Efficacy of durvalumab plus chemotherapy in advanced biliary duct cancer and biomarkers exploration.

BACKGROUND: The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking. METHODS: ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing. RESULTS: A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival. CONCLUSION: This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.

Phase II study of SOXIRI (S-1/oxaliplatin/irinotecan) chemotherapy in patients with unresectable pancreatic ductal adenocarcinoma.

BACKGROUND: To provide data on the safety and efficacy of a combination chemotherapy regimen consisting of S-1, oxaliplatin, and irinotecan (SOXIRI) as a first-line therapy in unresectable pancreatic ductal adenocarcinoma (UPDA) patients. METHODS: Patients with UPDA and no prior treatment chemotherapy in the UPDA setting were enrolled. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival (PFS) and adverse events. Patients received 80 mg/m2 S-1 twice a day for 2 weeks in an alternate-day administration cycle, 85 mg/m2 oxaliplatin on Day 1, and 150 mg/m2 irinotecan on Day 1 of a 2-week cycle. RESULTS: In these 62 enrolled patients, the ORR was 27.4 %, median OS was 12.1 months, and median PFS was 6.5 months. Major grade 3 or 4 toxicity included neutropenia (22.3 %), leucopenia (16.1 %), nausea (9.7 %), vomiting (9.7 %), thrombocytopenia (6.5 %), anorexia (8.5 %), anemia (4.8 %), and diarrhea (1.6 %). No treatment-related deaths occurred. In addition, the analysis of 32 patients suffering pain revealed that the rate of pain relief was 34.4 %. CONCLUSION: SOXIRI might be a standard regimen with an acceptable toxicity profile and favorable efficacy for use as chemotherapy in patients with UPDA.

A novel scoring model based on RNA modification "writers" can predict the prognosis and guide immunotherapy in gastric cancer.

Although extensive research has been carried out on the epigenetic regulation of single RNA modifications in gastric cancer, little is known regarding the crosstalk of four major RNA adenosine modifications, namely, m6A, m1A, alternative polyadenylation and adenosine-to-inosine RNA editing. By analyzing 26 RNA modification "writers" in 1750 gastric cancer samples, we creatively constructed a scoring model called the "Writers" of the RNA Modification Score (WRM_Score), which was able to quantify the RNA modification subtypes of individual patients. In addition, we explored the relationship between WRM_Score and transcriptional and posttranscriptional regulation, tumor microenvironment, clinical features and molecular subtypes. We constructed an RNA modification scoring model including two different subgroups: WRM_Score_low and WRM_Score_high. The former was associated with survival benefit and good efficacy of immune checkpoint inhibitors (ICIs) due to gene repair and immune activation, while the latter was related to poor prognosis and bad efficacy of ICIs because of stromal activation and immunosuppression. The WRM score based on immune and molecular characteristics of the RNA modification pattern is a reliable predictor of the prognosis of gastric cancer and the therapeutic efficacy of immune checkpoint inhibitors in gastric cancer.

Comparison the efficacy and safety of different neoadjuvant regimens for resectable and borderline resectable pancreatic cancer: a systematic review and network meta-analysis.

BACKGROUND: To date, the optimal recommended specific neoadjuvant regimens for resectable or borderline resectable pancreatic cancer (RPC or BRPC) remain an unanswered issue. METHODS: We systematically searched the electronic databases to identify randomized controlled trials (RCTs) comparing different neoadjuvant therapy strategies for RPC or BRPC. The primary outcome was overall survival (OS). Comprehensive analyses and evaluations were performed using the single-arm, paired, and network meta-analyses. RESULTS: Twelve RCTs involving 1279 patients with RPC or BRPC were enrolled. The paired meta-analysis showed that neoadjuvant therapy improved OS for both RPC (hazard ratio (HR) 0.69, 95% c.i. 0.54 to 0.87) and BRPC (HR 0.60, 0.42 to 0.86) compared with upfront surgery (UP-S). Neoadjuvant chemotherapy (NAC) also improved OS for both RPC (HR 0.63, 0.47 to 0.85) and BRPC (HR 0.44, 0.27 to 0.71), while neoadjuvant chemoradiotherapy (NACR) improved OS only for BRPC (HR 0.68, 0.52 to 0.89) and not for RPC (HR 0.79, 0.54 to 1.16). Network meta-analysis found that NAC was superior to NACR in OS for RPC/BRPC (HR 0.58, 0.37 to 0.90). Neoadjuvant chemotherapy based on modified fluorouracil/folinic acid/irinotecan/oxaliplatin (NAC-mFFX) and neoadjuvant chemotherapy based on abraxane/gemcitabine (NAC-AG) ranked first and second in OS for RPC/BRPC. CONCLUSIONS: Both RPC and BRPC could obtain OS benefits from neoadjuvant therapy compared with UP-S, and NAC improved OS both in RPC and BRPC while NACR only improved OS in BRPC. Furthermore, NAC was superior to NACR, and NAC-mFFX and NAC-AG might be recommended sequentially as the best neoadjuvant therapy strategies.

Efficacy of Aidi injection combined with chemotherapy, radiotherapy or chemoradiotherapy for unresectable esophageal cancer treatment: A meta-analysis and systematic review of 29 randomized controlled trials based on Asian populations (China).

OBJECTIVES: This study aimed to assess the efficacy of Aidi combined with standard treatment, including radiotherapy (R), chemotherapy (C), or chemoradiotherapy (CR), for unresectable esophageal cancer (EC). METHODS: Eight online databases were queried to collect randomized controlled trials (RCTs) published from database construction to August 2022. Patients in the control group underwent standard treatment with R, C, or CR, whereas those in the experimental group underwent Aidi combined with standard treatment. RESULTS: In this meta-analysis, 29 reports with 2079 patients were included. The results showed that the Aidi-based combination therapy groups had higher objective response rates (ORRs), disease control rates (DCRs), one-year overall survival (OS) and improvement and stability of Karnofsky performance status (KPS) than the control group (risk ratio (RR) = 1.24 (95% CI = 1.17-1.33), 1.09 (95% CI = 1.05-1.14), 1.50 (95% CI = 1.31-1.72), and 1.28 (95% CI = 1.16-1.41)). The Aidi-based combination therapy groups also had lower total incidence rates of bone marrow suppression (BMS), chemotherapy-induced nausea and vomiting (CINV) and radiation esophagitis (RE) than the control group (RR = 0.48 (95% CI = 0.41-0.56), 0.46 (95% CI = 0.36-0.58), and 0.49 (95% CI = 0.38-0.62)). In addition, subgroup analysis suggested that the optimal dose and cycle of Aidi injection combined therapy was 80-100 ml/time and 30 days/2 cycles. The efficacy of Aidi combined with DP (docetaxel + cisplatin) was better than the Aidi combined with PF (cisplatin plus fluorouracil). CONCLUSION: Aidi-based combination therapy showed high efficacy for unresectable EC treatment and reduced the incidence rates of adverse events. However, further studies including higher-quality RCTs are needed to validate these findings. TRIAL REGISTRATION NUMBER: INPLASY 202290020.

Curcumin protects against Aflatoxin B1-induced liver injury in broilers via the modulation of long non-coding RNA expression.

Aflatoxin B1 (AFB1) is a potent hepatotoxic and carcinogenic agent. Curcumin possesses potential anti-inflammatory, anti-oxidative and hepatoprotective effects. However, the role of LncRNAs in the protective mechanisms of curcumin against AFB1-induced liver damage is still elusive. Experimental broilers were randomly divided into 1) control group, 2) AFB1 group (1 mg/kg feed), 3) cur + AFB1 group (1 mg/kg AFB1 plus 300 mg/kg curcumin diet) and 4) curcumin group (300 mg/kg curcumin diet). Liver transcriptome analyses and qPCR were performed to identify shifts in genes expression. In addition, histopathological assessment and oxidant status were determined. Dietary AFB1 caused hepatic morphological injury, significantly increased the production of ROS, decreased liver antioxidant enzymes activities and induced inflammation and apoptosis. However, dietary curcumin partially attenuated the abnormal morphological changes, oxidative stress, and apoptosis in liver tissues. Transcriptional profiling results showed that 34 LncRNAs and 717 mRNAs were differentially expressed with AFB1 and curcumin co-treatment in livers of broilers. Analysis of the LncRNA-mRNA network, GO and KEGG enrichment data suggested that oxidative stress, inflammation and apoptosis pathway were crucial in curcumin's alleviating AFB1-induced liver damage. In conclusion, curcumin prevented AFB1-induced oxidative stress, inflammation and apoptosis through LncRNAs. These results provide new insights for unveiling the protective mechanisms of curcumin against AFB1-induced liver damage.

Prognostic value of total number of lymph nodes retrieved differs between left-sided colon cancer and right-sided colon cancer in stage III patients with colon cancer.

BACKGROUND: The consensus is that a minimum of 12 lymph nodes should be analyzed at colectomy for colon cancer. However, right colon cancer and left colon cancer have different characteristics, and this threshold value for total number of lymph nodes retrieved may not be universally applicable. METHODS: The data of 63,243 patients with colon cancer treated between 2004 and 2012 were retrieved from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Multivariate Cox regression analysis was used to determine the predictive value of total number of lymph nodes for survival after adjusting for lymph nodes ratio. The predictive value in left-sided colon cancer and right-sided colon cancer was compared. The optimal total number of lymph nodes cutoff value for prediction of overall survival was identified using the online tool Cutoff Finder. Survival of patients with high total number of lymph nodes (≥12) and low total number of lymph nodes (< 12) was compared by Kaplan-Meier analysis. RESULTS: After stratifying by lymph nodes ratio status, total number of lymph nodes≥12 remained an independent predictor of survival in the whole cohort and in right-sided colon cancer, but not in left-sided colon cancer. The optimal cutoff value for total number of lymph nodes was determined to be 11. Low total number of lymph nodes (< 11) was associated with significantly poorer survival after adjusting for lymph nodes ratio in all subgroups except in the subgroup with high lymph nodes ratio (0.5-1.0). CONCLUSIONS: Previous reports of the prognostic significance of total number of lymph nodes on node-positive colon cancer were confounded by lymph nodes ratio. The 12-node standard for total number of lymph nodes may not be equally applicable in right-sided colon cancer and left-sided colon cancer.

Prognostic value of inflammation-based scores in patients receiving radical resection for colorectal cancer.

BACKGROUND: The modified Glasgow Prognostic Score (mGPS) and the neutrophil-to-lymphocyte ratio (NLR) are conventional inflammation-based scores for colorectal cancer (CRC). The systemic inflammation score (SIS) has been shown to be more informative than the mGPS in CRC. The albumin-NLR, composed of albumin and the NLR, can also be a candidate for a valuable inflammation score. However, about the utility of the mGPS, SIS, and albumin-NLR for CRC patients who have received radical resections remains unclear. METHODS: This study enrolled 877 CRC patients, who underwent radical surgical resection between January 1, 2007 and December 31, 2014. The prognostic values of the mGPS, SIS, and albumin-NLR were compared by the Kaplan-Meier survival analysis, multivariate Cox regression modelling, and the time-dependent receiver operating characteristic curve analysis (ROC). RESULTS: In the Kaplan-Meier analysis, all three inflammation scores were significantly associated with overall survival (OS) in the group including all the patients (mGPS, p = 0.016; SIS, p < 0.001; albumin-NLR, p = 0.007) and in the left-sided colon tumour subgroup (mGPS, p = 0.029; SIS p = 0.0013; albumin-NLR, p = 0.001). In the right-sided colon tumour subgroup, only the albumin-NLR was associated with OS (p = 0.048). The albumin-NLR was the only independent prognostic factor of the three scores for OS in the multivariate survival analysis. CONCLUSIONS: The albumin-NLR outperformed both the SIS and mGPS in predicting OS in CRC patients undergoing radical resection.

Intraganglionic interactions between satellite cells and adult sensory neurons.

Perineuronal satellite cells have an intimate anatomical relationship with sensory neurons that suggests close functional collaboration and mutual support. We examined several facets of this relationship in adult sensory dorsal root ganglia (DRG). Collaboration included the support of process outgrowth by clustering of satellite cells, induction of distal branching behavior by soma signaling, the capacity of satellite cells to respond to distal axon injury of its neighboring neurons, and evidence of direct neuron-satellite cell exchange. In vitro, closely adherent coharvested satellite cells routinely clustered around new outgrowing processes and groups of satellite cells attracted neurite processes. Similar clustering was encountered in the pseudounipolar processes of intact sensory neurons within intact DRG in vivo. While short term exposure of distal growth cones of unselected adult sensory neurons to transient gradients of a PTEN inhibitor had negligible impacts on their behavior, exposure of the soma induced early and substantial growth of their distant neurites and branches, an example of local soma signaling. In turn, satellite cells sensed when distal neuronal axons were injured by enlarging and proliferating. We also observed that satellite cells were capable of internalizing and expressing a neuron fluorochrome label, diamidino yellow, applied remotely to distal injured axons of the neuron and retrogradely transported to dorsal root ganglia sensory neurons. The findings illustrate a robust interaction between intranganglionic neurons and glial cells that involve two way signals, features that may be critical for both regenerative responses and ongoing maintenance.

Transformation of the education of health professionals in China: progress and challenges.

In this Review we examine the progress and challenges of China's ambitious 1998 reform of the world's largest health professional educational system. The reforms merged training institutions into universities and greatly expanded enrolment of health professionals. Positive achievements include an increase in the number of graduates to address human resources shortages, acceleration of production of diploma nurses to correct skill-mix imbalance, and priority for general practitioner training, especially of rural primary care workers. These developments have been accompanied by concerns: rapid expansion of the number of students without commensurate faculty strengthening, worries about dilution effect on quality, outdated curricular content, and ethical professionalism challenged by narrow technical training and growing admissions of students who did not express medicine as their first career choice. In this Review we underscore the importance of rebalance of the roles of health sciences institutions and government in educational policies and implementation. The imperative for reform is shown by a looming crisis of violence against health workers hypothesised as a result of many factors including deficient educational preparation and harmful profit-driven clinical practices.

Isotetrandrine protects against lipopolysaccharide-induced acute lung injury by suppression of mitogen-activated protein kinase and nuclear factor-kappa B.

BACKGROUND: Mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) signaling pathways are pleiotropic regulator of many genes involved in lipopolysaccharide (LPS)-induced acute lung injury (ALI). The present study aimed to reveal the protective effect of isotetrandrine (ITD), a small molecule inhibitor, on various aspects of LPS-induced inflammation in vitro and in vivo. METHODS: In vitro, RAW 264.7 cells were pretreated with different dose of ITD 1 h before treatment with 1 mg/L of LPS. In vivo, to induce ALI, male BALB/c mice were injected intranasally with LPS and treated with ITD (20 and 40 mg/kg) 1 h before LPS. RESULTS: In vitro, the cytokine levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in supernatant were reduced by ITD. Meanwhile, in vivo, pulmonary inflammatory cell infiltration, myeloperoxidase activity, total cells, neutrophils, macrophages, along with the levels of tumor necrosis factor-α, IL-1ß, and IL-6 in bronchoalveolar lavage fluid were dose-dependently attenuated by ITD. Furthermore, our data showed that ITD significantly inhibited the activation of MAPK and NF-κB, which are induced by LPS in ALI model. CONCLUSIONS: These results suggested that ITD dose-dependently suppressed the severity of LPS-induced ALI by inactivation of MAPK and NF-κB, which may involve the inhibition of tissue oxidative injury and pulmonary inflammatory process.

A multifunctional nanoplatform for precision-guided therapeutic intervention in bacterial infection.

Skin wound infection has become a global clinical problem in recent years. Curcumin (Cur) and polylysine (PLL) are natural products with strong antibacterial properties. However, the poor water solubility and low stability of Cur and the cationic toxicity of PLL limit their application. In this study, we synthesized a macromolecular hyaluronic acid (HA)-curcumin drug (HC) via esterification. HC was attracted by electrostatic interactions with positively charged PLL to form a spherical nanocomplex (HCP) with hyaluronidase (HAase) and pH dual response under ultrasonication. HCP was found to target the bacterial infection microenvironment and release Cur and PLL for synergistic antibacterial action. In addition, HCP was proven to exhibit good biocompatibility and broad spectrum antibacterial activity to bacterial strains S. aureus and E. coli and antibacterial biofilm activities in vitro. In vivo experiments showed that HCP could inhibit pathogens and promote wound healing. These results prove that HCP can be used as a new strategy for the treatment and management of infected wounds.

Impaired glymphatic clearance in multiple system atrophy: A diffusion spectrum imaging study.

INTRODUCTION: Impaired α-synuclein clearance is pivotal in the pathogenesis of neurodegenerative diseases. We evaluated glymphatic clearance in multiple system atrophy (MSA) patients using advanced imaging. METHODS: Forty-four MSA patients (11 with MSA-parkinsonian type [MSA-P] and 33 with MSA-cerebellar type [MSA-C]) and 30 healthy controls were studied using diffusion spectrum magnetic resonance imaging (DSI-MRI). Diffusivities were measured along the x-, y-, and z-axes to calculate the Analysis Along the Perivascular Space (ALPS) index. Comparisons of the ALPS index were conducted between MSA patients and controls and among MSA subtypes. The ALPS index correlation with the Unified Multiple System Atrophy Rating Scale (UMSARS) scores was also analyzed. RESULTS: The ALPS index differed significantly between patients with MSA and healthy controls, with lower values observed in the former (1.46 ± 0.17 versus1.63 ± 0.12, p < 0.001). Both MSA-P and MSA-C patients had lower ALPS-index (1.40 ± 0.13, p < 0.001; 1.47 ± 0.18, p = 0.003, respectively), but there was no significant difference between the two (p = 0.22). No correlation was found between the ALPS index and clinical scores for UMASRS I (r = -0.08, p = 0.61), UMASRS II (r = -0.04, p = 0.81), or UMASRS I + II (r = -0.05, p = 0.74). CONCLUSION: MSA patients show reduced glymphatic clearance as measured by the ALPS index, underscoring the utility of this imaging method in neurodegenerative disease research.

Anatomical classification of advanced biliary tract cancer predicts programmed cell death protein 1 blockade efficacy.

Background: Immune checkpoint blockade (ICB)-based immunotherapy has inspired new hope for advanced biliary tract cancer (BTC) treatment; however, there are no prior studies that primarily focus on different anatomical types of unresectable BTCs reacting differently to ICB. Methods: We retrospectively collected data on advanced BTC patients who received anti-programmed cell death protein 1 (anti-PD1) therapy from two affiliated hospitals of Sun Yat-Sen university. The effects of anti-PD1 were compared for different anatomical sites. The GSE32225 and GSE132305 datasets were used to further analyze differences in the immune microenvironments between intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). Results: A total of 198 advanced BTC patients were enrolled in this study, comprising 142 patients with ICC and 56 with other cancer types ("Others" group), including ECC and gallbladder cancer. In the anti-PD1 treated patients, the ICC group (n = 90) achieved longer median progression-free survival (mPFS) (9.5 vs. 6.2 months, p = 0.02) and median overall survival (mOS) (15.1 vs. 10.7 months, p = 0.02) than the Others group (n = 26). However, chemotherapy did not show different effects between the two groups (mOS: 10.6 vs. 12.1 months, p = 0.20; mPFS: 4.9 vs. 5.7 months, p = 0.83). For the first-line anti-PD1 therapy, the ICC group (n = 70) achieved higher mOS (16.0 vs. 11.8 months, p = 0.04) than the Others group (n = 19). Moreover, most chemokines, chemokine receptors, major histocompatibility complex molecules, immunostimulators, and immunoinhibitors were stronger in ICC than ECC; furthermore, CD8+ T cells and M1 macrophages were higher in ICC than ECC for most algorithms. The immune differential genes were mainly enriched in antigen processing and presentation as well as the cytokine receptors. Conclusions: This study shows that the efficacy of anti-PD1 therapy was higher in ICC than in other types of BTCs. Differences in the immune-related molecules and cells between ICC and ECC indicate that ICC could benefit more from immunotherapy.

Integrating depression and acute coronary syndrome care in low resource hospitals in China: the I-CARE randomised clinical trial.

Background: Acute coronary syndrome (ACS) often co-occurs with depression, which adversely affects prognosis and increases medical costs, but effective treatment models are lacking, particularly in low-resource settings. This study aims to determine the effectiveness of an ACS and depression integrative care (IC) model compared to usual care (UC) in improving depression symptoms and other health outcomes among patients discharged for ACS in Chinese rural hospitals. Methods: A multicentre, randomised controlled trial was conducted in sixteen rural county hospitals in China, from October 2014 to March 2017, to recruit consecutively all ACS patients aged 21 years and older after the disease stablised and before discharge. Patients were randomly assigned in a 1:1 ratio to receive either the IC or UC, stratified by hospital and depression severity. Patients allocated to IC received an ACS secondary prevention program and depression care including case screening, group counselling, and individual problem-solving therapy. Patients allocated to UC received usual care. The primary outcome was change in Patient Health Questionnaire-9 (PHQ-9) from baseline to 6 and 12 months. Main secondary outcomes included major adverse events (MAEs) composed of all-cause death, non-fatal myocardial infarction and stroke, and all-cause re-hospitalisation. Participants were followed up till March 2018. All data were collected in person by trained assessors blinded to treatment group and MAEs were adjudicated centrally. This trial is registered with ClinicalTrials.gov, NCT02195193. Findings: Among 4041 eligible patients (IC: 2051; UC: 1990), the mean age was 61 ± 10 years and 63% were men. The mean PHQ-9 score lowered at both 6 and 12 months in both groups but was not lower in IC compared to UC at 6 months (mean difference (MD): -0.04, 95% confidence interval (CI): -0.20, 0.11) or 12 months (MD: -0.06, 95% CI: -0.21, 0.09). There were no treatment group differences for MAEs or other secondary outcomes except for secondary prevention medications at 12 months (45.2% in IC vs 40.8% in UC; relative risk: 1.21, 95% CI: 1.05-1.40). Pre-specified subgroup analyses showed that IC, compared to UC, may be more effective in lowering PHQ-9 scores in women, older patients, and patients with low social support, but less effective in moderately and severely depressed patients (all p for interaction <0.05). Interpretation: The study found that the cardiology nurse-led ACS- and depression-integrated care, compared to usual care, did not improve depression symptoms in all patients discharged with ACS. Greater benefits in certain subgroups warrants further studies. Funding: R01MH100332 National Institute of Mental Health.

Expression of cytochrome P450 2A5 in a C57BL/6J mouse model of nonalcoholic fatty liver disease.

Cytochrome P450 2A5 (CYP2A5) expression is induced during the hepatotoxicity caused by various hepatotoxins and hepatitis. However, CYP2A5 expression during nonalcoholic fatty liver disease (NAFLD) is still unknown. In this study, serum biochemical parameters and liver histopathological analyses found that NAFLD had developed in C57BL/6J mice via administration of a high-fat diet continuously for 8 weeks. Subsequently, CYP2A5 expression was probed in the mice diagnosed with NAFLD that were treated with or without pyrazole, the inducer of chemical liver injury. It is shown that hepatic CYP2A5 mRNA, protein expression and coumarin 7-hydroxylase activity are enhanced with high-fat feed, and that pyrazole is able to further increase CYP2A5 expression and activity in mice with NAFLD. These results revealed that CYP2A5 is elevated during NAFLD and suggested that pyrazole and NAFLD act synergistically to induce the expression of CYP2A5 via an unclear mechanism.

Elder mistreatment in U.S. residential care facilities: the scope of the problem.

Many in the United States believe elder mistreatment in long-term care is serious and widespread, but until recently few studies focused on the problem. This study was designed to describe the scope of mistreatment in assisted living facilities (ALFs) in Arizona during a 3-year period. Findings showed that receiving citations for elder mistreatment was relatively rare. However, analysis of narrative reports from only 7% of facilities showed 598 allegations of mistreatment in complaint investigations, of which 372 (62.2%) were substantiated and given citations for something other than mistreatment. Results show that elder mistreatment in ALFs is seriously underidentified, even by state inspectors.

Inflammatory bowel disease increases the risk of hepatobiliary pancreatic cancer: A two-sample Mendelian randomization analysis of European and East Asian populations.

BACKGROUND: Both inflammatory bowel disease (IBD) and hepato-pancreato-biliary cancers (HPBC) have been established to cause a huge socioeconomic burden. Epidemiological studies have revealed a close association between IBD and HPBC. METHODS: Herein, we utilized inverse-variance weighting to conduct a two-sample Mendelian randomization analysis. We sought to investigate the link between various subtypes of IBD and HPBC. To ensure the accuracy and consistency of our findings, we conducted heterogeneity tests, gene pleiotropy tests, and sensitivity analyses. RESULTS: Compared to the general population, IBD patients in Europe exhibited a 1.22-fold increased incidence of pancreatic cancer (PC) with a 95% confidence interval (CI) of 1.0022-1.4888 (p = 0.0475). We also found a 1.14-fold increased incidence of PC in Crohn's disease (CD) patients with (95% CI: 1.0017-1.3073, p = 0.0472). In the East Asian population, the incidence of hepatocellular carcinoma (HCC) was 1.28-fold higher (95% CI = 1.0709-1.5244, p = 0.0065) in IBD patients than in the general population. Additionally, ulcerative colitis (UC) patients displayed 1.12-fold (95% CI: 1.1466-1.3334, p < 0.0001) and 1.31-fold (95% CI: 1.0983-1.5641, p = 0.0027) increased incidences of HCC and cholangiocarcinoma (CCA), respectively. Finally, the incidence of PC was 1.19-fold higher in CD patients than in the general population (95% CI = 1.0741-1.3132, p = 0.0008). CONCLUSION: Our study validated that IBD is a risk factor for HPBC. This causal relationship exhibited significant heterogeneity in different European and East Asian populations.

Efficacy and safety of SOXIRI versus mFOLFIRINOX in advanced pancreatic cancer.

Background: Modified fluorouracil/leucovorin/irinotecan/oxaliplatin (FOLFIRINOX) regimen (mFOLFIRINOX), comprised of fluorouracil, leucovorin, irinotecan and oxaliplatin, is the first-line standard chemotherapy in patients with advanced pancreatic cancer. The S-1/oxaliplatin/irinotecan (SOXIRI) regimen has also been studied recently under similar conditions. This study compared its efficacy and safety. Methods: All cases of locally advanced or metastatic pancreatic cancer treated with the SOXIRI or mFOLFIRINOX regimen in Sun Yat-sen University Cancer Centre from July 2012 to June 2021 were reviewed retrospectively. The data of patients who satisfied the inclusion criteria were compared between two cohorts, including overall survival (OS), progression-free survival (PFS), objective response rate, disease control rate and safety. Results: A total of 198 patients were enrolled in the study, including 102 patients treated with SOXIRI and 96 patients treated with mFOLFIRINOX. There was no significant difference in OS [12.1 months versus 11.2 months, hazard ratio (HR) = 1.04, p = 0.81] or PFS (6.5 months versus 6.8 months, HR = 0.99, p = 0.96) between patients treated with SOXIRI and mFOLFIRINOX. In the subgroup analysis, patients with slightly elevated baseline total bilirubin (TBIL) or underweight patients before chemotherapy were more likely to have a longer OS or PFS from SOXIRI than from mFOLFIRINOX. In addition, the carbohydrate antigen (CA)19-9 decline was a good predictor for the efficacy and prognosis of both chemotherapy regimens. All grade adverse events were parallel in all kinds of toxicities except that anaemia was more common in the SOXIRI group than in the mFOLFIRINOX group (41.4% versus 24%, p = 0.03). The occurrence of any grade 3 to 4 toxicity was similar in the two groups. Conclusions: For locally advanced or metastatic pancreatic cancer patients, the SOXIRI regimen had similar efficacy and controllable safety compared with the mFOLFIRINOX regimen.

Analysis of Risk Factors for Distant Metastasis of Pancreatic Ductal Adenocarcinoma without Regional Lymph Node Metastasis and a Nomogram Prediction Model for Survival.

Background: Negative regional lymph nodes do not indicate a lack of distant metastasis. A considerable number of patients with negative regional lymph node pancreatic cancer will skip the step of regional lymph node metastasis and directly develop distant metastasis. Methods: We retrospectively analyzed the clinicopathological characteristics of patients with negative regional lymph node pancreatic cancer and distant metastasis in the Surveillance, Epidemiology, and End Results database from 2010 to 2015. Multivariate logistic analysis and Cox analysis were used to determine the independent risk factors that promoted distant metastasis and the 1-, 2-, and 3-year cancer-specific survival in this subgroup. Results: Sex, age, pathological grade, surgery, radiotherapy, race, tumor location, and tumor size were significantly correlated with distant metastasis (P < 0.05). Among these factors, pathological grade II and above, tumor site other than the pancreatic head, and tumor size >40 mm were independent risk factors for distant metastasis; age ≥60 years, tumor size ≤21 mm, surgery, and radiation were protective factors against distant metastasis. Age, pathological grade, surgery, chemotherapy, and metastasis site were identified as predictors of survival. Among them, age ≥40 years, pathological grade II and above, and multiple distant metastasis were considered independent risk factors for cancer-specific survival. Surgery and chemotherapy were considered protective factors for cancer-specific survival. The prediction performance of the nomogram was significantly better than that of the traditional American Joint Committee on Cancer tumor, node, metastasis staging system. We also established an online dynamic nomogram calculator, which can predict the survival rate of patients at different follow-up time points. Conclusion: Pathological grade, tumor location, and tumor size were independent risk factors for distant metastasis in pancreatic ductal adenocarcinoma with negative regional lymph nodes. Older age, smaller tumor size, surgery, and radiotherapy were protective factors against distant metastasis. A new nomogram that was constructed could effectively predict cancer-specific survival in pancreatic ductal adenocarcinoma with negative regional lymph nodes and distant metastasis. Furthermore, an online dynamic nomogram calculator was established.