The intricate interplay between cancer stem cells and cell-of-origin of cancer: implications for therapeutic strategies.

Background: Cancer stem cells (CSCs) have emerged as pivotal players in tumorigenesis, disease progression, and resistance to therapies. Objective: This comprehensive review delves into the intricate relationship between CSCs and the cell-of-origin in diverse cancer types. Design: Comprehensive review of thematically-relevant literature. Methods: We explore the underlying molecular mechanisms that drive the conversion of normal cells into CSCs and the impact of the cell-of-origin on CSC properties, tumor initiation, and therapeutic responses. Moreover, we discuss potential therapeutic interventions targeting CSCs based on their distinct cell-of-origin characteristics. Results: Accruing evidence suggest that the cell-of-origin, the cell type from which the tumor originates, plays a crucial role in determining the properties of CSCs and their contribution to tumor heterogeneity. Conclusion: By providing critical insights into the complex interplay between CSCs and their cellular origins, this article aims to enhance our understanding of cancer biology and pave the way for more effective and personalized cancer treatments.

Beyond diagnosis: Leveraging routine blood and urine biomarkers to predict severity and functional outcome in acute ischemic stroke.

Background: The initial severity of acute ischemic stroke (AIS) is a crucial predictor of the disease outcome. In this study, blood and urine biomarkers from patients with AIS were measured to estimate stroke severity and predict long-term stroke outcomes. Methods: The medical records of patients with AIS between October 2016 and May 2020 were retrospectively analyzed. The relationships of blood and urine biomarkers with stroke severity at admission were evaluated in patients with AIS. Predictive models for initial stroke severity and long-term prognosis were then developed using a panel of identified biomarkers. Results: A total of 2229 patients were enrolled. Univariate analysis revealed 12 biomarkers associated with the National Institutes of Health Stroke Scale scores at admission. The area under the curve values for predicting initial stroke severity and long-term prognosis on the basis of these biomarkers were 0.7465, 0.7470, and 0.8061, respectively. Among multiple tested machine-learning, eXtreme gradient boosting exhibited the highest effectiveness in predicting 90-day modified Rankin Scale scores. SHapley Additive exPlanations revealed fasting glucose, albumin, hemoglobin, prothrombin time, and urine-specific gravity to be the top five most crucial biomarkers. Conclusion: These findings demonstrate that clinically available blood and urine biomarkers can effectively estimate initial stroke severity and predict long-term prognosis in patients with AIS. Our results provide a scientific basis for developing tailored clinical treatment and management strategies for AIS, through incorporating liquid biomarkers into stroke risk assessment and patient care protocols for patients with AIS.

Risk factor identification and prediction models for prolonged length of stay in hospital after acute ischemic stroke using artificial neural networks.

Background: Accurate estimation of prolonged length of hospital stay after acute ischemic stroke provides crucial information on medical expenditure and subsequent disposition. This study used artificial neural networks to identify risk factors and build prediction models for a prolonged length of stay based on parameters at the time of hospitalization. Methods: We retrieved the medical records of patients who received acute ischemic stroke diagnoses and were treated at a stroke center between January 2016 and June 2020, and a retrospective analysis of these data was performed. Prolonged length of stay was defined as a hospital stay longer than the median number of days. We applied artificial neural networks to derive prediction models using parameters associated with the length of stay that was collected at admission, and a sensitivity analysis was performed to assess the effect of each predictor. We applied 5-fold cross-validation and used the validation set to evaluate the classification performance of the artificial neural network models. Results: Overall, 2,240 patients were enrolled in this study. The median length of hospital stay was 9 days. A total of 1,101 patients (49.2%) had a prolonged hospital stay. A prolonged length of stay is associated with worse neurological outcomes at discharge. Univariate analysis identified 14 baseline parameters associated with prolonged length of stay, and with these parameters as input, the artificial neural network model achieved training and validation areas under the curve of 0.808 and 0.788, respectively. The mean accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of prediction models were 74.5, 74.9, 74.2, 75.2, and 73.9%, respectively. The key factors associated with prolonged length of stay were National Institutes of Health Stroke Scale scores at admission, atrial fibrillation, receiving thrombolytic therapy, history of hypertension, diabetes, and previous stroke. Conclusion: The artificial neural network model achieved adequate discriminative power for predicting prolonged length of stay after acute ischemic stroke and identified crucial factors associated with a prolonged hospital stay. The proposed model can assist in clinically assessing the risk of prolonged hospitalization, informing decision-making, and developing individualized medical care plans for patients with acute ischemic stroke.

Application of machine learning-based models to boost the predictive power of the SPAN index.

BACKGROUND: This study re-explored the predictive validity of Stroke Prognostication using Age and National Institutes of Health Stroke Scale (SPAN) index in patients who received different treatments for acute ischemic stroke (AIS) and developed machine learning-boosted outcome prediction models. METHODS: We evaluated the prognostic relevance of SPAN index in patients with AIS who received intravenous tissue-type plasminogen activator (IV-tPA), intra-arterial thrombolysis (IAT) or non-thrombolytic treatments (non-tPA), and applied machine learning algorithms to develop SPAN-based outcome prediction models in a cohort of 2145 hospitalized AIS patients. The performance of the models was assessed and compared using the area under the receiver operating characteristic curves (AUCs). RESULTS: SPAN index ≥100 was associated with higher mortality rate and higher modified Rankin Scale at discharge in AIS patients who received the different treatments. Compared to the lower AUCs for the SPAN-alone model across all groups, the AUCs of the logistic regression-boosted model were 0.838, 0.857, 0.766 and 0.875 for the whole cohort, non-tPA, IV-tPA and IAT groups, respectively. Similarly, the AUCs of the generated artificial neural network were 0.846, 0.858, 0.785 and 0.859 for the whole cohort, non-tPA, IV-tPA and IAT groups, respectively, while for gradient boosting decision tree model, we computed 0.850, 0.863, 0.779 and 0.815. CONCLUSIONS: SPAN index has prognostic relevance in patients with AIS who received different treatments. The generated machine learning-based models exhibit good performance for predicting the functional recovery of AIS; thus, their proposed clinical application to aid outcome prediction and decision-making for the patients with AIS.

Artificial neural network-boosted Cardiac Arrest Survival Post-Resuscitation In-hospital (CASPRI) score accurately predicts outcome in cardiac arrest patients treated with targeted temperature management.

Existing prognostic models to predict the neurological recovery in patients with cardiac arrest receiving targeted temperature management (TTM) either exhibit moderate accuracy or are too complicated for clinical application. This necessitates the development of a simple and generalizable prediction model to inform clinical decision-making for patients receiving TTM. The present study explores the predictive validity of the Cardiac Arrest Survival Post-resuscitation In-hospital (CASPRI) score in cardiac arrest patients receiving TTM, regardless of cardiac event location, and uses artificial neural network (ANN) algorithms to boost the prediction performance. This retrospective observational study evaluated the prognostic relevance of the CASPRI score and applied ANN to develop outcome prediction models in a cohort of 570 patients with cardiac arrest and treated with TTM between 2014 and 2019 in a nationwide multicenter registry in Taiwan. In univariate logistic regression analysis, the CASPRI score was significantly associated with neurological outcome, with the area under the receiver operating characteristics curve (AUC) of 0.811. The generated ANN model, based on 10 items of the CASPRI score, achieved a training AUC of 0.976 and validation AUC of 0.921, with the accuracy, precision, sensitivity, and specificity of 89.2%, 91.6%, 87.6%, and 91.2%, respectively, for the validation set. CASPRI score has prognostic relevance in patients who received TTM after cardiac arrest. The generated ANN-boosted, CASPRI-based model exhibited good performance for predicting TTM neurological outcome, thus, we propose its clinical application to improve outcome prediction, facilitate decision-making, and formulate individualized therapeutic plans for patients receiving TTM.

lnc-IL7R Expression Reflects Physiological Pulmonary Function and Its Aberration Is a Putative Indicator of COPD.

Despite rapidly evolving pathobiological mechanistic demystification, coupled with advances in diagnostic and therapeutic modalities, chronic obstructive pulmonary disease (COPD) remains a major healthcare and clinical challenge, globally. Further compounded by the dearth of available curative anti-COPD therapy, it is posited that this challenge may not be dissociated from the current lack of actionable COPD pathognomonic molecular biomarkers. There is accruing evidence of the involvement of protracted 'smoldering' inflammation, repeated lung injury, and accelerated lung aging in enhanced predisposition to or progression of COPD. The relatively novel uncharacterized human long noncoding RNA lnc-IL7R (otherwise called LOC100506406) is increasingly designated a negative modulator of inflammation and regulator of cellular stress responses; however, its role in pulmonary physiology and COPD pathogenesis remains largely unclear and underexplored. Our previous work suggested that upregulated lnc-IL7R expression attenuates inflammation following the activation of the toll-like receptor (TLR)-dependent innate immune system, and that the upregulated lnc-IL7R is anti-correlated with concomitant high PM2.5, PM10, and SO2 levels, which is pathognomonic for exacerbated/aggravated COPD in Taiwan. In the present study, our quantitative analysis of lnc-IL7R expression in our COPD cohort (n = 125) showed that the lnc-IL7R level was significantly correlated with physiological pulmonary function and exhibited COPD-based stratification implications (area under the curve, AUC = 0.86, p < 0.001). We found that the lnc-IL7R level correctly identified patients with COPD (sensitivity = 0.83, specificity = 0.83), precisely discriminated those without emphysematous phenotype (sensitivity = 0.48, specificity = 0.89), and its differential expression reflected disease course based on its correlation with the COPD GOLD stage (r = −0.59, p < 0.001), %LAA-950insp (r = −0.30, p = 0.002), total LAA (r = −0.35, p < 0.001), FEV1(%) (r = 0.52, p < 0.001), FVC (%) (r = 0.45, p < 0.001), and post-bronchodilator FEV1/FVC (r = 0.41, p < 0.001). Consistent with other data, our bioinformatics-aided dose−response plot showed that the probability of COPD decreased as lnc-IL7R expression increased, thus, corroborating our posited anti-COPD therapeutic potential of lnc-IL7R. In conclusion, reduced lnc-IL7R expression not only is associated with inflammation in the airway epithelial cells but is indicative of impaired pulmonary function, pathognomonic of COPD, and predictive of an exacerbated/ aggravated COPD phenotype. These data provide new mechanistic insights into the ailing lung and COPD progression, as well as suggest a novel actionable molecular factor that may be exploited as an efficacious therapeutic strategy in patients with COPD.

Determinants of Pulmonary Emphysema Severity in Taiwanese Patients with Chronic Obstructive Pulmonary Disease: An Integrated Epigenomic and Air Pollutant Analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) continues to pose a therapeutic challenge. This may be connected with its nosological heterogeneity, broad symptomatology spectrum, varying disease course, and therapy response. The last three decades has been characterized by increased understanding of the pathobiology of COPD, with associated advances in diagnostic and therapeutic modalities; however, the identification of pathognomonic biomarkers that determine disease severity, affect disease course, predict clinical outcome, and inform therapeutic strategy remains a work in progress. OBJECTIVES: Hypothesizing that a multi-variable model rather than single variable model may be more pathognomonic of COPD emphysema (COPD-E), the present study explored for disease-associated determinants of disease severity, and treatment success in Taiwanese patients with COPD-E. METHODS: The present single-center, prospective, non-randomized study enrolled 125 patients with COPD and 43 healthy subjects between March 2015 and February 2021. Adopting a multimodal approach, including bioinformatics-aided analyses and geospatial modeling, we performed an integrated analysis of selected epigenetic, clinicopathological, geospatial, and air pollutant variables, coupled with correlative analyses of time-phased changes in pulmonary function indices and COPD-E severity. RESULTS: Our COPD cohort consisted of 10 non-, 57 current-, and 58 ex-smokers (median age = 69 ± 7.76 years). Based on the percentages of low attenuation area below - 950 Hounsfield units (%LAA-950insp), 36 had mild or no emphysema (%LAA-950insp < 6), 22 were moderate emphysema cases (6 ≤ %LAA-950insp < 14), and 9 presented with severe emphysema (%LAA-950insp ≥ 14). We found that BMI, lnc-IL7R, PM2.5, PM10, and SO2 were differentially associated with disease severity, and are highly-specific predictors of COPD progression. Per geospatial levels, areas with high BMI and lnc-IL7R but low PM2.5, PM10, and SO2 were associated with fewer and ameliorated COPD cases, while high PM2.5, PM10, and SO2 but low BMI and lnc-IL7R characterized places with more COPD cases and indicated exacerbation. The prediction pentad effectively differentiates patients with mild/no COPD from moderate/severe COPD cases, (mean AUC = 0.714) and exhibited very high stratification precision (mean AUC = 0.939). CONCLUSION: Combined BMI, lnc-IL7R, PM2.5, PM10, and SO2 levels are optimal classifiers for accurate patient stratification and management triage for COPD in Taiwan. Low BMI, and lnc-IL7R, with concomitant high PM2.5, PM10, and SO2 levels is pathognomonic of exacerbated/aggravated COPD in Taiwan.

Blood Neurofilament Light Chain in Parkinson's Disease: Comparability between Parkinson's Progression Markers Initiative (PPMI) and Asian Cohorts.

Elevated blood neurofilament light chain (NfL), which indicates the loss of neuronal integrity, is increasingly implicated as a diagnostic and outcome-predicting biomarker for neurological diseases. However, its diagnostic implication for Parkinson's disease (PD) remains unclear, with conflicting data reported by several studies. This may result from the demographic heterogeneity of the studied cohorts. The present study investigated the comparability of blood NfL between a domestic, single-centered PD cohort from Shuang Ho Hospital (SHH) in Taiwan, with the large international, multi-center cohort, Parkinson's Progression Markers Initiative (PPMI). In the SHH PD cohort, with 61 people with PD (PwP) and 25 healthy non-PD controls, plasma NfL unexpectedly was significantly higher in the control group than PwP (14.42 ± 13.84 vs. 9.39 ± 6.91 pg/mL, p = 0.05). Interestingly, subgroup analysis revealed a non-significant difference of plasma NfL levels in male PwP compared with controls (8.58 ± 6.21 vs. 7.25 ± 4.43 pg/mL, p =0.575), whereas NfL levels were significantly lower in the female PwP group than in their healthy control peers (10.29 ± 7.62 vs. 17.79 ± 15.52 pg/mL, p = 0.033). Comparative analysis of the SHH and PPMI cohorts revealed a comparable gender-stratified distribution of blood NfL based on approximate theoretical quantiles. After adjusting for age and gender, no apparent difference in NfL value distribution was observed between the SHH and PPMI cohorts' control or PD groups. Significant downregulation of blood NfL levels were positively correlated with a reduced probability of having a PD diagnosis in both cohorts. These results demonstrated that the adjustment for demographic background enhances comparability between cohorts, and may be required to eliminate covariate/confounder-associated conflict in blood NfL results between different PD studies. This experience may be beneficial to other researchers around the world who are saddled with limited study participants, especially as data from small cohort sizes are often at greater risk of being skewed by specific variables.

Efficacy of Penile Low-Intensity Shockwave Therapy and Determinants of Treatment Response in Taiwanese Patients with Erectile Dysfunction.

BACKGROUND: Erectile dysfunction (ED) remains an emotional wrench to patients and a therapeutic challenge to urologists in andrology clinics worldwide. This is, in part, related to refraction to, or transient effect of phosphodiesterase 5 inhibitors (PDE5i), coupled with patients' dissatisfaction with this treatment modality. Low-intensity extracorporeal shockwave therapy (Li-ESWT) is an evolving treatment option, with promising curative potential. Current international guidelines are inconclusive, bear weak recommendation strength, and lack ethnogeographic consensus. OBJECTIVES: This study evaluated the safety, efficacy, and effect duration of Li-ESWT, as well as exploring disease-associated determinants of treatment success in Taiwanese males with ED. METHODS: A cohort of 69 eligible cases treated with 12 sessions of Li-ESWT and followed up for at least 12 months after treatment, between January 2018 and December 2019 at our medical facility, was used. The present single-center, retrospective, non-randomized, single-arm study employed standardized erectile function evaluation indices, namely, the five-item International Index of Erectile Function (IIEF-5) and Erection Hardness Score (EHS). Clinicopathological analyses of selected variables and comparative analyses of time-phased changes in the EF indices relative to baseline values were performed. Evaluation of treatment success was based on minimal clinically important difference (MCID), using a binomial logistic regression model. RESULTS: The median age and duration of ED for our Taiwanese cohort were 55 years and 12 months, respectively, and an average of 31.3% presented with co-morbidities. The mean improvement in IIEF-5, EHS, and quality of life (QoL) domain scores relative to the baseline values was statistically very significant (p < 0.001) at all indicated follow-up time-points. When stratified, Taiwanese patients with severe and moderate ED benefited more from Li-ESWT, compared with those in the mild or mild-to-moderate group. Patients' pre-Li-ESWT PDE5i response status was not found to significantly influence Li-ESWT response. Univariate analysis showed that age > 45 years (p = 0.04), uncontrolled diabetes mellitus (p = 0.04), and uncontrolled hyperlipidemia (p = 0.01) were strongly associated with Li-ESWT efficacy; however, only age > 45 years (p = 0.04) and uncontrolled hyperlipidemia (p = 0.03) were found to be independent negative predictors of Li-ESWT success by the multivariate logistic model. Follow-up was uneventful, with no treatment-related adverse events or side effects reported. Of the treated patients, 86.1% indicated satisfaction with the treatment regimen, and over 90% indicated they would recommend the same therapy to others. CONCLUSIONS: Li-ESWT is a safe and efficacious therapeutic modality for Taiwanese patients with ED. Uncontrolled hyperlipidemia and age > 45 years are independent negative predictors of treatment success for this cohort.

Combined Treatment with Acalabrutinib and Rapamycin Inhibits Glioma Stem Cells and Promotes Vascular Normalization by Downregulating BTK/mTOR/VEGF Signaling.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median duration of survival of approximately 14 months after diagnosis. High resistance to chemotherapy remains a major problem. Previously, BTK has been shown to be involved in the intracellular signal transduction including Akt/mTOR signaling and be critical for tumorigenesis. Thus, we aim to evaluate the effect of BTK and mTOR inhibition in GBM. We evaluated the viability of GBM cell lines after treatment with acalabrutinib and/or rapamycin through a SRB staining assay. We then evaluated the effect of both drugs on GBM stem cell-like phenotypes through various in vitro assay. Furthermore, we incubated HUVEC cells with tumorsphere conditioned media and observed their angiogenesis potential, with or without treatment. Finally, we conducted an in vivo study to confirm our in vitro findings and analyzed the effect of this combination on xenograft mice models. Drug combination assay demonstrated a synergistic relationship between acalabrutinib and rapamycin. CSCs phenotypes, including tumorsphere and colony formation with the associated expression of markers of pluripotency are inhibited by either acalabrutinib or rapamycin singly and these effects are enhanced upon combining acalabrutinib and rapamycin. We showed that the angiogenesis capabilities of HUVEC cells are significantly reduced after treatment with acalabrutinib and/or rapamycin. Xenograft tumors treated with both drugs showed significant volume reduction with minimal toxicity. Samples taken from the combined treatment group demonstrated an increased Desmin/CD31 and col IV/vessel ratio, suggesting an increased rate of vascular normalization. Our results demonstrate that BTK-mTOR inhibition disrupts the population of GBM-CSCs and contributes to normalizing GBM vascularization and thus, may serve as a basis for developing therapeutic strategies for chemoresistant/radioresistant GBM.

Concomitant High Apoptosis Inhibitor of Macrophage (AIM) and Low Prostate-Specific Antigen (PSA) Indicates Activated T Cell-Mediated Anticancer Immunity, Enhance Sensitivity to Pembrolizumab, and Elicit Good Prognosis in Prostate Cancer.

BACKGROUND: Despite its widespread use, the use of prostate-specific antigen (PSA) alone as a screening biomarker for prostate cancer (PCa) leads often to unwarranted prostate biopsy, over-diagnosis, and consequently, over-treatment, because of its limited specificity. There are reports that the apoptosis inhibitor of macrophage (AIM), secreted mainly by macrophages and epithelial cells, is upregulated during inflammation and facilitates immune recognition of cancerous cells by blocking human regulator of complement activation. OBJECTIVE: These controversies around the PSA utility necessitate a reexamination of its use as a screening tool. More so, despite the suggested implication of AIM in anticancer immunosurveillance, there is a dearth of information on its role in therapy response, disease progression, and clinical outcomes of patients with PCa. These inform the present study to probe the nature and role of AIM/PSA signaling in anticancer immunity and prognosis in PCa. METHODS: A combination of bioinformatics-aided statistical analyses, gene function annotation, and immune infiltrate analyses, coupled with tissue staining, and function assays, namely migration, invasion, and clonogenicity assays, we employed. RESULTS: We demonstrated that AIM and PSA expression levels are inversely correlated in PCa clinical samples and cell lines, with AIMlowPSAhigh defining PCa, compared to AIMhighPSAlow in normal samples. Concomitant aberrant PSA and significantly suppressed AIM expression levels positively correlated with high-grade disease and characterized by advanced stage prostate cancer, regardless of mutation status. We found that a high PSA/AIM ratio is associated with disease recurrence in patients with prostate cancer but is equivocal for overall survival. In addition, PSA-associated AIM suppression is implicated in the enhanced 'metastability' of PCa and a high AIM/PSA ratio is associated with strong castration-induced regression. CRISPR-mediated AIM knockout was associated with higher PSA expression while ectopic expression of AIM significantly attenuated the migration and invasive capability of PC3 and DU145 cells. Interestingly, compared to normal samples, we observed that AIM, biomarkers of T-cell activation and M1 phenotype markers are co-suppressed in PCa samples. CONCLUSION: Herein, we demonstrate that AIM/CD5L binds to PSA and that a high PSA/AIM ratio defines advanced stage PCa (regardless of mutation status), is implicated in enhanced metastability, and associated with disease recurrence, while a high AIM/PSA ratio is associated with strong castration-induced regression. More so, the ectopic expression of AIM significantly enhances the anticancer effect of Pembrolizumab and elicits an increased CD8+ T-cell count in AIMhiPSAloPDL1+ PCa cases that are respondent to Pembrolizumab treatment.

Plasma extracellular vesicles tau and ß-amyloid as biomarkers of cognitive dysfunction of Parkinson's disease.

The contribution of circulatory tau and ß-amyloid in Parkinson's disease (PD), especially the cognitive function, remains inconclusive. Extracellular vesicles (EVs) cargo these proteins throughout the bloodstream after they are directly secreted from many cells, including neurons. The present study aims to investigate the role of the plasma EV-borne tau and ß-amyloid as biomarkers for cognitive dysfunction in PD by investigating subjects with mild to moderate stage of PD (n = 116) and non-PD controls (n = 46). Plasma EVs were isolated, and immunomagnetic reduction-based immunoassay was used to assess the levels of α-synuclein, tau, and ß-amyloid 1-42 (Aß1-42) within the EVs. Artificial neural network (ANN) models were then applied to predict cognitive dysfunction. We observed no significant difference in plasma EV tau and Aß1-42 between PD patients and controls. Plasma EV tau was significantly associated with cognitive function. Moreover, plasma EV tau and Aß1-42 were significantly elevated in PD patients with cognitive impairment when compared to PD patients with optimal cognition. The ANN model used the plasma EV α-synuclein, tau, and Aß1-42, as well as the patient's age and gender, as predicting factors. The model achieved an accuracy of 91.3% in identifying cognitive dysfunction in PD patients, and plasma EV tau and Aß1-42 are the most valuable factors. In conclusion, plasma EV tau and Aß1-42 are significant markers of cognitive function in PD patients. Combining with the plasma EV α-synuclein, age, and sex, plasma EV tau and Aß1-42 can identify cognitive dysfunction in PD patients. This study corroborates the prognostic roles of plasma EV tau and Aß1-42 in PD.

Exosomal lncRNA PVT1/VEGFA Axis Promotes Colon Cancer Metastasis and Stemness by Downregulation of Tumor Suppressor miR-152-3p.

BACKGROUND: Treating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear. METHODS: Computational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)). RESULTS: The in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated. CONCLUSION: Exosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.

Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2).

BACKGROUND: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. OBJECTIVE: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. METHODS: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. RESULTS: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1-TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. CONCLUSION: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1-TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

Extracorporeal Shockwave Therapy (ESWT) Alleviates Pain, Enhances Erectile Function and Improves Quality of Life in Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

PURPOSE: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), affecting over 90% of patients with symptomatic prostatitis, remains a therapeutic challenge and adversely affects patients' quality of life (QoL). This study probed for likely beneficial effects of ESWT, evaluating its extent and durability. PATIENTS AND METHODS: Standardized indices, namely the pain, urinary, and QoL domains and total score of NIH-CPSI, IIEF-5, EHS, IPSS, and AUA QoL_US were employed in this study of patients with CP/CPPS who had been refractory to other prior treatments (n = 215; age range: 32-82 years; median age: 57.5 ± 12.4 years; modal age: 41 years). RESULTS: For CP symptoms, the mean pre-ESWT NIH-CPSI total score of 27.1 ± 6.8 decreased by 31.3-53.6% over 12 months after ESWT. The mean pre-ESWT NIH-CPSI pain (12.5 ± 3.3), urinary (4.98 ± 2.7), and QoL (9.62 ± 2.1) domain scores improved by 2.3-fold, 2.2-fold, and 2.0-fold, respectively, by month 12 post-ESWT. Compared with the baseline IPSS of 13.9 ± 8.41, we recorded 27.1-50.9% amelioration of urinary symptoms during the 12 months post-ESWT. For erectile function, compared to pre-ESWT values, the IIEF-5 also improved by ~1.3-fold by month 12 after ESWT. This was corroborated by EHS of 3.11 ± 0.99, 3.37 ± 0.65, 3.42 ± 0.58, 3.75 ± 0.45, and 3.32 ± 0.85 at baseline, 1, 2, 6, and 12 months post-ESWT. Compared to the mean pre-ESWT QoL score (4.29 ± 1.54), the mean QoL values were 3.26 ± 1.93, 3.45 ± 2.34, 3.25 ± 1.69, and 2.6 ± 1.56 for months 1, 2, 6, and 12 after ESWT, respectively. CONCLUSIONS: This study shows ESWT, an outpatient and easy-to-perform, minimally invasive procedure, effectively alleviates pain, improves erectile function, and ameliorates quality of life in patients with refractory CP/CPPS.

Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer.

Background: Testosterone plays a critical role in prostate development and pathology. However, the impact of the molecular interplay between testosterone-associated genes on therapy response and susceptibility to disease relapse in PCa patients remains underexplored. Objective: This study investigated the role of dysregulated or aberrantly expressed testosterone-associated genes in the enhanced dissemination, phenoconversion, and therapy response of treatment-resistant advanced or recurrent PCa. Methods: Employing a combination of multi-omics big data analyses, in vitro, ex vivo, and in vivo assays, we assessed the probable roles of HSD17B2, HSD17B3, SHBG, and SRD5A1-mediated testosterone metabolism in the progression, therapy response, and prognosis of advanced or castration-resistant PCa (CRPC). Results: Our bioinformatics-aided gene expression profiling and immunohistochemical staining showed that the aberrant expression of the HSD17B2, HSD17B3, SHBG, and SRD5A1 testosterone metabolic tetrad characterize androgen-driven PCa and is associated with disease progression. Reanalysis of the TCGA PRAD cohort (n = 497) showed that patients with SRD5A1-dominant high expression of the tetrad exhibited worse mid-term to long-term (≥5 years) overall survival, with a profoundly shorter time to recurrence, compared to those with low expression. More so, we observed a strong association between enhanced HSD17B2/SRD5A1 signaling and metastasis to distant lymph nodes (M1a) and bones (M1b), while upregulated HSD17B3/SHBG signaling correlated more with negative metastasis (M0) status. Interestingly, increased SHBG/SRD5A1 ratio was associated with metastasis to distant organs (M1c), while elevated SRD5A1/SHBG ratio was associated with positive biochemical recurrence (BCR) status, and shorter time to BCR. Molecular enrichment and protein-protein connectivity network analyses showed that the androgenic tetrad regulates testosterone metabolism and cross-talks with modulators of drug response, effectors of cell cycle progression, proliferation or cell motility, and activators/mediators of cancer stemness. Moreover, of clinical relevance, SHBG ectopic expression (SHBG_OE) or SRD5A1 knockout (sgSRD5A1) induced the acquisition of spindle fibroblastoid morphology by the round/polygonal metastatic PC-3 and LNCaP cells, attenuated their migration and invasion capability, and significantly suppressed their ability to form primary or secondary tumorspheres, with concomitant downregulation of stemness KLF4, OCT3/4, and drug resistance ABCC1, ABCB1 proteins expression levels. We also showed that metronomic dutasteride synergistically enhanced the anticancer effect of low-dose docetaxel, in vitro, and in vivo. Conclusion: These data provide proof of concept that re-reprogramming of testosterone metabolism through "SRD5A1 withdrawal" or "SHBG induction" is a workable therapeutic strategy for shutting down androgen-driven oncogenic signals, reversing treatment resistance, and repressing the metastatic/recurrent phenotypes of patients with PCa.

A cross-country comparison of malaria policy as a premise for contextualized appropriation of foreign aid in global health.

BACKGROUND: Foreign aid continues to play an essential role in health sector development in low-resource countries, particularly in terms of providing a vital portion of their health expenditures. However, the relationship between foreign aid allocation and malaria policy formulation and/or implementation among state aid recipients remains unknown. METHODS: Publicly available data were collected with the country as observational unit to set up the conceptual framework. The quality and strength of relationships between socioeconomic, environmental and institutional parameters were estimated by Pearson and polychoric correlations. A correlation matrix was explored by factor analysis. RESULTS: The first policy index captured policy variation related to malaria burden and development assistance. Funding per capita from all international agencies was correlated with malaria burden, whereas governmental funding for national malaria programmes per capita was not. The second policy index captured variation beyond malaria endemicity and country size. Variation was found to be related to international country risk instruments and funding from the United States Agency for International Development President's Malaria Initiative. CONCLUSIONS: Not all agencies involved in malaria policy allocate assistance in alignment with the gross domestic product and malaria burden. While the country size does not negatively impact malaria burden, it does account for greater development assistance per capita from selected international agencies. Novel policy indexes describe complex relationships between malaria policy, international foreign aid and socioeconomic parameters. Small countries have distinct environmental and sociopolitical properties.

The JAK inhibitor Tofacitinib inhibits structural damage in osteoarthritis by modulating JAK1/TNF-alpha/IL-6 signaling through Mir-149-5p.

BACKGROUND: Osteoarthritis (OA), a common articular bone degenerative disease, is exacerbated by proinflammatory cytokine signaling. Mounting evidence suggests that epigenetic modifiers, namely microRNAs (miRs), are dysregulated in articular chondrocytes (ACs) during OA. METHODS: An initial database search led to the identification of miR-149-5p, which was downregulated in clinical OA samples and contributed to chronic inflammation, by increasing TNF-α/IL-6 signaling within the synovium, and OA progression. RESULTS: We overexpressed miR-149-5p in the human chondrocyte cell lines C20A4 and C28/I2 to examine its role in chondrocyte hypertrophy and osteoclastogenesis and found a significant decrease in IL-6 expression, an increase in SOX9 expression, and a reduction in chondrocyte hypertrophy. We evaluated the therapeutic effects of tofacitinib (JAK inhibitor) by suppressing inflammation and restoring miR-149-5p expression. Tofacitinib-treated C20A4 and C28/I2 cells had a significantly lower expression of JAK/IL-6/TNF-α and an increased level of miR-149-5p. Notably, tofacitinib treatment reduced AC hypertrophy and secretion of RANKL and IL-6. Finally, an OA mouse model was used to evaluate the therapeutic potential of tofacitinib. Intra-articular injection of tofacitinib significantly lowered arthritis scores and bone degradation in treated mice compared with their control counterparts. CONCLUSION: We show for the first time that tofacitinib suppresses the expression level of JAK1/TNF-α/IL-6 by upregulating miR-149-5p level. Our findings revealed the functional association between proinflammatory JAK1/TNF-α/IL-6 signaling and ACs development and highlight the therapeutic potential of tofacitinib in OA.

Adipose-derived stem cell induced-tissue repair or wound healing is mediated by the concomitant upregulation of miR-21 and miR-29b expression and activation of the AKT signaling pathway.

BACKGROUND: Adipose-derived stem cells (ADSCs), a subpopulation of mesenchymal stem cells, are characterized by their potential to differentiate into multiple cell lineages. Due to their abundance and relative ease of procurement, ADSCs are widely used for tissue repair and regeneration. However, the molecular mechanisms of the therapeutic effect of ADSCs remain unknown. METHODS: MicroRNAs have emerged as important signaling molecules in skin wound healing, and their roles in ADSC-based therapies must be addressed. Here, we investigated the potential of ADSCs in improving cutaneous wound healing in vitro and in vivo. RESULTS: We simulated the microenvironment of the wound site by coculturing human dermal fibroblasts (HDFs) with ADSCs. We found that cocultured HDFs expressed significantly higher levels of miR-29b and miR-21 and had higher proliferation and migration rates than ADSCs cultured without HDFs. Moreover, increased expression of Collagen Type I Alpha 1 Chain (COL1A1), Collagen Type III Alpha 1 Chain (COL3A1), alpha-smooth muscle actin (α-SMA), vascular endothelial growth factor (VEGF), and Phosphoinositide 3-kinase (PI3K), p-Akt and decreased expression of Phosphatase and tensin homolog (PTEN) and matrix metalloproteinase (MMP)-1 was detected, suggesting extracellular remodeling and fibroblast activation and proliferation. We validated the in vitro results by using a rodent skin excisional wound model and implanted ADSC sheets in the wound. Compared with the controls, wounds implanted with ADSC sheets had significantly higher rates of wound-closure; increased expression of α-SMA, VEGF, PI3k, PTEN, COL1A1, and COL3A1; decreased expression of PTEN and MMP1; and upregulated levels of miR-29b and miR-21 in the skin. CONCLUSION: In summary, we evidenced that ADSCs facilitate the increase in miR-29b and miR-21 levels and promote the activation and proliferation of dermal fibroblasts and extracellular matrix (ECM) remodeling, with the associated release of VEGF. Thus, the ADSC-mediated increase in microRNAs is essential in tissue repair and has a therapeutic potential in cutaneous wound healing.

High-Grade B-Cell Lymphoma (HGBL) with MYC and BCL2 and/or BCL6 Rearrangements Is Predominantly BCL6-Rearranged and BCL6-Expressing in Taiwan.

This study investigated the epidemiological and clinical peculiarities of BCL2 and BCL6 rearrangement in patients with high grade B-cell lymphoma (HGBL) from Taiwan, compared with data from Western countries. Two hundred and eighty-two DLBCL cases from Taipei Medical University-affiliated hospitals (n = 179) and Tri-Service General Hospital (n = 103) were enrolled for this study. From the 282, 47 (16.7%) had MYC translocation; 24 of these harbored concurrent BCL2 and/or BCL6 translocation (double-hit, DH or triple-hit, TH). Twelve DH-HGBL cases had simultaneous MYC and BCL6 translocations, 8 harbored MYC and BCL2 rearrangement, while the remaining 4 patients exhibited TH. Together, 66.7% of DH/TH-HGBL patients were BCL6 rearrangement positive. Among these BCL6-rearranged DH/TH-HGBL patients, only 6 (37.5%) overexpressed MYC and BCL6 proteins simultaneously, indicating that MYC-BCL6 co-overexpression may not be plausible surrogate biomarker for screening BCL6-rearranged DH-HGBL. By the end of year 5, all patients with TH-HGBL, BCL2 DH-HGBL and all but one BCL6 DH-HGBL cases had expired or were lost to follow-up. Progression-free survival (PFS) was longer for the non-DH/TH-HGBL group compared with the DH/TH-HGBL group. While the patients with BCL2 DH-HGBL were lost to follow-up by day 800, their remaining TH-HGBL and BCL6 DH-HGBL peers exhibited very poor PFS, regardless of age strata. More so, patients with BCL6 rearrangement were 5.5-fold more likely associated with extranodal involvement compared with their BCL2-rearranged peers. Moreover, ~60.0% of the BCL6-rearranged DH-HGBL cases were non-GCB, suggesting that including screening for BCL6 rearrangement in patients with the non-GCB phenotype may aid medical decision-making and therapeutic strategy. Contrary to contemporary data from western countries, 2 in every 3 patients with DH/TH-HGBL in Taiwan harbor BCL6 rearrangement. Consistent with present findings, we recommend mandatory screening for BCL6 rearrangement in patients with aggressive HGBL in Taiwan.