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.

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.

Response to programmed cell death protein 1 antibody in patients with Epstein-Barr virus-associated intrahepatic cholangiocarcinoma.

AIM: Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) has a distinct genomic profile and increased CD3+ and CD8+ T cells infiltration. However, the efficacy of immunotherapy in EBVaICC remains largely unknown. This study aimed to assess the efficacy of programmed cell death protein 1 (PD-1) antibody therapy in EBVaICC. METHODS: Patients with metastatic biliary tract cancer (BTC) diagnosed at Sun Yat-sen University Cancer Center from January 2016 to December 2021 were identified. In situ hybridisation was performed to detect EBV. Overall survival (OS) and progression-free survival (PFS) were measured. RESULTS: A total of 698 patients with metastatic BTC were identified, of whom 39 (5.6%) had EBVaICC. Among the 136 patients who were not administered PD-1 antibody, the OS was similar between patients with EBVaICC and EBV-negative ICC (median OS 12.5 versus 9.5 months, respectively; P = 0.692). For the 205 patients who were administered PD-1 antibody, patients with EBVaICC had significantly longer OS than patients with EBV-negative ICC (median OS 24.9 versus 11.9 months, respectively; P = 0.004). Seventeen patients with EBVaICC were administered PD-1 antibody. Eight patients (47%) achieved a partial response, and 17 patients achieved disease control. The median PFS was 17.5 months. CONCLUSIONS: This study identified a clinically actionable subset of patients with EBVaICC with a promising response to the PD-1 antibody.

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.

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.

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 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.

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.

Soil conditions and the plant microbiome boost the accumulation of monoterpenes in the fruit of Citrus reticulata 'Chachi'.

BACKGROUND: The medicinal material quality of Citrus reticulata 'Chachi' differs depending on the bioactive components influenced by the planting area. Environmental factors, such as soil nutrients, the plant-associated microbiome and climatic conditions, play important roles in the accumulation of bioactive components in citrus. However, how these environmental factors mediate the production of bioactive components of medicinal plants remains understudied. RESULTS: Here, a multi-omics approach was used to clarify the role of environmental factors such as soil nutrients and the root-associated microbiome on the accumulation of monoterpenes in the peel of C. reticulata 'Chachi' procured from core (geo-authentic product region) and non-core (non-geo-authentic product region) geographical regions. The soil environment (high salinity, Mg, Mn and K) enhanced the monoterpene content by promoting the expression of salt stress-responsive genes and terpene backbone synthase in the host plants from the core region. The microbial effects on the monoterpene accumulation of citrus from the core region were further verified by synthetic community (SynCom) experiments. Rhizosphere microorganisms activated terpene synthesis and promoted monoterpene accumulation through interactions with the host immune system. Endophyte microorganisms derived from soil with the potential for terpene synthesis might enhance monoterpene accumulation in citrus by providing precursors of monoterpenes. CONCLUSIONS: Overall, this study demonstrated that both soil properties and the soil microbiome impacted monoterpene production in citrus peel, thus providing an essential basis for increasing fruit quality via reasonable fertilization and precision microbiota management. Video Abstract.

Regorafenib with or without a programmed cell death protein 1 antibody as third-line treatment for microsatellite stable metastatic colorectal cancer.

BACKGROUND: Although the use of regorafenib plus nivolumab demonstrates promising outcomes in patients with refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC), this effect has not been substantiated in other studies. Moreover, a comparison between the outcomes of regorafenib and programmed cell death protein 1 (PD-1) antibody combination therapy and regorafenib monotherapy remains unexplored. In this study, we aimed to assess whether regorafenib and PD-1 antibody combination therapy is superior to regorafenib monotherapy as a third-line treatment for MSS mCRC. METHODS: Patients with MSS mCRC who received regorafenib and PD-1 antibody or regorafenib monotherapy as third-line treatment were eligible for inclusion. RESULTS: In total, 179 patients were enrolled, of which 84 were administered regorafenib combined with a PD-1 antibody and 95 were administered regorafenib monotherapy. Patients administered regorafenib combined with a PD-1 antibody had similar progression-free survival (PFS) as those on regorafenib monotherapy (median PFS was 2.4 months and 1.9 months, respectively, p = 0.086). The administration of regorafenib combined with a PD-1 antibody resulted in significantly longer PFS than that seen with regorafenib monotherapy in both male (5.2 months vs. 2.4 months, p = 0.001) and female (3.9 months vs. 1.8 months, p = 0.037) patients without liver metastasis. Female patients with liver metastasis who were administered regorafenib combined with a PD-1 antibody had shorter PFS than those administered regorafenib monotherapy (1.8 months vs. 2.0 months, p = 0.030). CONCLUSION: Liver metastasis and sex are predictors of survival benefit following the addition of a PD-1 antibody to regorafenib in patients with MSS mCRC.

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.

PD-1-mAb Plus Regimen in the First and Second Lines of Advanced and Unresectable Biliary Tract Carcinoma: A Real-World, Multicenter Retrospective Analysis.

Introduction: Advanced biliary tract carcinoma (BTC) has a poor prognosis and few treatment options. We compared the efficacy of the PD-1 monoclonal antibody (PD-1-mAb) combined regimens with the standard chemotherapy in the first-line and second-line treatment of advanced BTC. Methods: We retrospectively assessed the patients with advanced BTC, who received treatment at the First Affiliated Hospital of Sun Yat-Sen University and the Sun Yat-Sen University Cancer Center. The patients were treated with PD-1-mAb combined regimens or standard chemotherapy at the first line or treated with PD-1-mAb combined regimens or systematic therapy at the second line. Further subgroup analyses were assessed to identify superior regimens. Results: This study included 210 patients. The first-line PD-1-mAb combination group (n = 83) achieved longer median PFS (mPFS) (7.3 vs 5.3 months, p=0.001) and median OS (mOS) (15.6 vs 11.4 months, p=0.002) than the first-line standard chemotherapy group (n=76). Similarly, the second-line PD-1-mAb combination group (n=50) yielded longer mPFS (6.1 vs 2.6 months, p<0.001) and mOS (11.7 vs 7.2 months, p=0.008) than the second-line systematic therapy group (n=51). Subgroup analyses showed that the PD-1-mAb combined with TKI group achieved better mPFS than the chemotherapy group whether in the first-line (HR = 0.468, p=0.005) or the second-line setting (HR = 0.45, p=0.009), but did not achieve superiority in mOS (both p>0.05). Compared with the chemotherapy group, the PD-1-mAb combined with chemotherapy group achieved longer mOS (HR = 0.53, p=0.023) in the first-line setting and longer mPFS in the second-line setting (HR = 0.54, p=0.044). Conclusion: The PD-1-mAb combination therapy is superior to the standard chemotherapy in advanced or unresectable BTC, whether as a first-line or second-line treatment. Among the combination therapy, both the PD-1-mAb combined with TKI and combined with standard chemotherapy were promising options for advanced BTC patients.

Efficacy of the Nourishing Yin and Clearing Heat Therapy Based on Traditional Chinese Medicine in the Prevention and Treatment of Radiotherapy-Induced Oral Mucositis in Nasopharyngeal Carcinomas: A Systematic Review and Meta-Analysis of Thirty Randomized Controlled Trials.

This study aimed to evaluate the efficacy of nourishing Yin and clearing heat therapy (NYCH therapy) based on traditional Chinese medicine (TCM) in the treatment of radiotherapy-induced oral mucositis (RTOM) in nasopharyngeal carcinomas (NPCs). A total of eight online databases were searched from inception to September 2021 for randomized controlled trials (RCTs). The control group was treated with Western medicine (WM) alone, whereas the experimental group was treated with a combined NYCH and WM therapy. A total of 30 RCTs involving 2562 participants were ultimately included. NYCH therapy combined with conventional WM delayed the onset time (days) of RTOM (MD = 10.80, p < 0.001), and at that time, a higher cumulative radiotherapy dose (Gy) (MD = 5.72, p < 0.001) was completed in the experimental group. The combination regimen also reduced the incidence of severe oral mucositis (Grade III-IV) (RR = 0.25, p < 0.001). In addition, the treatment efficacy of the experimental group was significantly better than that of the control group (RR = 1.31, p < 0.001). Compared with the patients in the control group, the experimental group had lower xerostomia scores (MD = -1.07, p < 0.001) and more saliva (MD = 0.36, p < 0.001). NYCH combined with WM improved the efficacy of treating RTOM in NPC. This study provides a sufficient basis for conducting further large RCTs to prove the efficacy of NYCH.

Efficacy and Safety of Anti-PD1/PDL1 in Advanced Biliary Tract Cancer: A Systematic Review and Meta-Analysis.

Background: Anti-programmed cell death protein 1 and its ligand (anti-PD1/PDL1) have been proposed as a promising therapeutic option for advanced biliary tract cancer (aBTC). Given the scarce quantitative analyses of anti-PD1/PDL1 in aBTC, we thus did a meta-analysis to assess the benefits and risks of this emerging treatment strategy in patients with aBTC. Methods: PubMed, Embase, the Cochrane Library, Web of Science, and meeting resources were searched for relevant studies. The main endpoints were median progression-free survival (mPFS), median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), any-grade adverse events (AEs), and grade 3-4 AEs. Results: Twenty-eight studies with 1,338 participants were included. The best curative effect was found in the anti-PD1/PDL1 combined with anti-CTLA4 and chemotherapy group (mPFS: 12.4 months; mOS: 16.0 months; ORR: 45.1%; DCR: 95.0%), followed by the anti-PD1/PDL1 plus chemotherapy group (mPFS: 8.2 months; mOS: 14.8 months; ORR: 36.3%; DCR: 84.6%), the anti-PD1/PDL1 plus antiangiogenesis group (mPFS: 4.9 months; mOS: 10.2 months; ORR: 17.5%; DCR: 68.7%), the anti-PD1/PDL1 plus anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA4) group (mPFS: 2.9 months; mOS: 8.3 months; ORR: 9.9%; DCR: 36.8%), and the anti-PD1/PDL1 monotherapy group (mPFS: 2.5 months; mOS: 7.6 months; ORR: 6.8%; DCR: 34.7%). Compared with anti-PD1-containing regimens, anti-PDL1-containing regimens achieved preferable mPFS (11.1 vs. 3.8 months), mOS (12.2 vs. 9.8 months), and ORR (23.7% vs. 17.4%), despite a similar DCR (61.1% vs. 61.3%). The mPFS, mOS, ORR, and DCR were 10.6 months, 15.8 months, 42.3%, and 88.6% of first-line anti-PD1/PDL1 and 3.0 months, 9.1 months, 11.6%, and 51.1% of second-line therapy or beyond, respectively. There were 80.6% and 34.0% of the patients suffering any-grade AEs and grade 3-4 AEs. Anti-PD1/PDL1 monotherapy might be considered as a safer alternative than combination regimens. Meanwhile, obvious toxicities in the first-line setting could not be neglected. Conclusions: Anti-PD1/PDL1 showed encouraging efficacy and acceptable safety profile in aBTC and, thus, could be an alternative treatment.

Comparison of Biochemical Parameters between Mouse Model and Human after Paraquat Poisoning.

BACKGROUND: This study was designed to investigate differences in biochemical parameters between mouse and humans after paraquat (PQ) poisoning and develop a suitable animal model for studying organ damage after PQ poisoning. The prognostic factors of PQ-poisoned patients were further analyzed. METHODS: Thirty C57BL/6J mice were randomly divided into five groups (control, sham, and 3 PQ doses), and the mouse model was established by intragastric administration of PQ. Physiological indexes such as the body weight, mental state, and mortality rate were observed. Biochemical parameters were analyzed 24 h after PQ poisoning. We also performed a retrospective analysis of clinical data from 29 patients with PQ poisoning admitted to the Emergency Department of the Affiliated Hospital of Taishan Medical College between April 2016 and February 2018. Biochemical parameters were compared between the mouse model and patients with PQ poisoning. RESULTS: In the PQ poisoning mouse model, the lethal dose group PQ360 showed remarkable increases in serum levels of potassium (K+), carbon dioxide (CO2), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) compared with the nonlethal dose PQ100 and PQ200 groups. The biochemical results of the patients showed that K+ and Cl- levels were significantly reduced in the death group compared to the survival group. Levels of ALT, AST, blood urea nitrogen (BUN), and amylase were higher, and the neutrophil-to-lymphocyte ratio (NLR) was increased in the death group compared with the survival group. CONCLUSIONS: The combination of age, PQ dosage, K+, Cl-, BUN, ALT, AST, amylase, and NLR can be used to more accurately predict the outcome of patients with PQ poisoning. C57 mice are an appropriate animal model to study liver and kidney functions following PQ exposure.

Impact of professionally facilitated peer support for family carers of people with dementia in a WeChat virtual community.

INTRODUCTION: Dementia is an important issue affecting families and society. Family carers face challenges accessing support due to homebound duties of caring for people with dementia. Internet-based support provides feasible and accessible opportunities. METHODS: A single-group repeated-measures study was conducted with carers who provide primary care or regularly participate in care for relatives with dementia in a WeChat virtual community. Interventions included three to six months of peer and professional support, included peer emotional support, lectures and consultation, technique support and articles. Self-administered online questionnaires were used pre and post intervention to collect carers' feedback on activities, indicators of depression, helplessness, perceived stress, carer burden, distress caused by responsive behaviours and self-efficacy. RESULTS: A total of 159 carers participated. Of these, 136 (85.5%) were active members according to the amount of information shared in community. A total of 92.4% of carers thought the help and support from the community were important or very important. There were statistically significant differences after intervention for depression (p < 0.05), perceived stress (p < 0.05), helplessness (p < 0.001), self-efficacy total score (p < 0.05) and two domains of gathering information and obtaining support (p < 0.05). There was no statistically significant decrease after intervention for distress caused by responsive behaviours and carer burden (p>0.05). DISCUSSION: Professional facilitated peer support based on WeChat virtual community is feasible and acceptable for family carers of people with dementia. It can reduce carers' perceived pressure, helplessness and depression, and improve self-efficacy compared to pre participation.

Retraction Note to: Lycopsamine inhibits the proliferation of human lung cancer cells via induction of apoptosis and autophagy and suppression of interleukin-2.

Retraction of "Lycopsamine inhibits the proliferation of human lung cancer cells via induction of apoptosis and autophagy and suppression of interleukin-2", by Zhengang Yu, Guifang Guo, Bingzhe Wang. JBUON 2020;25(5):2358-2363; PMID: 33277856 Following the publication of the above article, readers drew to our attention that part of the data was unreliable: Figures of this article appeared in other articles (by totally different authors). The authors were requested to provide the raw data and were also asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. Given above, we decided to retract this article. Authors were informed of the retraction. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.

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.

Lycopsamine inhibits the proliferation of human lung cancer cells via induction of apoptosis and autophagy and suppression of interleukin-2.

PURPOSE: Lycopsamine is an active pyrrolizidine alkaloid that shows significant bioactivity. Herein, lycopsamine was evaluated for the first time for its anti-lung cancer activity. Its effects on cellular apoptosis, autophagy, cell cycle and IL-2 gene were also examined. METHODS: The human lung cancer A549 and normal MRC5 cells were used in the study. MTT assay was used to determine the cytotoxicity of lycopsamine. Transmission electron microscopy (TEM) and western blotting were implemented for analyzing autophagy. DAPI staining, Annexin V/FITC/Propidium iodide (PI) and western blotting assays were used to study cellular apoptosis. Cell cycle was examined through flow cytometry. The expression of IL-2 gene was monitored by western blotting. RESULTS: Lycopsamine targeted the proliferation rate and reduced it remarkably in a dose-dependent manner. On searching for underlying mechanism, the antiproliferative effect of lycopsamine was due to autophagy and the expressions of pro-autophagy proteins (LC3-I, LC3-II, Beclin-1) increased on drug exposure. Furthermore, the antiproliferative effects were also found to be mediated via apoptosis induction and were associated with increased Bax and decreased Bcl-2 levels. Next, flow cytometry showed that lycopsamine inhibited cell cycle progression at G2/M-check point in lung cancer cells. Furthermore, the expressions of IL-2 gene decreased after lycopsamine treatment of these cells. In conclusion, on testifying the current designed hypothesis, lycopsamine showed significant antiproliferative effects in A549 lung cancer cells in a dose reliant manner. The antiproliferative effects of lycopsamine were associated with its autophagy inducing, apoptosis inducing, and inhibiting IL-2 expression, potential. CONCLUSION: Taken together, lycopsamine is a potent anti-lung cancer agent and can be a lead molecule in lung cancer treatment.

Safety and Efficacy of Long-Term Zoledronic Acid in Advanced Breast Cancer with Bone Metastasis in South China.

BACKGROUND: This retrospective study aimed to characterize the long-term (>24 months) safety profile of zoledronic acid (ZA). We aimed to investigate whether long-term ZA treatment had greater benefits than short-term treatment in patients from southern China with advanced breast cancer (ABC) with bone metastasis. Patients and Methods. A total of 566 metastatic breast cancer cases were included and divided into two groups according to the duration of ZA treatment. The included patients had at least one lytic bone lesion and had no skeletal-related events (SREs) prior to ZA therapy. The primary endpoint was to analyze the safety and long-term adverse effects, which covered osteonecrosis of jaws (ONJ), renal impairment, and hearing impairment. The second objective was to determine the efficacy of long-term ZA treatment by the incidence of SREs. RESULTS: Fifteen patients were diagnosed with ONJ (2.7%): nine in the short-term group (3.1%) and six in the long-term group (2.2%, P = 0.606). Five cases (0.9%) had renal function impairment: two in the short-term group (0.7%) and four in the long-term group (1.1%, P = 0.676). One patient (0.2%) in the long-term group had hearing impairment after 23 months of ZA treatment (0.4%, P = 0.482). In total, 103 cases in the short-term group (35.2%) and 138 cases in long-term group (50.5%) developed SREs (P < 0.001). The mean annual SRE rate was 0.3 in the short-term group (range, 0-3.1) versus 0.2 in the long-term group (0-1.0, P = 0.269). Subgroup analysis suggested that cases with non-load-bearing bone involvement and those who received systematic anticancer therapy without chemotherapy might benefit from long-term ZA treatment. Cox regression analysis indicated poor performance status, and nonvisceral organ involvement predicted high risk for SRE. CONCLUSIONS: The extension of ZA treatment did not increase the long-term adverse events and reduced the annual incidence of SREs beyond 24 months. Although longer treatment of ZA over 24 months appeared to be safe, further prospective investigation is required.