive performance. The MMSE, MoCA, and FAB test scores after the rehabilitation program (T1) were significantly higher compared to the scores obtained at the baseline (T0). Moreover, further analyses on subgroups of the patients who scored below the cut-off in the MMSE showed that at least 50% of patients overcame the cut-off score. Interestingly, the same analyses performed for the MoCA and FAB revealed a higher rate of improvement in cognitive functions, with normal scores in both tests after 6 weeks of multidisciplinary intensive rehabilitation treatment. Conclusions: This study revealed the potential effects of a 6-week multidisciplinary rehabilitation program in improving cognitive status in a PD inpatient cohort.

RNA binding protein RALY facilitates colorectal cancer metastasis via enhancing exosome biogenesis in m6A dependent manner

Tumor metastasis is the leading cause of cancer-related death in patients with colorectal cancer (CRC). Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins, involved in the tumorigenesis and metastasis of various cancers. However, the molecular mechanisms of hnRNPs in CRC metastasis remain unclear. This study aims to uncover the pivotal roles and molecular mechanisms of hnRNPs in CRC metastasis. Clinical database analysis suggested that the expression of hnRNP-Associated with Lethal Yellow (RALY, an important member of hnRNPs) was strongly correlated with the aggressiveness and survival of CRC patients. Gain- and loss-of-function studies demonstrated that RALY promotes the production of exosomes by increasing the formation of multivesicular bodies (MVBs) and enhancing the fusion of MVBs with the plasma membrane. Notably, RALY directly interacts with phospholipase D2 (PLD2) to enable exosome biogenesis, and cooperates with RBM15b to control PLD2 mRNA stability in an m6A-dependent manner. RALY-mediated exosome secretion activates pro-tumor macrophages and further facilitates CRC metastasis, while rescue experiments in vivo further confirmed that RALY-mediated exosome biogenesis facilitates CRC metastasis. Collectively, our findings demonstrate that RALY promotes exosome biogenesis and facilitates colorectal cancer metastasis by upregulating PLD2 and enhancing exosome production in an m6A-dependent manner, suggesting potential therapeutic strategies for combating CRC metastasis.

FRI-123 Measuring the burden and impact of comorbidity in cirrhosis: insights from clinical database analysis

FRI-123 Measuring the burden and impact of comorbidity in cirrhosis: insights from clinical database analysis

Microbial landscape of periodontal pockets against local antibacterial therapy of chronic generalized periodontitis: a multicenter clinical trial

Background. A microbial nature of periodontitis requires an accurate analysis of the pathogenic potential of the periodontal pocket microflora thereby enabling correct diagnosis to be made and the most effective pharmacological agent to be selected for treating chronic periodontitis. Metronidazole demonstrates excellent results for anaerobic microorganisms in the periodontal pocket, whereas minocycline hydrochloride, moxifloxacin and amoxicillin/clavulanate are efficient for aerobic microorganisms. However, specialists find considerably relevant to analyze the correlations between specific bacterial associations in the periodontal pocket against local antibacterial therapy, as well as to track the contents of periodontal pockets long after antibacterial therapy. Therefore, a microbiological analysis of periodontal pocket contents is considered necessary in order to select and monitor the effectiveness of local antibacterial therapy.Objective. To evaluate the effectiveness of local antibacterial therapy for chronic generalized periodontitis by means of analysis of changes in the microbiological composition of periodontal pockets.Methods. The clinical trial involved 144 patients with chronic generalized periodontitis. The study included examination of patients and analysis of clinical data bases of the Department for General Practice Dentistry, Kuban State Medical University and the Dentistry Department, Stavropol State Medical University of the Ministry of Health of the Russian Federation. The trial included patients aged 30 to 60 with a diagnosis of chronic generalized periodontitis of different severity. All periodontitis patients were divided into 2 groups depending on the therapy: main and control groups. Each group had three subgroups depending on the severity of the pathologic process. The first subgroup of the control group (chronic generalized periodontitis of mild degree) consisted of 16 people (11.1%), the second subgroup (chronic generalized periodontitis of moderate degree) — 31 people (21.5%), the third subgroup (chronic generalized periodontitis of severe degree) — 7 people (4.9%). The first, second and third subgroups of the main group consisted of 28 (19.4%), 48 (33.3%) and 14 persons (9.7%) respectively. The severity of periodontitis was determined by the depth of the periodontal pocket, degree of bone resorption (according to x-ray examination), and pathologic tooth mobility. A local anti-inflammatory therapy for the patients of the control group included oral baths with propolis (15–20 drops of 10% propolis tincture diluted in 100 ml of warm water) 3 times a day for 7 days starting from the first visit. At the final stage of treatment after preliminary scaling and rootplaning, patients of the control group received antiseptic gel with 10% metronidazole and 2% chlorhexidine bigluconate to be injected into periodontal pockets with over 4 mm depth. Additionally, applications of adhesive dental films Diplene Denta L (with lincomycin) and Diplene Denta M (with metronidazole) were prescribed to be done in the home. In addition to the above-mentioned comprehensive therapy, patients of the main group received a single insufflation of minocycline hydrochloride microspheres into each periodontal pocket. The tools for the patients of the main group included plastic cannulas with minocycline hydrochloride microspheres in the form of powder in the tip of the cartridge, and a special syringe-insufflator. The technique of antibiotic insufflation into the periodontal pocket was preliminary trained on the model of jaws with the studied pathology. Statistical analysis of the results was performed using variance analysis in the Excel Microsoft Office 2016 (Microsoft, USA).Results. According to the systematic observation of the patients from the control group, periodic fluctuations in microbial population in the majority of pathologic pockets obtained a specific regularity: a decrease in the number of microorganisms on day 21 was followed by its increase in the subsequent period of observation after 30 and especially 60 days. According to the ongoing follow-up of the patients of the main group, fluctuations of microbial population in the majority of pathologic pockets obtained a certain regularity: a significant reduction in the number of microorganisms on day 21 was followed by its slight rise in the subsequent period of observation after 30 and a slight increase again in 60 days. Fluctuations in the number of microorganisms of periodontal pockets in the main group reveal their specific character: their number remained invariably lower than that of the control group throughout the observation period, while the total number of detected periodontopathogens decreased.Conclusion. The established correlations between the main indicators of microbiological status of periodontal pockets and the severity of chronic generalized periodontitis within different periods after the local therapy confirm the positive dynamics of treatment in the main group, where patients were insufflated with minocycline hydrochloride microspheres, proved by a change in the typology of microbial status of periodontal pockets and a number of periodontopathogenic microorganisms.

Moesin affects the plasma membrane expression and the immune checkpoint function of CD47 in human ovarian clear cell carcinoma

Among major histological subtypes of epithelial ovarian cancer, a higher incidence of ovarian clear cell carcinoma (OCCC) is observed in East Asian populations, particularly in Japan. Despite recent progress in the immune checkpoint inhibitors for a wide variety of cancer cell types, patients with OCCC exhibit considerably low response rates to these drugs. Hence, urgent efforts are needed to develop a novel immunotherapeutic approach for OCCC. CD47, a transmembrane protein, is overexpressed in almost all cancer cells and disrupts macrophage phagocytic activity in cancer cells. Ezrin-Radixin-Moesin (ERM) family member of proteins serve as scaffold proteins by crosslinking certain transmembrane proteins with the actin cytoskeleton, contributing to their plasma membrane localization. Here, we examined the role of ERM family in the plasma membrane localization and functionality of CD47 in OCCC cell lines derived from Japanese women. Confocal laser scanning microscopy analysis showed colocalization of CD47 with all three ERM in the plasma membrane of OCCC cells. RNA interference-mediated gene silencing of moesin, but not others, decreased the plasma membrane expression and immune checkpoint function of CD47, as determined by flow cytometry and in vitro phagocytosis assay using human macrophage-like cells, respectively. Interestingly, clinical database analysis indicated that moesin expression in OCCC was higher than that in other histological subtypes of ovarian cancers, and the expression of CD47 and moesin increased with the cancer stage. In conclusion, moesin is overexpressed in OCCC and may be the predominant scaffold protein responsible for CD47 plasma membrane localization and function in OCCC.

Cryptocaryone induces apoptosis in human hepatocellular carcinoma cells by inhibiting aerobic glycolysis through Akt and c-Src signaling pathways.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with the second highest mortality rate in all cancer. Energy reprogramming is one of the hallmarks of cancer, and emerging evidence showed that targeting glycolysis is a promising strategy for HCC treatment. Cryptocaryone has been shown to display promising anti-cancer activity against numerous types of cancer. Previous study also indicated that cryptocaryone induces cytotoxicity by inhibiting glucose transport in cancer cells, but the detailed mechanism still needs to be elucidated. Therefore, this study aimed to investigate the relationship between the anti-cancer effect and glycolytic metabolism of cryptocaryone in human HCC cells. In this study, we found that cryptocaryone potently induced growth inhibition by apoptotic cell death in HCC cells. Cryptocaryone also suppressed the ATP synthesis, lactate production and glycolytic capacity of HCC cells. Mechanistic investigations showed that phosphorylation of Akt and c-Src, as well as the expression of HK1 were impeded by cryptocaryone. Moreover, cryptocaryone markedly increased the expression level of transcription factor FoxO1. Importantly, clinical database analysis confirmed the negative correlation between HK1 and FoxO1. High expression levels of HK-1 were positively correlated with poorer survival in patients with HCCs. These results suggest that cryptocaryone may promote cell apoptosis by inhibiting FoxO1-mediated aerobic glycolysis through Akt and c-Src signaling cascades in human HCC cells. This is the first study to indicate that cryptocaryone exerts anti-cancer property against human HCC cells. Cryptocaryone is a potential natural product worthy of further development into a promising candidate for HCC treatment.

Inhibition of TCA cycle improves the anti-PD-1 immunotherapy efficacy in melanoma cells via ATF3-mediated PD-L1 expression and glycolysis

Backgroundanti-Programmed Death-1 (anti-PD-1) immunotherapy has shown promising manifestation in improving the survival rate of patients with advanced melanoma, with its efficacy closely linked to Programmed cell death-Ligand 1 (PD-L1) expression....

Preclinical evaluation of 68Ga-radiolabeled trimeric affibody for PDGFRβ-targeting PET imaging of hepatocellular carcinoma

PurposeHepatocellular carcinoma (HCC) is a highly vascularized solid carcinoma and tumor vessel–targeted molecular imaging might be effective for early diagnosis of HCC. Herein, we developed a novel trimeric affibody (ZTRI) with highly specific binding to the platelet-derived growth factor receptor beta (PDGFRβ). The aim of this study is to evaluate the feasibility of 68Ga-radiolabeled ZTRI ([68Ga]Ga-DOTA-ZTRI) as PET tracer for diagnosis of HCC.MethodsThe bioinformatics analysis of clinical database and immunoblotting of clinical specimens were performed to validate the potential of PDGFRβ as HCC biomarker. The trimeric affibody ZTRI was conjugated with DOTA-NHS-ester and radiolabeled with 68Ga to produce [68Ga]Ga-DOTA-ZTRI conjugate. Immunoreactivity and specific uptake of [68Ga]Ga-DOTA-ZTRI were assessed by dose-dependent cell binding, autoradiography, and biodistribution analysis. [68Ga]Ga-DOTA-ZTRI PET/CT scanning of diethylnitrosamine (DEN)-induced primary HCC rats and a rare case of idiopathical HCC rhesus monkey was performed to evaluate the imaging capability and radiation dosimetry of [68Ga]Ga-DOTA-ZTRI in vivo.ResultsExcessive PDGFRβ was validated as a representative biomarker of HCC neovascularization. The radiolabeling of [68Ga]Ga-DOTA-ZTRI was achieved at more than 95% radiochemical yield. In vitro assays showed specific uptake of [68Ga]Ga-DOTA-ZTRI in HCC tumor vessels by autoradiography. Animal PET/CT imaging with [68Ga]Ga-DOTA-ZTRI successfully visualized the tumor lesions in primary HCC rats and rhesus monkey, and indicated radiation absorbed dose of 2.03E-02 mSv/MBq for each scanning.ConclusionsOur results demonstrated that [68Ga]Ga-DOTA-ZTRI conjugate could be applied as a promising PET tracer for early diagnosis of hepatocellular carcinoma.

Pemafibrate inhibited renal dysfunction and fibrosis in a mouse model of adenine-induced chronic kidney disease

AimsPeroxisome proliferator-activated receptor-alpha (PPARα) levels are markedly lower in the kidneys of chronic kidney disease (CKD) patients. Fibrates (PPARα agonists) are therapeutic agents against hypertriglyceridemia and potentially against CKD. However, conventional fibrates are eliminated by renal excretion, limiting their use in patients with impaired renal function. Here, we aimed to evaluate the renal risks associated with conventional fibrates via clinical database analysis and investigate the renoprotective effects of pemafibrate, a novel selective PPARα modulator mainly excreted into the bile. Main methodsThe risks associated with conventional fibrates (fenofibrate, bezafibrate) to the kidneys were evaluated using the Food and Drug Administration Adverse Event Reporting System. Pemafibrate (1 or 0.3 mg/kg/day) was administered daily using an oral sonde. Its renoprotective effects were examined in unilateral ureteral obstruction (UUO)-induced renal fibrosis model mice (UUO mice) and adenine-induced CKD model mice (CKD mice). Key findingsThe ratios of glomerular filtration rate decreased and blood creatinine increased were markedly higher after conventional fibrate use. Pemafibrate administration suppressed increased gene expressions of collagen-I, fibronectin, and interleukin 1 beta (IL-1β) in the kidneys of UUO mice. In CKD mice, it suppressed increased plasma creatinine and blood urea nitrogen levels and decreased red blood cell count, hemoglobin, and hematocrit levels, along with renal fibrosis. Moreover, it inhibited the upregulation of monocyte chemoattractant protein-1, IL-1β, tumor necrosis factor-alpha, and IL-6 in the kidneys of CKD mice. SignificanceThese results demonstrated the renoprotective effects of pemafibrate in CKD mice, confirming its potential as a therapeutic agent for renal disorders.

Identification of potential biomarkers for colorectal cancer by clinical database analysis and Kaplan-Meier curves analysis.

This study aimed to explore critical genes as potential biomarkers for the diagnosis and prognosis of colorectal cancer (CRC) for clinical utility. To identify and screen candidate genes involved in CRC carcinogenesis and disease progression, we downloaded microarray datasets GSE89076, GSE73360, and GSE32323 from the GEO database identified differentially expressed genes (DEGs), and performed a functional enrichment analysis. A protein-protein interaction network was constructed, and correlated module analysis was performed using STRING and Cytoscape. The Kaplan-Meier survival curve shows the survival of the hub genes. The expression of cyclin-dependent kinase (CDK1), cyclin B1 (CCNB1), and PCNA in tissues and changes in tumor grade were analyzed. A total of 329 DEGs were identified, including 264 upregulated and 65 downregulated genes. The functions and pathways of DEGs include the mitotic cell cycle, poly(A) RNA binding replication, ATP binding, DNA replication, ribosome biogenesis in eukaryotes, and RNA transport. Forty-seven Hub genes were identified, and biological process analysis showed that these genes were mainly enriched in cell cycle and DNA replication. Patients with mutations in CDK1, PCNA, and CCNB1 had poorer survival rates. CDK1, PCNA, and CCNB1 were significantly overexpressed in the tumor tissues. The expression of CDK1 and CCNB1 gradually decreased with increasing tumor grade. CDK1, CCNB1, and PCNA can be used as potential markers for the diagnosis and prognosis of CRC. These genes are overexpressed in colon cancer tissues and are associated with low survival rates in CRC patients.

Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma

PurposeGlioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. Experimental designWe developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. ResultsThese studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. ConclusionsThese findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.

Down-regulating Nrf2 by tangeretin reverses multiple drug resistance to both chemotherapy and EGFR tyrosine kinase inhibitors in lung cancer

Multiple drug resistance (MDR) is the major obstacle for both chemotherapy and molecular-targeted therapy for cancer, which is mainly caused by overexpression of ABC transporters or genetic mutation of drug targets. Based on previous studies, we hypothesized that ROS/Nrf2 is the common target for overcoming acquired drug resistance to both targeted therapy and chemotherapy treatments. In this study, we firstly proved that the levels of ROS and Nrf2 were remarkably up-regulated in both H1975 (Gefitinib-resistant lung cancer cells with T790M) and A549/T (paclitaxel-resistant) cells, which is consistent with the clinical database analysis results of lung cancer patients that Nrf2 expression level is negatively related to survival rate. Nrf2 Knockdown with siRNA or tangeretin (TG, a flavonoid isolated from citrus peels) inhibited the MDR cell growth by suppressing the Nrf2 pathway, and efficiently enhanced the anti-tumor effects of paclitaxel and AZD9291 (the third generation of TKI) in A549/T or H1975, respectively. Moreover, TG sensitized A549/T cells-derived xenografts to paclitaxel via inhibiting Nrf2 and its downstream target P-gp, leading to an increased paclitaxel concentration in tumors. Collectively, targeting Nrf2 to enhance ROS may be a common target for overcoming the acquired drug resistance and enhancing the therapeutic effects of chemotherapy and molecular-targeted therapy.

Protective roles of cytoplasmic p21Cip1/Waf1 in senolysis and ferroptosis of lung cancer cells

Therapy-induced senescent cancer cells increase the expression of the cyclin-dependent kinase inhibitors p16Ink4a and p21Cip1/Waf1 . Given that p21 regulates not only the cell cycle but also cell death, we investigated the roles of p21 in cell death using a p16-negative A549 human lung adenocarcinoma cell line. Senescence was induced by doxorubicin (DXR) or pemetrexed (PEM). The protein expression of p21 was examined by immunoblot. Cell death, reactive oxygen species (ROS) and lipid peroxidation were determined by flow cytometry. ABT-263 and ABT-737 were used as senolytic drugs. In vivo growth of A549 cells with different levels of p21 and their sensitivity to PEM were examined in xenograft models. DXR-induced senescent A549 cells increased the expression of cytoplasmic p21, and the sensitivity to ABT-263 was augmented in p21-knockout A549 (A549-KOp21) cells. A similar senolytic effect was observed when PEM was combined with ABT-737. PEM alone induced a higher level of non-apoptotic cell death, ferroptosis, in A549-KOp21 cells than in A549 cells. Although there was no difference in the level of lipid peroxidation, ROS levels were higher in PEM-treated A549-KOp21 cells than in PEM-treated A549 cells. A loss of p21 increased the sensitivity of A549 cells to PEM both in vitro and in vivo. A clinical database analysis showed that CDKN1Ahigh lung adenocarcinoma patients had a poorer prognosis compared to CDKN1Alow patients. Cytoplasmic p21, which was increased in therapy-induced senescent lung cancer cells, plays protective roles in senolysis and ferroptosis.

Omeprazole Suppresses Oxaliplatin-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

(1) Background: Oxaliplatin is used as first-line chemotherapy not only for colorectal cancer but also for gastric and pancreatic cancers. However, it induces peripheral neuropathy with high frequency as an adverse event, and there is no effective preventive or therapeutic method. (2) Methods: The effects of omeprazole, a proton pump inhibitor (PPI), on oxaliplatin-induced peripheral neuropathy (OIPN) was investigated using an in vivo model and a real-world database. (3) Results: In a rat model, oxaliplatin (4 mg/kg, i.p., twice a week for 4 weeks) caused mechanical hypersensitivity accompanied by sciatic nerve axonal degeneration and myelin sheath disorder. Repeated injection of omeprazole (5–20 mg/kg, i.p., five times per week for 4 weeks) ameliorated these behavioral and pathological abnormalities. Moreover, omeprazole did not affect the tumor growth inhibition of oxaliplatin in tumor bearing mice. Furthermore, clinical database analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) suggests that the group using omeprazole has a lower reporting rate of peripheral neuropathy of oxaliplatin-treated patients than the group not using (3.06% vs. 6.48%, p < 0.001, reporting odds ratio 0.44, 95% confidence interval 0.32–0.61). (4) Conclusions: These results show the preventing effect of omeprazole on OIPN.

Id2 exerts tumor suppressor properties in lung cancer through its effects on cancer cell invasion and migration.

BackgroundDespite advances in prognosis and treatment of lung adenocarcinoma (LADC), a notable non–small cell lung cancer subtype, patient outcomes are still unsatisfactory. New insight on novel therapeutic strategies for LADC may be gained from a more comprehensive understanding of cancer progression mechanisms. Such strategies could reduce the mortality and morbidity of patients with LADC. In our previous study, we performed cDNA microarray screening and found an inverse relationship between inhibitor of DNA binding 2 (Id2) expression levels and the invasiveness of LADC cells.Materials and MethodsTo identify the functional roles of Id2 and its action mechanisms in LADC progression, we successfully established several Id2-overexpressing and Id2-silenced LADC cell clones. Subsequently, we examined in vitro the effects exerted by Id2 on cell morphology, proliferation, colony formation, invasive, and migratory activities and examined in vivo those exerted by Id2 on cell metastasis. The mechanisms underlying the action of Id2 were investigated using RNA-seq and pathway analyses. Furthermore, the correlations of Id2 with its target gene expression and clinical outcomes were calculated.ResultsOur data revealed that Id2 overexpression could inhibit LADC cells’ migratory, invasive, proliferation, and colony formation capabilities. Silencing Id2 expression in LADC cells reversed the aforementioned inhibitory effects, and knockdown of Id2 increased LADC cells’ metastatic abilities in vivo. Bioinformatics analysis revealed that these effects of Id2 on cancer progression might be regulated by focal adhesion kinase (FAK) signaling and CD44/Twist expression. Furthermore, in online clinical database analysis, patients with LADC whose Id2 expression levels were high and FAK/Twist expression levels were low had superior clinical outcomes.ConclusionOur data indicate that the Id2 gene may act as a metastasis suppressor and provide new insights into LADC progression and therapy.

Association of Long-Acting Injectable Antipsychotics and Oral Antipsychotics With Disease Relapse, Health Care Use, and Adverse Events Among People With Schizophrenia

Evidence for improved clinical outcomes with long-acting injectable antipsychotics (LAIAs) vs oral antipsychotics (OAs) is limited in Asian populations and special patient groups, including older people (>65 years), people with substance use, and early initiators of LAIAs. To compare the risk of disease relapse, health care use, and adverse events associated with the use of LAIAs vs OAs among people in Hong Kong with schizophrenia. In this self-controlled case series study, individuals with a diagnosis of schizophrenia who were prescribed LAIAs and OAs between January 1, 2004, and December 31, 2019, were identified from the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority. Data analysis was conducted from May to August in 2021. Use of LAIAs vs OAs. Risk of disease relapse (hospitalizations for psychiatric disorders, hospitalizations for schizophrenia, and suicide attempts), health care use (all-cause emergency department visits and hospitalizations), and adverse events (hospitalizations for somatic disorders, hospitalizations for cardiovascular diseases, and extrapyramidal symptoms) between the period in which patients were treated with LAIAs and the period in which patients were treated with OAs were compared using Poisson regression. Of the 70 396 individuals with schizophrenia (37 200 women [52.8%]; mean [SD] age, 44.2 [15.8] years), 23 719 (33.7%) were prescribed both LAIAs and OAs. Compared with OAs, LAIAs were associated with a lower risk of hospitalizations for any cause (n = 20 973; incidence rate ratio [IRR], 0.63 [95% CI, 0.61-0.65]), hospitalizations for psychiatric disorders (n = 19 283; IRR, 0.52 [95% CI, 0.50-0.53]), hospitalizations for schizophrenia (n = 18 385; IRR, 0.53 [95% CI, 0.51-0.55]), and incident suicide attempts (n = 1453; IRR, 0.56 [95% CI, 0.44-0.71]). During full treatment with LAIAs, there was a reduction in hospitalizations for somatic disorders (n = 15 396; IRR, 0.88 [95% CI, 0.85-0.91]), hospitalizations for cardiovascular diseases (n = 3710; IRR, 0.88 [95% CI, 0.81-0.96]), and extrapyramidal symptoms (n = 22 182; IRR, 0.86 [95% CI, 0.82-0.91]) compared with full treatment with OAs. No significant difference was found for emergency department visits. Similar associations were observed during the subsequent treatment periods (beyond 90 days) and among older people and those with substance use, except for an increased risk of extrapyramidal symptoms among older people when initiating LAIAs (first 90 days). Compared with late initiators, early LAIA initiators had a greater reduction in these outcome events. This self-controlled case series study of people in Hong Kong with schizophrenia suggests that LAIAs were associated with a lower risk of disease relapse and hospitalization than OAs, without an increased risk of adverse events. Clinicians should more broadly consider the long-term use of LAIAs for Chinese people with schizophrenia, especially early in the course of illness.

Abstract LB013: Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma

Abstract Purpose: Glioblastoma (GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying therapeutic opportunities to target this tumor. Experimental Design: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens (pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. Results: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed increased expression of this transcriptional profile to be significantly associated with worse median overall survival (248 days vs 430 days, p=0.0004), and upregulation of this profile at recurrence. Most notably, we identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Utilizing cell sorting, we observed that THY1-positive cells represented &amp;lt;10% of cells in the treatment-naïve tumors and 75-96% in the recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model samples, which co-localized with macrophages within the perivascular niche. Since TGFβ signaling contributes to a mesenchymal/stem-like phenotype, we inhibited TGFβRI activity in vivo which resulted in decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. Conclusions: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal/stem-like cells within the perivascular niche. Furthermore, our data demonstrate the promise of targeting upregulated pathways in resistant subclones as a novel mechanism to achieve therapeutic response, and specifically that THY1 expression may represent a biomarker of response to TGFβ inhibition. Citation Format: Wajd N. Al-Holou, Hanxiao Wang, Visweswaran Ravikumar, Morgan Oneka, Roel G. Verhaak, Hoon Kim, Drew Pratt, Sandra Camelo-Piragua, Corey Speers, Daniel Wahl, Sunita Shankar, Todd Hollon, Oren Sagher, Jason Heth, Karin M. Muraszko, Theodore S. Lawrence, Ana C. deCarvalho, Tom Mikkelsen, Arvind Rao, Alnawaz Rehemtulla. Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB013.

Aboriginal social housing in remote Australia: crowded, unrepaired and raising the risk of infectious diseases

Sufficient, well-maintained housing infrastructure can support healthy living practices for hygiene, safety and nutrition. This article focuses on the relationship between housing and health through a case study in the remote Barkly region in the Northern Territory, Australia. A research partnership between Anyinginyi Health Aboriginal Corporation and academic researchers employed a mixed methodological approach, involving interviews with residents, clinical and outreach staff, and clinical database analysis. The results revealed much higher levels of crowding in remote communities and in Tennant Creek than officially recorded, with up to 22 residents in surveyed households. Interviews with clinicians and public health staff highlighted the impact of crowding on infection transmission, poor sleep and reduced personal safety, and damage to health hardware. The database analysis detailed the types of preventable, hygiene-related infectious diseases that dominated, with over half of the total infectious disease diagnoses being skin, respiratory and ear, nose and throat infections. Repeated infection likely contributes to increased rates of chronic kidney and rheumatic heart diseases. The combined overall findings highlight the parallel conditions of the prevalence of hygiene-related infectious diseases, crowding and environmental health issues (including health hardware). No objective evidence of direct causal relationships was obtained due to the small scale and methodological limitations of the study. More complex future research is outlined in order to understand how to further investigate the burden of disease that the affects morbidity and mortality of Aboriginal Australians, and underlies the urgency for housing policy reform and funding to upgrade housing.