Risk factors for inpatient malnutrition and length of stay assessed by 'NutritionDay' in China.

BACKGROUND AND OBJECTIVES: NutritionDay is a yearly global point-prevalence study of malnutrition or nutritional risk in hospitals. We aimed to provide a comprehensive nutritional survey of hospitalized patients and analyze the risk factors of malnutrition and prolonged hospitalization in Chinese inpatients. METHODS AND STUDY DESIGN: The international daylong cross-sectional survey was performed on November 07th, 2019. Ten hospitals were invited to participate in this NutritionDay survey. Nutritional risk was identified by nutritional risk screening 2002, and malnutrition was identified by the ESPEN criteria. We measured the incidence of malnutrition and nutritional risk. And we analysed risk factors for malnutrition and length of stay in Chinese hospitalized patients. RESULTS: 875 hospitalized patients from 6 departments were included in the analysis. The malnutrition rate was 11.6% and the incidence of nutritional risk was 17.8%. It was analyzed that tumor load, end-stage disease, motility, self-rated health, types of oral medicine, and food intake during the past week were independent risk factors for malnutrition or nutritional risk. 56.2% (118/210) of patients at nutritional risk or malnutrition received extra nutritional support, whereas 22.5% (88/391) well-nourished patients did. Moreover, nutrition status, ever stayed in ICU and self-rated health were associated with prolonged length of stay. CONCLUSIONS: In a word, the prevalence of malnutrition or nutritional risk was about 29.4%. Patients with malnutrition or nutritional risk had a higher transfer rate, lower rehabilitation rate and longer hospital stays. The attention to malnutrition patients needs to be further strengthened.

Microvesicles and chemokines in tumor microenvironment: mediators of intercellular communications in tumor progression.

Increasing evidence indicates that the ability of cancer cells to convey biological information to recipient cells within the tumor microenvironment (TME) is crucial for tumor progression. Microvesicles (MVs) are heterogenous vesicles formed by budding of the cellular membrane, which are secreted in larger amounts by cancer cells than normal cells. Recently, several reports have also disclosed that MVs function as important mediators of intercellular communication between cancerous and stromal cells within the TME, orchestrating complex pathophysiological processes. Chemokines are a family of small inflammatory cytokines that are able to induce chemotaxis in responsive cells. MVs which selective incorporate chemokines as their molecular cargos may play important regulatory roles in oncogenic processes including tumor proliferation, apoptosis, angiogenesis, metastasis, chemoresistance and immunomodulation, et al. Therefore, it is important to explore the association of MVs and chemokines in TME, identify the potential prognostic marker of tumor, and develop more effective treatment strategies. Here we review the relevant literature regarding the role of MVs and chemokines in TME.

Profiles and Bioinformatics Analysis of Differentially Expressed Circrnas in Taxol-Resistant Non-Small Cell Lung Cancer Cells.

BACKGROUND/AIMS: Circular RNAs (circRNAs) act as microRNA (miRNA) sponges that regulate gene expression and are involved in physiological and pathological processes. In this study, we evaluated the roles of circRNAs in the chemoresistance of non-small cell lung cancer (NSCLC) to taxol. METHODS: High-throughput circRNA microarrays were employed to investigate the circRNA profiles of parental A549 and taxol-resistant A549/Taxol cells. We predicted the miRNA targets of differentially expressed circRNAs via miRNA prediction software and then constructed a circRNA/miRNA network using Cytoscape. Bioinformatics analyses were performed to annotate dysregulated circRNAs in detail. RESULTS: We detected 2909 significantly upregulated and 8372 downregulated circRNAs in A549/Taxol cells compared with A549 cells. The circRNA/miRNA network displayed their interactions, suggesting that circRNAs exert biological effects by absorbing and sequestering miRNA molecules. Computational Gene Ontology and pathway analyses were used to determine the biological function and signaling pathways of host genes of dysregulated circRNAs and to identify potential molecular mechanisms prompting the resistance of NSCLC to taxol. CONCLUSION: This study focusing on circRNAs related to taxol resistance provides a basis for clarifying the development and progression of drug resistance and for identifying therapeutic targets in NSCLC.

TNF-α sensitizes chemotherapy and radiotherapy against breast cancer cells.

PURPOSE: Despite new developments in cancer therapy, chemotherapy and radiotherapy remain the cornerstone of breast cancer treatment. Therefore, finding ways to reduce the toxicity and increase sensitivity is particularly important. Tumor necrosis factor alpha (TNF-α) exerts multiple functions in cell proliferation, differentiation and apoptosis. In the present study, we investigated whether TNF-α could enhance the effect of chemotherapy and radiotherapy against breast cancer cells. METHODS: Cell growth was determined by MTT assay in vitro, and by using nude mouse tumor xenograft model in vivo. Cell cycle and apoptosis/necrosis were evaluated by flow cytometry. DNA damage was visualized by phospho-Histone H2A.X staining. mRNA expression was assessed by using real-time PCR. Protein expression was tested by Western blot assay. RESULTS: TNF-α strengthened the cytotoxicity of docetaxel, 5-FU and cisplatin against breast cancer cells both in vitro and in vivo. TNF-α activated NF-κB pathway and dependently up-regulated expressions of CyclinD1, CyclinD2, CyclinE, CDK2, CDK4 and CDK6, the key regulators participating in G1→S phase transition. As a result, TNF-α drove cells out of quiescent G0/G1 phase, entering vulnerable proliferating phases. Treatment of TNF-α brought more DNA damage after Cs137-irradiation and strengthened G2/M and S phase cell cycle arrest induced by docetaxel and cisplatin respectively. Moreover, the up-regulation of RIP3 (a necroptosis marker) by 5-FU, and the activation of RIP3 by TNF-α, synergistically triggered necroptosis (programmed necrosis). Knockdown of RIP3 attenuated the synergetic effect of TNF-α and 5-FU. CONCLUSION: TNF-α presented radiotherapy- and chemotherapy-sensitizing effects against breast cancer cells.

Downregulation of DAB2IP results in cell proliferation and invasion and contributes to unfavorable outcomes in bladder cancer.

The DOC-2/DAB2 interactive protein (DAB2IP) is a member of the Ras GTPase-activating protein family. It has been shown to be often downregulated and a poor prognostic factor in several human malignancies. In this study, we analyzed the clinicopathological features and outcomes of DAB2IP expression in 135 patients with urothelial carcinoma of the bladder (UCB) treated by radical cystectomy plus bilateral lymph node dissection, and evaluated the effect of DAB2IP knockdown in vitro using the MTT method, colony formation assay, cell cycle assay, and cell migration and invasive assay. We found low expression of DAB2IP was significantly associated with high pathological stage (P = 0.002), high pathological grade (P = 0.02), tumor size more than 3 cm (P = 0.04), and presence of histological variants (P = 0.01). DAB2IP was an independent prognostic factor of disease recurrence (hazard ratio, 2.67; P = 0.034) and cancer-specific survival (hazard ratio, 2.79; P = 0.038). Knockdown of DAB2IP could promote cell proliferation, migration, and invasion. Downregulation of DAB2IP could activate the ERK and Akt pathways and was correlated with the expression of epithelial-mesenchymal transition markers, such as E-cadherin and vimentin. In conclusion, downregulation of DAB2IP is associated with features of biologically aggressive UCB and results in cell proliferation, migration, and invasion of bladder cancer. DAB2IP may serve as a promising biomarker in patients with UCB treated by radical cystectomy and bilateral lymph node dissection.

Down-regulation of Dicer and Ago2 is associated with cell proliferation and apoptosis in prostate cancer.

Dicer and Argonaute2 (Ago2) are critical components responsible not only for RNA interference but also for microRNA synthesis. The present study investigated the roles of Dicer and Ago2 in prostate cancer (Pca). First, the expression levels of Dicer and Ago2 in Pca tissues were determined by immunohistochemistry (IHC) and compared with pathological features. Next, RNA interference was used to down-regulate the expression levels of Dicer and Ago2 in the Pca cell lines LNCaP, PC-3, and DU145, and effects on proliferation, apoptosis, and cell cycle were detected using the CCK-8 assay and flow cytometry, respectively. We found that Dicer and Ago2 expression levels in Pca tissues were higher than those in adjacent benign tissues and correlated with lower Gleason patterns, with the exception of Dicer expression in localized Pca. In vitro, silencing Dicer or Ago2 inhibited cell proliferation and induced apoptosis in LNCaP, PC-3, and DU145, as well as arrested the cell cycle at the G2/M phase in androgen-dependent LNCaP, or at S phase in the androgen-independent PC-3 and DU145. Altogether these findings suggest that Dicer and Ago2 play important roles in proliferation, apoptosis, and the cell cycle in Pca and might serve as both promising biomarkers for Pca progression and potential therapeutic targets.

Network meta-analysis of combination strategies in metastatic hormone-sensitive prostate cancer.

This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5-59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e ., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8-31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.

Nutritional support therapy for liver transplantation in an adult-onset type II citrullinemia patient: a case report.

Liver transplantation is an effective measure to treat adult-onset type II citrullinemia (CTLN2). Active and effective perioperative nutrition support is a very important treatment for the prognosis of such patients. In this paper, we analyzed the process, results, and outcome of nutritional support therapy in a case of CTLN2, and concluded that the perioperative nutritional support program for CTLN2 patients should be followed prior to surgery:1.because of the prevalence of severe malnutrition in CTLN2 patients, Enteral nutrition (EN) combined with Parenteral nutrition (PN) should be the first choice for nutritional support; 2. daily energy intake should be 35 ~ 40 kcal/kg; 3. the nutritional formula should be composed of low-carbohydrates and high medium-chain triglyceride (MCT). Postoperative: initiating EN as soon as possible is recommended to restore intestinal function and adjuvant PN might be taken into consideration in the early stage. The purpose of this case was to provide experience for the development and adjustment of the perioperative nutritional support regimen for CTLN2 patients.

Integration Analysis of Single-Cell Multi-Omics Reveals Prostate Cancer Heterogeneity.

Prostate cancer (PCa) is an extensive heterogeneous disease with a complex cellular ecosystem in the tumor microenvironment (TME). However, the manner in which heterogeneity is shaped by tumors and stromal cells, or vice versa, remains poorly understood. In this study, single-cell RNA sequencing, spatial transcriptomics, and bulk ATAC-sequence are integrated from a series of patients with PCa and healthy controls. A stemness subset of club cells marked with SOX9highARlow expression is identified, which is markedly enriched after neoadjuvant androgen-deprivation therapy (ADT). Furthermore, a subset of CD8+CXCR6+ T cells that function as effector T cells is markedly reduced in patients with malignant PCa. For spatial transcriptome analysis, machine learning and computational intelligence are comprehensively utilized to identify the cellular diversity of prostate cancer cells and cell-cell communication in situ. Macrophage and neutrophil state transitions along the trajectory of cancer progression are also examined. Finally, the immunosuppressive microenvironment in advanced PCa is found to be associated with the infiltration of regulatory T cells (Tregs), potentially induced by an FAP+ fibroblast subset. In summary, the cellular heterogeneity is delineated in the stage-specific PCa microenvironment at single-cell resolution, uncovering their reciprocal crosstalk with disease progression, which can be helpful in promoting PCa diagnosis and therapy.

Correlation of PSA and survival in metastatic hormone-sensitive prostate cancer treated with rezvilutamide plus ADT in the CHART trial.

BACKGROUND: This exploratory analysis of the CHART trial (ClinicalTrials.gov: NCT03520478) investigated prostate-specific antigen (PSA) kinetics and the correlation between PSA and survival outcomes in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC). METHODS: A total of 654 patients were randomized 1:1 to receive either rezvilutamide plus androgen deprivation therapy (ADT; n = 326) or bicalutamide plus ADT (n = 328). PSA kinetics were evaluated, and the correlation between survival and the achievement of undetectable PSA (≤0.2 ng/mL) or ≥90% PSA reduction (PSA90) was assessed. FINDINGS: The rezvilutamide group exhibited higher proportions of ≥50% PSA reduction (PSA50; 98.2% vs. 87.5%), PSA90 (88.7% vs. 63.1%), and undetectable PSA (38.3% vs. 17.7%) responses compared to the bicalutamide group by 3 months. The rezvilutamide group demonstrated superior efficacy in delaying PSA progression compared to the bicalutamide group (hazard ratio [HR] 0.21, 95% confidence interval 0.16-0.27). The achievement of undetectable PSA and PSA90 by 6 months in the rezvilutamide group was associated with prolonged overall survival (undetectable PSA, HR = 0.34; PSA90, HR = 0.22), radiographic progression-free survival (HR = 0.36, HR = 0.26), time to PSA progression (HR = 0.25, HR = 0.17), and time to castration resistance (HR = 0.34, HR = 0.23) compared to those who did not achieve these PSA milestones. Stratification by baseline PSA level revealed consistent survival improvements with rezvilutamide plus ADT across quartiles. CONCLUSIONS: PSA kinetics is a valuable prognostic factor in mHSPC treated with rezvilutamide plus ADT, and the achievement of undetectable PSA and PSA90 is associated with improved survival. These findings highlight the importance of monitoring PSA kinetics in the management of mHSPC. FUNDING: This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Community pandemic prevention and control measures and their influence on citizen satisfaction during the COVID-19 pandemic in China.

At the forefront of the fight against the pandemic, the community' s measures and services would have a greater impact than ever before on citizen satisfaction. However, the influence of citizen satisfaction on community pandemic prevention and control measures (CPPCM) during the pandemic is poorly understood. This study aims to investigate the allocation of CPPCM and its impact on CS. The Chinese national data was analyzed for the outcome. (1) Pandemic prevention propaganda (PPP), disinfection (DT), and body temperature tests (BTTs) were the primary measures taken by the Chinese community. (2) The CS for pandemic prevention and control is high, and urban and central Chinese communities express greater satisfaction. (3) The impact of disinfection, body temperature tests, free supplies, and assistance purchasing supplies on CS was greater in rural areas than in urban areas. (4) Regional variations exist in the impact of CS on CPPCM. (5) The number of measures has an inverted U-shaped relationship with citizen satisfaction. This study also suggests that the government should disseminate information about pandemic prevention in a timely manner, provide basic health and medical services, and evaluate the measures taken to avoid the discount effect.

Relationships of body composition and adipocytokines with outcomes in metastatic castration-resistant prostate cancer patients receiving docetaxel chemotherapy.

We evaluated the relationships of body composition and serum adipocytokine levels with progression-free survival (PFS) and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel. The medical records of mCRPC patients who received docetaxel between January 2011 and December 2015 at Fudan University Shanghai Cancer Center (Shanghai, China) were reviewed. The following body composition parameters were calculated using computed tomography: skeletal muscle index (SMI), visceral adipose tissue index (VATI), and subcutaneous adipose tissue index (SATI). Pretreatment serum adipocytokine levels, including interleukin 6, insulin, leptin, monocyte chemoattractant protein-1, adiponectin, and resistin, were measured using the multiplex bead-based immunoassays. Cox regression and Kaplan-Meier methods were used for survival analyses. Of the 453 mCRPC patients initially identified, 105 were included in the analysis. High VATI group patients had longer PFS (median, 10 months vs 7 months, P = 0.008) and OS (median, 24 months vs 15 months, P = 0.017), compared with low VATI group patients. SMI and SATI were not significantly associated with PFS or OS. Of the six detected adipocytokines, only leptin was associated with mCRPC prognosis. High leptin group patients had shorter PFS (median, 7 months vs 12 months, P = 0.0018) and OS (median, 17 months vs 22 months, P = 0.042), compared with low leptin group patients. Multivariate analysis showed that a high VATI was an independent protective factor for PFS and OS, while a high leptin level was an independent risk factor for PFS and OS. Therefore, VATI and serum leptin levels could provide important information concerning mCRPC prognosis.

[Docetaxel plus prednisone versus mitoxantrone plus prednisone as first-line chemotherapy for metastatic hormone-refractory prostate cancer: long-term effects and safety].

OBJECTIVE: To compare docetaxel plus prednisone with mitoxantrone plus prednisone as first-line chemotherapy for metastatic hormone-refractory prostate cancer (mHRPC). METHODS: From January 2007 through August 2010, 62 patients with mHRPC received 5 mg of prednisone twice daily were randomly assigned to receive mitoxantrone 12 mg/m² every three weeks (group A) or 75 mg/m² every three weeks (group B). The cycles of each regimen were less than 10 times. The primary end point was overall survival. The secondary end points were the prostate-specific antigen (PSA) response rate, the duration of PSA response and the objective tumor response rate (ORR). All the t test, χ² test and Fisher's exact test were performed between 2 groups. RESULTS: Thirty-one patients enrolled in group A received a median 4 cycles of regimen (range 1 - 10), whereas 30 patients enrolled in group B received a median of 7 cycles of regimen (range 2 - 10). There were 45.2% patients in group A and 70.0% in group B had PSA response (χ² = 3.85, P < 0.05). The duration time of PSA response was 121 days (range 20-323 days) in group A and 168 days (range 42 - 447 days) in group B, respectively. The ORR was 15.0(3/20) in group A and 10.3% (3/29) in group B, respectively. The median survival was 511 days (95%CI: 357 - 665 days) in group A and 833 days (95%CI: 634 - 1032 days) in group B, respectively (χ² = 4.20, P = 0.040). The incidence of thrombocytopenia in group A was higher than group B (χ² = 5.60, P = 0.018); the incidences of nausea and vomiting (χ² = 4.32, P = 0.038), diarrhea (P = 0.024), fatigue (χ² = 5.90, P = 0.015), and alopecia (χ² = 5.42, P = 0.020) in group B were higher than group A. CONCLUSION: Docetaxel plus prednisone can lead to superior overall survival and PSA response rate in patients with mHRPC.

Targeting HIC1/TGF-ß axis-shaped prostate cancer microenvironment restrains its progression.

Prostate cancer (PCa) is a malignant tumor that seriously threatens men's health worldwide. Recently, stromal cells in the tumor microenvironment (TME) have been reported to contribute to the progression of PCa. However, the role and mechanism of how PCa cells interact with stromal cells to reshape the TME remain largely unknown. Here, using a spontaneous prostate adenocarcinoma (PRAD) model driven by the loss of Pten and Hic1, we found that M2 macrophages markedly infiltrated the stroma of Pten and Hic1 double conditional knockout (dCKO) mice compared with those in control (Ctrl) mice due to higher TGF-ß levels secreted by HIC1-deleted PCa cells. Mechanistically, TGF-ß in TME promoted the polarization of macrophages into "M2" status by activating the STAT3 pathway and modulating c-Myc to upregulate CXCR4 expression. Meanwhile, TGF-ß activated the fibroblasts to form cancer-associated fibroblasts (CAFs) that secrete higher CXCL12 levels, which bound to its cognate receptor CXCR4 on M2 macrophages. Upon interaction with CAFs, M2 macrophages secreted more CXCL5, which promoted the epithelial-mesenchymal transition (EMT) of PCa via CXCR2. Moreover, using the TGF-ß receptor I antagonist, galunisertib, significantly inhibited the tumor growth and progression of the TRAMP-C1 cell line-derived subcutaneous tumor model. Finally, we confirmed that the stromal microenvironment was shaped by TGF-ß in HIC1-deficient PCa and was associated with the progression of PCa.

Camrelizumab plus famitinib for advanced or metastatic urothelial carcinoma after platinum-based therapy: data from a multicohort phase 2 study.

BACKGROUND: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. Camrelizumab is a monoclonal antibody against PD-1, and famitinib is a multitargeted receptor tyrosine kinase inhibitor with antiangiogenesis and antiproliferation activities against tumor cells. We conducted an open-label, multicenter phase 2 basket study of camrelizumab and famitinib in eight cohorts of genitourinary or gynecological cancers. Here, findings in cohort of advanced or metastatic urothelial carcinoma with platinum-progressive disease (cohort 2) are presented. METHODS: Patients who had progressed after platinum-based chemotherapy for advanced or metastatic disease or had progressed within 12 months after completion of platinum-based (neo)adjuvant therapy were given camrelizumab (200 mg intravenously every 3 weeks) plus famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Totally, 36 patients were recruited. With a median duration from enrollment to data cut-off of 11.9 months (range 6.1-28.5), ORR was 30.6% (95% CI 16.3% to 48.1%). Median duration of response (DoR) was 6.3 months (95% CI 2.1 to not reached). Median progression-free survival (PFS) was 4.1 months (95% CI 2.2 to 8.2), and median overall survival (OS) was 12.9 months (95% CI 8.8 to not reached). Patients with bladder cancer (n=18) had numerically better outcomes, with an ORR of 38.9% (95% CI 17.3% to 64.3%) and a median PFS of 8.3 months (95% CI 4.1 to not reached). Median DoR and OS in this subpopulation had not been reached with lower limit of 95% CI of 4.2 months for DoR and 11.3 months for OS, respectively. Of 36 patients, 22 (61.1%) had grade 3 or 4 treatment-related adverse events, mainly decreased platelet count and hypertension. CONCLUSIONS: Camrelizumab plus famitinib showed potent antitumor activity in advanced or metastatic urothelial carcinoma patients after platinum-based chemotherapy. Patients with bladder cancer seemed to have better response to this combination. TRIAL REGISTRATION NUMBER: NCT03827837.

Comprehensive analysis of alternative splicing profiling reveals novel events associated with prognosis and the infiltration of immune cells in prostate cancer.

BACKGROUND: Alternative splicing (AS) is believed to play a vital role in tumor development. Therefore, comprehensive investigation of AS and its biological function in prostate cancer (PCa) is crucial. METHODS: The AS profiling of 489 patients with PCa was obtained from The Cancer Genome Atlas (TCGA) SpliceSeq database. Bioinformatics tools were used to describe splicing associations and build prognostic models. Unsupervised clustering of the determined prognostic AS events and the relationship with immune characteristics were also explored. RESULTS: In total, 20,723 AS events were detected and 2,805 were identified in PCa. In the regulatory networks, the data suggested a significant correlation between splicing factor (SF) expression and AS events. To stratify the progression risk of PCa patients, prognostic models were constructed using splicing patterns. Six AS events were screened out as independent prognostic factors for progression-free survival. Based on the gene features, we constructed the combined prognostic predictors model, and the receiver operating characteristic (ROC) curve for this model reached a high area under the ROC curve (AUC) of 0.729793, indicating a favorable ability to predict patient outcomes. Through unsupervised clustering analysis, the correlations between AS-based clusters and prognosis as well as immune characteristics were revealed. The correlation analysis on TIMER revealed the relationship between gene expression and immune cell infiltration. CONCLUSIONS: This in-depth genome-wide analysis of the AS profiling in PCa revealed unique AS events associated with cancer progression and the infiltration of immune cells, with potential for predicting outcomes and therapeutic responses.

Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression.

Prostate cancer shows remarkable clinical heterogeneity, which manifests in spatial and clonal genomic diversity. By contrast, the transcriptomic heterogeneity of prostate tumours is poorly understood. Here we have profiled the transcriptomes of 36,424 single cells from 13 prostate tumours and identified the epithelial cells underlying disease aggressiveness. The tumour microenvironment (TME) showed activation of multiple progression-associated transcriptomic programs. Notably, we observed promiscuous KLK3 expression and validated the ability of cancer cells in altering T-cell transcriptomes. Profiling of a primary tumour and two matched lymph nodes provided evidence that KLK3 ectopic expression is associated with micrometastases. Close cell-cell communication exists among cells. We identified an endothelial subset harbouring active communication (activated endothelial cells, aECs) with tumour cells. Together with sequencing of an additional 11 samples, we showed that aECs are enriched in castration-resistant prostate cancer and promote cancer cell invasion. Finally, we created a user-friendly web interface for users to explore the sequenced data.

Comparison of visceral fat area measured by CT and bioelectrical impedance analysis in Chinese patients with gastric cancer: a cross-sectional study.

OBJECTIVES: Bioelectrical impedance analysis (BIA) is a simple and inexpensive method to estimate body composition. However, the accuracy of BIA is unknown. We aimed to assess the accuracy of BIA in estimating visceral fat area (VFA) in patients with gastric cancer. STUDY DESIGN: This was a cross-sectional study comparing the accuracy of BIA in estimating VFA with the gold standard method measured by CT. VFA was measured in enrolled patients both by CT and BIA. VFA by CT at umbilical level ≥100 cm2 was considered as visceral obesity. Reliability between the two methods was assessed by intraclass correlation coefficient (ICC) and consistency was assessed by Bland-Altman method (95% limits of agreement). The area under the receiver operating characteristic curve (AUROC) was used to assess the performance of BIA in diagnosing visceral obesity. SETTING: The study was conducted in China. PARTICIPANTS: From 1 January 2017 to 1 December 2018, a total of 157 patients diagnosed with gastric cancer were enrolled. RESULTS: Overall, VFA by CT and BIA in patients was 84.39±46.43 cm2 and 71.94±22.44 cm2, respectively. VFA estimated by BIA was positively correlated with VFA measured by CT using Pearson's test (r=0.650, p<0.001). Overall, ICC for the two methods was 0.675. The mean bias between the two measurements was 12.45±36.13 cm2. The 95% limits of agreement ranged from -58.36 cm2 to 83.26 cm2. The cut-off value for diagnosing visceral obesity by BIA was 81 cm2 (AUROC: 0.822, p<0.001, 95% CI 0.758 to 0.887). CONCLUSIONS: VFA measured by BIA showed satisfactory reliability with that measured by CT. However, the absolute values of the two methods were not interchangeable. The cut-off value for VFA by BIA in diagnosing visceral obesity was 81 cm2 for patients with gastric cancer in the Chinese population.

LINC00675 activates androgen receptor axis signaling pathway to promote castration-resistant prostate cancer progression.

The development of prostate cancer (PCa) from androgen-deprivation therapy (ADT) sensitive to castration resistant (CRPC) seriously impacts life quality and survival of PCa patients. Emerging evidence shows that long noncoding RNAs (lncRNAs) play vital roles in cancer initiation and progression. However, the inherited mechanisms of how lncRNAs participate in PCa progression and treatment resistance remain unclear. Here, we found that a long noncoding RNA LINC00675 was upregulated in androgen-insensitive PCa cell lines and CRPC patients, which promoted PCa progression both in vitro and in vivo. Knockdown of LINC00675 markedly suppressed tumor formation and attenuated enzalutamide resistance of PCa cells. Mechanistically, LINC00675 could directly modulate androgen receptor's (AR) interaction with mouse double minute-2 (MDM2) and block AR's ubiquitination by binding to it. Meanwhile, LINC00675 could bind to GATA2 mRNA and stabilize its expression level, in which GATA2 could act as a co-activator in the AR signaling pathway. Notably, we treated subcutaneous xenografts models with enzalutamide and antisense oligonucleotides (ASO) targeting LINC00675 in vivo and found that targeting LINC00675 would benefit androgen-deprivation-insensitive models. Our findings disclose that the LINC00675/MDM2/GATA2/AR signaling axis is a potential therapeutic target for CRPC patients.

Determination of tegaserod by LC-ESI-MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers.

A simple, rapid and sensitive high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) assay for determination of tegaserod in human plasma using diazepam as internal standard (IS) was established. After adjustment to a basic pH with sodium hydroxide, plasma was extracted by ethyl acetate and separated by high performance liquid chromatography (HPLC) on a reversed-phase C18 column with a mobile phase of methanol: 5 mM ammonium acetate (75:25, v/v, adjusting the pH to 3.5 with glacial acetic acid). The quantification of target compounds was obtained by using multiple reaction monitoring (MRM) transitions; m/z 302.5, 173.2 and 285.4, 193.2 were measured in positive mode for tegaserod and internal standard (diazepam), respectively. The lower limit of quantification (LLOQ) was 0.05 ng/ml. The calibration curves were linear over the range 0.05-8.0 ng/ml (r=0.9996) for tegaserod. The mean absolute recovery of tegaserod was more than 85.56%. Intra- and inter-day variability values were less than 9.21% and 10.02%, respectively. The samples were stable for 8h under room temperature (25 degrees C, three freeze-thaw cycles in 30 days and for 30 days under -70 degrees C). After administration of a single dose of tegaserod maleate 4 mg, 6 mg and 12 mg, respectively, the area under the plasma concentration versus time curve from time 0 h to 12 h (AUC0-12) were (2.89+/-0.88), (5.32+/-1.21) and (9.38+/-3.42) ng h/ml, respectively; peak plasma concentration (Cmax) were (1.25+/-0.53), (2.21+/-0.52) and (4.34+/-1.66) ng/ml, respectively; apparent volume of distribution (Vd/F) were (6630.5+/-2057.8), (7615.2+/-2242.8) and (7163.7+/-2057.2) l, respectively; clearance rate (CL/F) were (1851.4+/-496.9), (1596.2+/-378.5) and (1894.2+/-459.3) l/h, respectively; time to Cmax (Tmax) were (1.00+/-0.21), (1.05+/-0.28) and (1.04+/-0.16) h, respectively; and elimination half-life (t1/2) were (3.11+/-0.78), (3.93+/-0.92) and (3.47+/-0.53) h, respectively; MRT were (3.74+/-0.85), (4.04+/-0.56) and (3.28+/-0.66) h, respectively. The essential pharmacokinetic parameters after oral multiple doses (6mg, b.i.d) were as follows: Cssmax, (2.72+/-0.61) ng/ml; Tmax, (1.10+/-0.25) h; Cssmin, (0.085+/-0.01) ng/ml; Cav, (0.54+/-0.12) ng/ml; DF, (4.84+/-0.86); AUCss, (6.53+/-1.5) ngh/ml. This developed and validated assay method had been successfully applied to a pharmacokinetic study after oral administration of tegaserod maleate in healthy Chinese volunteers at a single dose of 4 mg, 6 mg and 12 mg, respectively. The pharmacokinetic parameters can provide some information for clinical medication.