PBI-05204, a supercritical CO2 extract of Nerium oleander, suppresses glioblastoma stem cells by inhibiting GRP78 and inducing programmed necroptotic cell death.

Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression in both GSC types. Knocking down GRP78 expression through GRP78 siRNA transfection in GBM9 and GSC28 GSCs also resulted in reduced spheroid size and CD44 expression. Combining PBI-05204 with GRP78 siRNA further decreased spheroid numbers compared to GRP78 siRNA treatment alone. PBI-05204 treatment led to increased expression of pRIP1K and pRIP3K, along with enhanced binding of RIPK1/RIPK3 in GBM9 and GSC28 cells, resembling the effects observed in GRP78-silenced GSCs, suggesting that PBI-05204 induced necroptosis in these cells. Furthermore, oleandrin, a principle active cardiac glycoside component of PBI-05204, showed the ability to inhibit the self-renewal capacity in GSCs. These findings highlight the potential of PBI-05204 as a promising candidate for the development of novel therapies that target GBM stem cells.

Colorectal ALOX15 as a host factor determinant of EPA and DHA effects on colorectal carcinogenesis.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 polyunsaturated fatty acids (ω-3 PUFAs) derived from fish oil, are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. However, studies investigating the effects of EPA and DHA on colorectal carcinogenesis (CRC) have yielded conflicting results. The factors that determine these discrepant results remain unknown. Resolvins, oxidative metabolites of EPA and DHA, inhibit key pro-tumorigenic cytokine and chemokine signaling of colorectal cancer (e.g., IL-6, IL-1ß, and CCL2). 15-lipoxygenase-1 (ALOX15), a critical enzyme for resolvin generation is commonly lost during human CRC. Whether ALOX15 expression, as a host factor, modulates the effects of EPA and DHA on CRC remains unknown. Therefore, we evaluated the effects of ALOX15 transgenic expression in colonic epithelial cells on resolvin generation by EPA and DHA and CRC in mouse models representative of human CRC. Our results revealed that 1) EPA and DHA effects on CRC were diverse, ranging from suppressive to promotive, and these effects were occasionally altered by the formulations of EPA and DHA (free fatty acid, ethyl ester, triglyceride); 2) EPA and DHA uniformly suppressed CRC in the presence of intestinal ALOX15 transgenic expression, which induced the production of resolvins, decreased colonic CCL3-5 and CXCL-5 expression and tumor associated macrophages while increasing CD8 T cell abundance in tumor microenvironment; and 3) RvD5, the predominant resolvin produced by ALOX15, inhibited macrophage generation of pro-tumorigenic cytokines. These findings demonstrate the significance of intestinal ALOX15 expression as a host factor in determining the effects of EPA and DHA on CRC. Significance: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. Studies of EPA and DHA effects on colorectal carcinogenesis (CRC) have revealed inconsistencies; factors determining the direction of their impact on CRC have remained unidentified. Our data show that EPA and DHA effects on CRC were divergent and occasionally influenced by their formulations. More importantly, intestinal 15-lipoxgenase-1 (ALOX15) expression modulated EPA and DHA effects on CRC, leading to their consistent suppression of CRC. ALOX15 promoted EPA and DHA oxidative metabolism to generate resolvins, which inhibited key pro-tumorigenic inflammatory cytokines and chemokines, including IL-6. IL-1ß, and CCL2. ALOX15 is therefore an important host factor in determining EPA and DHA effects on CRC.

Creatine Kinase-MM/Proto-oncogene Tyrosine-Protein Kinase Receptor as a Sensitive Indicator for Duchenne Muscular Dystrophy Carriers.

Duchenne muscular dystrophy (DMD), a lethal X-linked recessive genetic disease, is characterized by progressive muscle wasting which will lead to premature death by cardiorespiratory complications in their late twenties. And 2.5-19% DMD carriers that also suffer from skeletal muscle damage or dilated cardiomyopathy when diagnosed as soon as possible is meaningful for prenatal diagnosis and advance warning for self-health. The current DMD carrier screening mainly relies on detecting serum creatine kinase activity, covering only 50-70% DMD carriers which will cause many false negatives and require the discovery of highly effective biomarker and simple detection procedure for DMD carriers. In this article, we have compiled a comprehensive summary of all documented biomarkers associated with DMD and categorized them based on their expression patterns. We specifically pinpointed novel DMD biomarkers, previously unreported in DMD carriers, and conducted further investigations to explore their potential. Compared to creatine kinase activity alone in DMD carriers, creatine kinase-MM can improve the specificity from 73 to 81%. And our investigation revealed another promising protein: proto-oncogene tyrosine-protein kinase receptor (RET). When combined with creatine kinase-MM (creatine kinase-MM/RET ratio), it significantly enhances the specificity (from 81 to 83%) and sensitivity (from 71.4 to 93%) of detecting DMD carriers in serum. Moreover, we successfully devised an efficient method for extracting RET from dried blood spots. This breakthrough allowed us to detect both creatine kinase-MM and RET using dried blood spots without compromising the detection rate.

Acupuncture for Chronic Radiation-Induced Xerostomia in Head and Neck Cancer: A Multicenter Randomized Clinical Trial.

Importance: Patients with head and neck cancer who undergo radiotherapy can develop chronic radiation-induced xerostomia. Prior acupuncture studies were single center and rated as having high risk of bias, making it difficult to know the benefits of acupuncture for treating radiation-induced xerostomia. Objective: To compare true acupuncture (TA), sham acupuncture (SA), and standard oral hygiene (SOH) for treating radiation-induced xerostomia. Design, Setting, and Participants: A randomized, blinded, 3-arm, placebo-controlled trial was conducted between July 29, 2013, and June 9, 2021. Data analysis was performed from March 9, 2022, through May 17, 2023. Patients reporting grade 2 or 3 radiation-induced xerostomia 12 months or more postradiotherapy for head and neck cancer were recruited from community-based cancer centers across the US that were part of the Wake Forest National Cancer Institute Community Oncology Research Program Research Base. Participants had received bilateral radiotherapy with no history of xerostomia. Interventions: Participants received SOH and were randomized to TA, SA, or SOH only. Participants in the TA and SA cohorts were treated 2 times per week for 4 weeks. Those experiencing a minor response received another 4 weeks of treatment. Main Outcomes and Measures: Patient-reported outcomes for xerostomia (Xerostomia Questionnaire, primary outcome) and quality of life (Functional Assessment of Cancer Therapy-General) were collected at baseline, 4 (primary time point), 8, 12, and 26 weeks. All analyses were intention to treat. Results: A total of 258 patients (201 men [77.9%]; mean [SD] age, 65.0 [9.16] years), participated from 33 sites across 13 states. Overall, 86 patients were assigned to each study arm. Mean (SD) years from diagnosis was 4.21 (3.74) years, 67.1% (n = 173) had stage IV disease. At week 4, Xerostomia Questionnaire scores revealed significant between-group differences, with lower Xerostomia Questionnaire scores with TA vs SOH (TA: 50.6; SOH: 57.3; difference, -6.67; 95% CI, -11.08 to -2.27; P = .003), and differences between TA and SA (TA: 50.6; SA: 55.0; difference, -4.41; 95% CI, -8.62 to -0.19; P = .04) yet did not reach statistical significance after adjustment for multiple comparisons. There was no significant difference between SA and SOH. Group differences in Functional Assessment of Cancer Therapy-General scores revealed statistically significant group differences at week 4, with higher scores with TA vs SOH (TA: 101.6; SOH: 97.7; difference, 3.91; 95% CI, 1.43-6.38; P = .002) and at week 12, with higher scores with TA vs SA (TA: 102.1; SA: 98.4; difference, 3.64; 95% CI, 1.10-6.18; P = .005) and TA vs SOH (TA: 102.1; SOH: 97.4; difference, 4.61; 95% CI, 1.99-7.23; P = .001). Conclusions and Relevance: The findings of this trial suggest that TA was more effective in treating chronic radiation-induced xerostomia 1 or more years after the end of radiotherapy than SA or SOH. Trial Registration: ClinicalTrials.gov Identifier: NCT02589938.

Newborn genetic screening for Fabry disease: Insights from a retrospective analysis in Nanjing, China.

Fabry disease (FD), an X-linked disorder resulting from dysfunction of α-galactosidase A, can result in significant complications. Early intervention yields better outcomes, but misdiagnosis or delayed diagnosis is common, impacting prognosis. Thus, early detection is crucial in the clinical diagnosis and treatment of FD. While newborn screening for FD has been implemented in certain regions, challenges persist in enzyme activity detection techniques, particularly for female and late-onset patients. Further exploration of improved screening strategies is warranted. This study retrospectively analyzed genetic screening results for pathogenic GLA variants in 17,171 newborns. The results indicated an estimated incidence of FD in the Nanjing region of China of approximately 1 in 1321. The most prevalent pathogenic variant among potential FD patients was c.640-801G > A (46.15 %). Furthermore, the residual enzyme activity of the pathogenic variant c.911G > C was marginally higher than that of other variants, and suggesting that genetic screening may be more effective in identifying potential female and late-onset patients compared to enzyme activity testing. This research offers initial insights into the effectiveness of GLA genetic screening and serves as a reference for early diagnosis, treatment, and genetic counseling in FD.

[Analysis of pathogenicity and genotype-phenotype correlation of the c.158G>A variant of phenylalanine hydroxylase gene].

OBJECTIVE: To explore the pathogenicity and genotype-phenotype correlation of the c.158G>A variant of phenylalanine hydroxylase (PAH) gene among patients with PAH deficiency. METHODS: Thirty seven children diagnosed with PAH deficiency at the Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University between July 2016 and June 2021 were selected as the study subjects. Clinical data and results of genetic testing were retrospectively analyzed. RESULTS: Among the 37 patients, mild hyperphenylalaninemia (HPA) was observed in 34 cases, two PAH variants (including c.158G>A), which formed a compound heterozygous mutation genotype, were detected in 33 patients, and the remainder one was found to harbor three PAH variants, including homozygous c.158G>A variants and a heterozygous c.842+2T>A variant. Classical phenylketonuria (PKU) was observed in 3 patients, and three PAH variants were detected in each of them, including two with c.[158G>A,842+2T>A]/c.728G>A and c.[158G>A,842+2T>A]/c.611A>G, respectively, and one with c.[158G>A, c.722G>A]/c.728G>A. The c.158G>A variant has a minimal influence on the PAH activity and is associated with a mild HPA phenotype. The variant should thereby be classified as likely benign. CONCLUSION: When the c.158G>A variant and other pathogenic variants are arranged in cis position, the ultimate phenotype will be determined by the pathogenicity of other variants.

Utility, benefits, and risks of newborn genetic screening carrier reports for families.

Background: Newborn genetic screening (NBGS) based on next-generation sequencing offers enhanced disease detection and better detection rates than traditional newborn screening. However, challenges remain, especially around reporting the NBGS carrier results. Therefore, we aimed to investigate the NBGS carrier parents' views on NBGS and NBGS reports in China. Methods: We distributed a survey querying demographic information, knowledge and perceptions of NBGS, the impact of NBGS on a total of 2930 parents, and their decision-making to parents of newborns reported as carriers in NBGS in Nanjing, China in 2022. Results: The average age of the survey respondents was 30.7 years (standard deviation = 3.6). Most (68.38%) felt informed about NBGS, especially women, the highly educated, and high earners. Nearly all (98.74%) saw NBGS as crucial for early disease detection, with 73.18% believing it positively impacts their future. However, 19.16% felt it might cause anxiety, especially among the less educated. Concerns included potential discrimination due to exposed genetic data and strained family ties. Many suggested NBGS coverage by medical insurance to ease financial burdens. Conclusions: Through our study, we gained insights into parents' perspectives and concerns regarding the NBGS carrier result reporting, thus providing relevant information for further refinement and clinical promotion of the NBGS project.

Evaluation of the Protective Effect of Compound Kushen Injection Against Radiation- induced Pneumonitis in Mice.

Background Radiation-induced lung injury (RILI) via inflammation is a common adverse effect of thoracic radiation that negatively impacts patient quality of life and survival. Compound kushen injection (CKI), a botanical drug treatment, was examined for its ability to reduce RILI, and inflammatory responses and improve survival in mice exposed total lung irradiation (TLI). CKI's specific mechanisms of action were also evaluated. Methods C3H mice underwent TLI and were treated with CKI (2, 4, or 8 mL/kg) intraperitoneally once a day for 8 weeks. The effects of CKI on survival were estimated by Kaplan-Meier survival analysis and compared by log-rank test. RILI damage was evaluated by histopathology and micro-computed tomography (CT). Inflammatory cytokines and cyclooxygenase metabolites were examined by IHC staining, western blot, and ELISA. Results Pre-irradiation treatment with 4 or 8 mL/kg CKI starting 2 weeks before TLI or concurrent treatment with 8 mL/kg CKI were associated with a significantly longer survival compared with TLI vehicle-treated group ( P < 0.05). Micro-CT images evaluations showed that concurrent treatment with 8 mL/kg CKI was associated with significantly lower incidence of RILI ( P < 0.05). Histological evaluations revealed that concurrent TLI treatment of CKI (4 and 8 mL/kg) significantly reduced lung inflammation (p < 0.05). Mechanistic investigation showed that at 72 hours after radiation, TLI plus vehicle mice had significantly elevated serum IL6, IL17A, and TGF-ß levels compared with non-irradiated, age-matched normal mice; in contrast, levels of these cytokines in mice that received TLI plus CKI treatment were lower than those in the TLI plus vehicle-treated mice ( P < 0.05) and similar to the nonirradiated mice. IHC staining showed that the CKI treatment led to a reduction of TGF-ß positive cells in the lung tissues of TLI mice (P < 0.01). The concurrent CKI with TLI treatment group had a significant reduction in COX-2 activity and COX-2 metabolites compared with the TLI vehicle-treated group ( P < 0.05). Conclusions These data suggest that CKI treatment was associated with reduced radiation-induced inflammation in lung tissues, reduced RILI, and improved survival. Further investigation of CKI in human clinical trials as a potential radioprotector against RILI to improve patients' quality of life and survival is warranted.

Using meta-analysis and CNN-NLP to review and classify the medical literature for normal tissue complication probability in head and neck cancer.

PURPOSE: The study aims to enhance the efficiency and accuracy of literature reviews on normal tissue complication probability (NTCP) in head and neck cancer patients using radiation therapy. It employs meta-analysis (MA) and natural language processing (NLP). MATERIAL AND METHODS: The study consists of two parts. First, it employs MA to assess NTCP models for xerostomia, dysphagia, and mucositis after radiation therapy, using Python 3.10.5 for statistical analysis. Second, it integrates NLP with convolutional neural networks (CNN) to optimize literature search, reducing 3256 articles to 12. CNN settings include a batch size of 50, 50-200 epoch range and a 0.001 learning rate. RESULTS: The study's CNN-NLP model achieved a notable accuracy of 0.94 after 200 epochs with Adamax optimization. MA showed an AUC of 0.67 for early-effect xerostomia and 0.74 for late-effect, indicating moderate to high predictive accuracy but with high variability across studies. Initial CNN accuracy of 66.70% improved to 94.87% post-tuning by optimizer and hyperparameters. CONCLUSION: The study successfully merges MA and NLP, confirming high predictive accuracy for specific model-feature combinations. It introduces a time-based metric, words per minute (WPM), for efficiency and highlights the utility of MA and NLP in clinical research.

Are Published Cancer Care Trial Protocols With Traditional Chinese Medicine Interventions Concordant With SPIRIT-TCM Extension 2018? A Scoping Review on Published Trial Protocols Between 2019 and 2022.

BACKGROUND: The SPIRIT-TCM Extension 2018 was created to guide the design and reporting of Traditional Chinese Medicine (TCM) clinical trial protocols. This study aims to investigate the extent of concordance with this guideline in the relevant field of cancer care research. METHODS: A scoping review of TCM cancer trial protocols published in English and Chinese since January 2019 was conducted. Five major academic databases (MEDLINE, EMBASE, CINAHL, CENTRAL, and China National Knowledge Infrastructure) were searched. Concordance with the SPIRIT-TCM Extension 2018 was assessed by descriptive analysis. RESULTS: Fifty-three TCM cancer care trial protocols were identified, comprising 23 acupuncture, 26 Chinese herbal medicine (CHM), and 4 Tai Chi/Qigong (TCQ) interventions. The majority of the checklist items had a low rate of concordance, especially in the reporting of quality control and safety, dosage, TCM diagnostic patterns, possible interactions between Western Medicine and TCM interventions, and TCM-related outcome assessments. CONCLUSIONS: Although the SPIRIT-TCM Extension 2018 guideline was established through extensive Delphi consultation, there are low rates of concordance between published TCM cancer care clinical trial protocols with the guideline. Further research is necessary to understand the low rate of concordance and how scientific rigors of reporting can be improved in TCM cancer care research.

Traditional Chinese medicines for non-small cell lung cancer: Therapies and mechanisms.

The most common subtype of lung cancer is non-small cell lung cancer (NSCLC), which has a poor prognosis and seriously threatens the health of human beings. The multidisciplinary comprehensive treatment model has gradually become the mainstream of NSCLC treatment. Traditional Chinese medicine (TCM) can be used effectively either as an adjunctive therapy or alone throughout the NSCLC therapy, which has a significant impact on survival, quality of life, and reduction of toxicity. Therefore, this paper reviewed the theoretical basis, the latest clinical application, and combined treatment mechanisms in order to explore the advantage stage of TCM treatment and the synergistic therapeutic mechanisms.

Newborn genetic screening is highly effective for high-risk infants: A single-centre study in China.

Background: Newborn genetic screening (NBGS) is promising for early detection of genetic diseases in newborns. However, little is known about its clinical effectiveness in special groups like high-risk infants. To address this gap, we aimed to investigate the impact of NBGS on high-risk infants. Methods: We screened 10 334 healthy newborns from the general maternity unit and 886 high-risk infants from the neonatal ward using both traditional newborn screening (tNBS) and NBGS, and collected clinical data from electronic medical records. Results: We found that high-risk infants had a higher proportion of eutocia (P < 0.01) and prematurity (P < 0.01). For high-risk infants vs healthy newborns screened by tNBS, the primary screening positive rate was 3.84% vs 1.31%, the false positive rate (FPR) was 3.62% vs 1.18% (P < 0.001), and the positive predictive value (PPV) was 5.88% vs 8.27%. For NBGS vs tNBS in high-risk infants, the primary screening positive rate was 0.54% vs 3.68%, the FPR was 0.22% vs 3.47%, and the PPV was 60.00% vs 5.88%. Conclusions: We found that combined newborn screening can effectively reduce the FPR caused by the high-risk symptoms and improve the PPV in high-risk infants, sufficient for more accurately showing the true status of the disease.

Association of sleep behavior with depression: a cross-sectional study in northwestern China.

Background: This study aimed to examine the association between sleep duration, sleep problems, and depression in Northwest China. Method: Depression was diagnosed at the hospital and self-reported by the participants in the baseline survey. Sleep duration and problems, including difficulty initiating and maintaining sleep, early morning awakening, daytime dysfunction, use of sleeping pills or drugs, and any sleep problems, were obtained by a self-reported questionnaire. Logistic regression was used to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CIs) for exploring the association between sleep duration, sleep problems, and depression, adjusting for demographic and socioeconomic characteristics and health behaviors. The association between depression and sleep duration was also evaluated continuously with restricted cubic spline curves based on logistic models. Results: 36,515 adults from Regional Ethnic Cohort Study in Northwest China were included. About 24.04% of participants reported short sleep duration (<7 h), and 15.64% reported long sleep duration (≥9 h). Compared with standard sleep duration (7-9 h), short sleep duration was associated with a higher risk of depression (OR: 1.69, 95%CI: 1.26-2.27, p = 0.001). Self-reported sleep problems were also related to four times depression risk increased (OR: 4.02, 95%CI: 3.03-5.35, p < 0.001) compared with no sleep problems. In addition, a nonlinear relationship was found between sleep duration and depression after adjusting covariates (p = 0.043). Conclusion: Sleep duration and sleep problems are associated with depression. Enough sleep time and healthy sleep habits in life course might be a practical health promotion approach to reduce depression risk in Northwest Chinese adults. A further study from cohort study is needed to verify the temporal association.

The Expanded Exercise Addiction Inventory (EAI-3): Towards Reliable and International Screening of Exercise-Related Dysfunction.

Exercise addiction (EA) refers to excessive exercise, lack of control, and health risks. The Exercise Addiction Inventory (EAI) is one of the most widely used tools in its assessment. However, the cross-cultural psychometric properties of the EAI could be improved because it misses three pathological patterns, including guilt, exercise despite injury, and experienced harm. Therefore, the present study tested the psychometric properties of the expanded EAI (EAI-3) in a large international sample. The EAI-3 was administered to 1931 physically active adult exercisers speaking five languages (Chinese, German, Italian, Japanese, and Turkish) and other measures for obsessive-compulsive behavior, eating disorders, and personality traits. The assessment structure and reliability of the EAI-3 were tested with factorial analyses and through measurement invariance across languages and sex. Finally, a cutoff point for dysfunction-proneness was calculated. The EAI-3 comprised two factors, reflecting the positive and pathological sides of exercise. The structure had excellent reliability and goodness-of-fit indices and configural and metric invariances of the scale were supported. However, three items caused violations in scalar invariance. The results of partial measurement invariance testing suggested an adequate fit for the data. Following sensitivity and specificity analysis, the EAI-3's cutoff score was 34 out of a maximum score of 48. This preliminary study suggests that the EAI-3 is a promising tool for screening EA in an international sample, with a robust and reliable structure comparable across languages and sex. In addition, the proposed cutoff could pave the way toward a consensus on a threshold to screen for EA.

NiCu alloys anchored Co3O4 nanowire arrays as efficient hydrogen evolution electrocatalysts in alkaline and neutral media.

Robust and long-lasting non-precious metal electrocatalysts are essential to achieve sustainable hydrogen production. In this work, we synthesized Co3O4@NiCu by electrodepositing NiCu nanoclusters onto Co3O4 nanowire arrays that were formed in situ on nickel foam. The introduction of NiCu nanoclusters altered the inherent electronic structure of Co3O4, significantly increasing the exposure of active sites and enhancing endogenous electrocatalytic activity. Co3O4@NiCu exhibited overpotentials of only 20 and 73 mV, respectively, at 10 mA cm-2 current densities in alkaline and neutral media. These values were equivalent to those of commercial Pt catalysts. Finally, the electron accumulation effect at the Co3O4@NiCu, along with a negative shift in the d-band center, is finally revealed by theoretical calculations. Hydrogen adsorption on consequent electron-rich Cu sites was effectively weakened, leading to a robust catalytic activity for the hydrogen evolution reaction (HER). Overall, this study proposes a practical strategy for creating efficient HER electrocatalysts in both alkaline and neutral media.

Activation of Vitamin D/VDR Signaling Reverses Gemcitabine Resistance of Pancreatic Cancer Cells Through Inhibition of MUC1 Expression.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to its therapeutic resistance. Inactivation of vitamin D/vitamin D receptor (VDR) signaling may contribute to the malignant phenotype of PDA and altered expression of oncoprotein mucin 1 (MUC1) may be involved in drug resistance of cancer cells. AIM: To determine whether vitamin D/VDR signaling regulates the expression and function of MUC1 and its effect on acquired gemcitabine resistance of pancreatic cancer cells. METHODS: Molecular analyses and animal models were used to determine the impact of vitamin D/VDR signaling on MUC1 expression and response to gemcitabine treatment. RESULTS: RPPA analysis indicated that MUC1 protein expression was significantly reduced in human PDA cells after treatment with vitamin D3 or its analog calcipotriol. VDR regulated MUC1 expression in both gain- and loss-of-function assays. Vitamin D3 or calcipotriol significantly induced VDR and inhibited MUC1 expression in acquired gemcitabine-resistant PDA cells and sensitized the resistant cells to gemcitabine treatment, while siRNA inhibition of MUC1 was associated with paricalcitol-associated sensitization of PDA cells to gemcitabine treatment in vitro. Administration of paricalcitol significantly enhanced the therapeutic efficacy of gemcitabine in xenograft and orthotopic mouse models and increased the intratumoral concentration of dFdCTP, the active metabolite of gemcitabine. CONCLUSION: These findings demonstrate a previously unidentified vitamin D/VDR-MUC1 signaling axis involved in the regulation of gemcitabine resistance in PDA and suggests that combinational therapies that include targeted activation of vitamin D/VDR signaling may improve the outcomes of patients with PDA.

The Association between Plant-Based Diet Indices and Metabolic Syndrome in Chinese Adults: Longitudinal Analyses from the China Health and Nutrition Survey.

OBJECTIVES: To investigate the association between a plant-based diet and metabolic syndrome (MetS) among Chinese adults. METHODS: Based on the data from the 2004-2015 China Health and Nutrition Survey and the corresponding edition of China Food Composition, we calculated the healthy plant-based diet indices (hPDI) and unhealthy plant-based diet indices (uPDI). The Cox proportional hazards regression model was used to estimate the hazard ratios (HRs) with 95% confidence intervals (CIs) for MetS. Mediation analysis was further conducted to explore the mediator role of Body Mass Index (BMI) in the association between hPDI and MetS. RESULTS: We included 10,013 participants, and over a median follow-up of 5 years, 961 patients (9.60%) developed MetS. Compared to those in the lowest quintile of hPDI score, we found that those in the highest quintile of hPDI score had a 28% lower ([HR]: 0.72, 95% CI 0.56-0.93, Ptrend = 0.021) risk of developing MetS and had a 20% lower (hazard ratio [HR]: 0.80, 95% CI 0.70-0.92, Ptrend = 0.004) risk of developing abdominal obesity. No significant associations were observed between uPDI and the MetS, but those in the highest quintile of uPDI score had a 36% higher (hazard ratio [HR]: 1.36, 95% CI 1.20-1.64, Ptrend < 0.001) risk of developing abdominal obesity, compared to those in the lowest quintile of uPDI score. In exploratory analysis, we observed that BMI at baseline mediated 27.8% of the association between hPDI and incident MetS, and BMI at baseline mediated 29.7% of the association between hPDI and abdominal obesity. CONCLUSION: The current findings reveal a possible causal relationship between a healthy plant-based diet and a reduced risk of MetS, especially abdominal obesity. It is observed that BMI may mediate the relationship between hPDI score and MetS. Controlling early dietary patterns and BMI may help reduce the risk of MetS.

Medicinal Mushroom Supplements in Cancer: A Systematic Review of Clinical Studies.

PURPOSE OF REVIEW: Patients seek clinical guidance on mushroom supplements that can be given alongside conventional treatments, but most research on such fungi has been preclinical. The current systematic review focused on clinical studies of mushrooms in cancer care conducted in the past 10 years. We searched Medline (Ovid), Embase (Ovid), Scopus (Wiley), and Cochrane Library to identify all mushroom studies conducted in humans published from January 2010 through December 2020. Two authors independently assessed papers for inclusion. RECENT FINDINGS: Of 136 clinical studies identified by screening 2349, 39 met inclusion criteria. The studies included 12 different mushroom preparations. A survival benefit was reported using Huaier granules (Trametes robiniophila Murr) in 2 hepatocellular carcinoma studies and 1 breast cancer study. A survival benefit was also found in 4 gastric cancer studies using polysaccharide-K (polysaccharide-Kureha; PSK) in the adjuvant setting. Eleven studies reported a positive immunological response. Quality-of-life (QoL) improvement and/or reduced symptom burden was reported in 14 studies using various mushroom supplements. Most studies reported adverse effects of grade 2 or lower, mainly nausea, vomiting, diarrhea, and muscle pain. Limitations included small sample size and not using randomized controlled trial design. Many of the reviewed studies were small and observational. Most showed favorable effects of mushroom supplements in reducing the toxicity of chemotherapy, improving QoL, favorable cytokine response, and possibly better clinical outcomes. Nevertheless, the evidence is inconclusive to recommend the routine use of mushrooms for cancer patients. More trials are needed to explore mushroom use during and after cancer treatment.

Targeting Glutamine Metabolism with a Novel Na+/K+-ATPase Inhibitor RX108 in Hepatocellular Carcinoma.

The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify novel therapeutic modalities. Here, we describe the antitumor activity and underlying molecular mechanisms of a novel Na+/K+-ATPase inhibitor RX108 in human HCC cells and its xenograft model. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in a xenograft mouse model, and that the inhibition was associated with induction of apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentration in HCC cells and tumors. In addition, RX108 exposure led to a significant decrease in cell energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate. Furthermore, HCC cells exhibited evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCCs was associated with unfavorable survival. Taken together, these findings reveal a novel approach to target glutamine metabolism through inhibiting Na+/K+-ATPase and provide a rationale for using RX108 to treat HCC in patients whose tumors express ASCT2 at high levels. RX108 is currently under clinical development.

Psychometric evaluation of the inventory of dimensions of emerging adulthood (IDEA) in China

Background/Objective: Emerging adulthood (EA, age range between 18 to 29 years) is an important developmental stage that is characterized by marked social and psychological changes. Currently, its developmental features are quantified by the Inventory of the Dimensions of Emerging Adulthood (IDEA) but a validated Chinese version of this questionnaire (IDEA-C) is lacking. Thus, this research, which consists of two consecutive studies, aimed to investigate the psychometric properties of the translated IDEA in a Chinese sample of emerging adults. Method: Firstly, a forward-backward translation of the IDEA-C scale was conducted. Item analysis and exploratory factor analysis were performed in Sample 1a (n = 2438), followed by structural validity test in Sample 1b (n = 2461). Concurrent validity and internal consistency were evaluated in Sample 1(n = 4899). Finally, test-retest reliability was tested in Sample 2 (n = 185). Then, the second study aimed to test the factor structure proposed by study 1 in the non-student sample (n = 2200) by confirmatory factor analysis. In addition, the second study also investigated whether the attainment of college education influenced the EA experience of non-student emerging adults in China. And the association was examined between the socioeconomic status of emerging adults and the subscales of IDEA. Results: In the college sample, the IDEA-C scale presented a four-factor structure different from the original five-factor structure (χ2(190)=1116.84, p < 0.001; CFI = 0.97; TLI = 0.96; SRMR = 0.039; RMSEA = 0.050 [90%CI=0.047-0.052]). In addition, IDEA-C exhibited good internal consistency reliability (Cronbach's alpha >0.77), test-retest reliability (r>0.49, p < 0.01) and concurrent validity. (AU)