Search

BACKGROUND/PURPOSE This study aimed to explore the anatomical and physiological characteristics of patients with laryngopharyngeal reflux (LPR) symptoms, such as hoarseness, throat clearing, throat pain, globus, and chronic cough, with the novel high-resolution impedance manometry (HRIM). METHODS Consecutive patients exhibited at least one LPR symptom for ≥4 weeks after 2-month proton-pump inhibitor treatment were enrolled during November 2014 and March 2018 from single tertiary medical center. All patients completed validated symptom questionnaires, esophagogastroduodenoscopy, and HRIM. Healthy volunteers were also recruited for comparison of esophageal parameters on HRIM. RESULTS Eighty-nine LPR patients and 63 healthy volunteers were analyzed. Compared with healthy volunteers, LPR patients had significantly shorter upper and lower esophageal sphincters (UES and LES), a shorter intraabdominal esophagus (all P

Gastrointestinal bleeding is the most frequent major complication of antiplatelet therapy. In patients at low bleeding risk, however, clinically overt gastrointestinal bleeding is relatively uncommon.The authors sought to assess the effects of different antiplatelet regimens on gastrointestinal mucosal injury by means of a novel magnetically controlled capsule endoscopy system in patients at low bleeding risk.Patients (n = 505) undergoing percutaneous coronary intervention in whom capsule endoscopy demonstrated no ulcerations or bleeding (although erosions were permitted) after 6 months of dual antiplatelet therapy (DAPT) were randomly assigned to aspirin plus placebo (n = 168), clopidogrel plus placebo (n = 169), or aspirin plus clopidogrel (n = 168) for an additional 6 months. The primary endpoint was the incidence of gastrointestinal mucosal injury (erosions, ulceration, or bleeding) at 6-month or 12-month capsule endoscopy.Gastrointestinal mucosal injury through 12 months was less with single antiplatelet therapy (SAPT) than with DAPT (94.3% vs 99.2%; P = 0.02). Aspirin and clopidogrel monotherapy had similar effects. Among 68 patients without any gastrointestinal injury at randomization (including no erosions), SAPT compared with DAPT caused less gastrointestinal injury (68.1% vs 95.2%; P = 0.006), including fewer new ulcers (8.5% vs 38.1%; P = 0.009). Clinical gastrointestinal bleeding from 6 to 12 months was less with SAPT than with DAPT (0.6% vs 5.4%; P = 0.001).Despite being at low risk of bleeding, nearly all patients receiving antiplatelet therapy developed gastrointestinal injury, although overt bleeding was infrequent. DAPT for 6 months followed by SAPT with aspirin or clopidogrel from 6 to 12 months resulted in less gastrointestinal mucosal injury and clinical bleeding compared with DAPT through 12 months. (OPT-PEACE [Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury Evaluated by Ankon Magnetically Controlled Capsule Endoscopy]; NCT03198741).

Several studies have evaluated the association between thermal insulation (TI) and control after surgery, with various research designs, recruitment and exclusion criteria, and measurements. The current meta-analysis aimed to assess the correlation between TI and stroke during recovery from anesthesia.We searched for full-text articles of us of TI during anesthesia recovery in multiple databases including PubMed, Springer, EMBASE and Chinese journal full-text databases. Two reviewers read each article and extracted the relevant data of into a Microsoft Excel table: name of the first author, publication year, year of onset, sample size (TI/control group), patient age range, and other information related to TI patients and control group. The meta-analysis, sensitivity analysis and bias analysis were performed using Review Manager 5.0.A total of 723 patients from 7 studies met the eligibility criteria and were included in the final analysis. The meta-analysis showed that the recovery time after anesthesia in the TI group was significantly different from that in the control group [mean difference (MD) =-7.02, 95% confidence interval (CI): -10.10 to -3.95, P0.00001; P for heterogeneity0.00001, I2=99%], length of stay in Postanesthesia Care Unit (PACU) score [MD =-20.78, 95% CI: -31.32 to -10.24, P=0.0001; P for heterogeneity0.00001, I2=92%] and shivering rate [relative risk (RR) =0.25, 95% CI: 0.08 to 0.77, P=0.02; P for heterogeneity =0.07, I2=71%].TI is an important measure during recovery from anesthesia.

The possible mechanisms underlying the quantitative and qualitative effects of cinacalcet on bone were explored in a chronic kidney disease-mineral and bone disorder (CKD-MBD) mouse model in relation to the influence of the interactions among the osteoclast (OC) endoplasmic reticulum (ER) stress, autophagy and apoptosis pathways on OC differentiation. Body weight and biochemical parameters improved significantly in the CKD + cinacalcet groups compared to the CKD group. Micro-computed tomography (μCT) revealed both cortical and trabecular parameters deteriorated significantly in the CKD group and were reversed by cinacalcet in a dose-dependent manner. Nanoindentation analysis of bone quality proved that both cortical hardness and elastic modulus improved significantly with high dose cinacalcet treatment. In vitro studies revealed that cinacalcet inhibited receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK)-induced OC differentiation in a concentration-dependent manner through a close interaction between activation of caspase-related apoptosis, reversal of OC autophagy through the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathways, and attenuation of the OC ER stress/CREBH/NFATc1 signaling pathway. Cinacalcet improves both bone quantity and bone quality in CKD mouse model and inhibits OC differentiation through regulation of the interactions among the apoptosis, ER stress, and autophagy pathways within OCs. © 2021 American Society for Bone and Mineral Research (ASBMR).

During the past decade, we have entered an era of biologics for the treatment of Crohn's disease and ulcerative colitis. The therapeutic goal of inflammatory bowel disease (IBD) management has evolved from symptom control and clinical remission to mucosal healing or even deep remission. Histological remission for ulcerative colitis and transmural healing of Crohn's disease are potential future goals. With the adoption of the treat-to-target concept, and given the need for tight control of IBD activity, therapeutic drug monitoring (TDM) is an important element of precision medicine. TDM involves the measurement of serum biologics and anti-drug antibodies levels, to confirm whether the right drug with the right dosage was prescribed to reach the right serum levels. TDM may help clinicians adjust biologics based on objective biomarkers instead of using empirical dosage escalation or making symptom-based therapeutic adjustments. Well-established reactive TDM algorithms have been proposed, and emerging evidence supports the clinical application of a proactive TDM strategy to enhance the duration of effective biologics and improve clinical outcomes. Recently, the proactive TDM strategy was shown to avoid the secondary loss of response to biologics, and improve long-term clinical outcomes in IBD patients. This review summarizes data from trials, and practice guidelines, on the clinical application of proactive and reactive TDM strategies for the daily care of biologic-treated IBD patients.

Objective: Coronavirus disease 2019 (COVID-19) was associated with a higher risk of arrhythmia in infected patients. However, there are no reports about the effect of the ongoing pandemic on arrhythmias in the non-infected population. We measured the arrhythmia burden in a non-infected population with cardiac implantable devices. Methods: The arrhythmia burden during the COVID-19 pandemic was compared to a 6-month interval in the pre-COVID-19 period. The COVID-19 pandemic was divided into high-risk (17 January 2020 to 16 March 2020) and low-risk periods (17 March 2020 to 17 July 2020) according to whether there were locally infected patients. Arrhythmia burdens were compared among the pre-COVID-19, high-risk, and low-risk periods. Results: A total of 219 patients with 1859 episodes were included. We observed a larger proportion of patients with atrial fibrillation (AF) during the COVID-19 pandemic (38.36% vs 26.03%, p = 0.006). There was not significantly more ventricular arrhythmia during the COVID period than the pre-COVID-19 period (p > 0.05). During the high-risk period, daily frequency of non-sustained ventricular tachycardia (NSVT) (0.0172, 0.0475 vs 0.0109, 0.0164, p < 0.05), atrial tachycardia (AT) (0.0345, 0.0518 vs 0.0164, 0.0219 p < 0.05) and AF (0.0345, 0.0432 vs 0.0164, 0.0186, p < 0.05) and daily duration of NSVT (0.1982, 0.2845 vs 0.0538, 0.1640 p < 0.05) were higher and longer than those in the pre-COVID-19 period. Regression modeling showed that the impact of COVID-19 pandemic lead to an increased onset of AF (odds ratio 2.465; p < 0.01). Patients with paroxysmal AF who had undergone a previous radiofrequency ablation had a lower burden of AF (incidence 21.43% vs 55.00%, P = 0.049, daily frequency 0.0000, 0.0027 vs 0.0000, 241.7978, P = 0.020) during the pandemic. Conclusion: The COVID-19 pandemic contributed to a higher burden of arrhythmias in non-infected patients. Patients would experience a lower burden of AF following radiofrequency ablation treatment, and this effect persisted during the pandemic.

Background Granulomatous capillary haemangioma refers to a benign vascular tumour that commonly affects the skin, with occasional involvement of the mucosa. Reports of conjunctival granulomatous capillary haemangioma in children are uncommon. In this article, we present a case of granulomatous capillary haemangioma and a brief review of the relevant literature. Case presentation An 11-year-old girl presented with a conjunctival mass. An excision of the entire lesion was performed. Histopathology showed a granulomatous capillary haemangioma. Conclusions The clinical manifestations of granulomatous capillary haemangioma lack specificity; pathological characteristics and immunohistochemistry are the main basis for diagnosis. We retrospectively analysed the diagnosis and treatment of a patient with conjunctival granulomatous capillary haemangioma to deepen the understanding and facilitate the diagnosis and treatment of this disease.

Ting Ye,1,&ast; Jia Feng,1,&ast; Meng Cui,2 Jia Yang,2 Xue Wan,1 Dan Xie,1 Jinbo Liu1 1Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2Department of Laboratory Medicine, The Leshan People’s Hospital, Luzhou, Sichuan, 614000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ting Ye; Jinbo LiuDepartment of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Jiangyang District, Luzhou, Sichuan, 646000, People’s Republic of ChinaTel +86-830-3165730Email yeting1103@163.com; liulab2019@163.comBackground: Myocardial infarction associated transcript (MIAT) is identified as a long chain non-coding RNA (lncRNA), which was associated with myocardial infarction susceptibility. While intense efforts have been made to elucidate the relationship between MIAT and carcinogenesis, the tumor immunoreaction of MIAT remains elusive. Thus, this study aimed to investigate the role of MIAT in the immunoregulation of breast cancer (BC) and further explore the better clinical significance.Methods: The differential expression of MIAT between BC and normal/adjacent tissues was compared using Wilcoxon rank sum test. The diagnostic and prognostic values of elevated MIAT expression in BC tissues were unveiled via receiver operating characteristic (ROC) analysis and KM-plotter analysis. Limma and edgeR package were used to identify differentially expressed genes (DEGs) and microRNAs (DEMs) from TCGA database respectively. A co-expression dataset was constructed to comprehensively understand the relationship between MIAT and DEGs based on the Pearson correlation coefficient. Furthermore, GO and KEGG analyses were conducted to predict the potential functions of MIAT. We next intersected immune-related genes (IRGs) from ImmPort database with MIAT-co-expressed genes to obtain MIAT-co-expressed IRGs, in order to construct MIAT-microRNA (miRNA)-mRNA network. And the correlation between MIAT and tumor-infiltrating immune cells (TICs) and immunophenoscore (IPS) analysis was analyzed by TIMER and CIBERSORT. Finally, the reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect the expression profiles of MIAT in serum samples.Results: The expression levels of MIAT were notably higher in BC than in normal or adjacent tissues. And MIAT expression could be used as a prognostic indicator of mortality risk in patients with BC in different aspects. Moreover, the enrichment analyses suggested that MIAT was strongly involved in BC immune response. In addition, TIMER database and CIBERSORT analyses indicated that MIAT was significantly correlated with 13 types of TICs (B cells, dendritic cells, neutrophils, CD8 T cells, CD4 memory resting T cells, CD4 memory activated T cells, gamma delta T cells, M1 macrophages, plasma cells, activated NK cells, monocytes, M2 macrophages, activated mast cells). Simultaneously, the IPS analysis implied that the higher the MIAT expression, the better the immunotherapy effect. The ROC curve analysis showed that the area under the curve (AUC) value of MIAT was 0.86 (sensitivity = 87.80%, specificity = 75.61%). And the high MIAT expression in serum was positive related to TNM stage (P = 0.032) and lymph node metastasis (P = 0.028).Conclusion: MIAT may be a valuable noninvasive diagnostic biomarker for BC and is associated with tumor-infiltrating immune cells in tumor microenvironment, suggesting MIAT as a potential target for future treatment of BC.Keywords: lncRNA MIAT, BC, biomarker, immune regulation, tumor-infiltrating, immune cells

Background In recent years, the rate of immunosuppressed patients has increased rapidly. Invasive fungal infections usually occur in these patients, especially those who have had hematological malignances and received chemotherapy. Fusariosis is a rare pathogenic fungus, it can lead to severely invasive Fusarium infections. Along with the increased rate of immune compromised patients, the incidence of invasive Fusarium infections has also increased from the past few years. Early diagnosis and therapy are important to prevent further development to a more aggressive or disseminated infection. Case summary We report a case of a 19-year-old male acute B-lymphocytic leukemia patient with fungal infection in the skin, eyeball, and knee joint during the course of chemotherapy. We performed skin biopsy, microbial cultivation, and molecular biological identification, and the pathogenic fungus was finally confirmed to be Fusarium solani. The patient was treated with oral 200 mg voriconazole twice daily intravenous administration of 100 mg liposomal amphotericin B once daily, and surgical debridement. Granulocyte colony-stimulating factor was administered to expedite neutrophil recovery. The disseminated Fusarium solani infection eventually resolved, and there was no recurrence at the 3 mo follow-up. Conclusion Our case illustrates the early detection and successful intervention of a systemic invasive Fusarium infection. These are important to prevent progression to a more aggressive infection. Disseminate Fusarium infection requires the systemic use of antifungal agents and immunotherapy. Localized infection likely benefits from surgical debridement and the use of topical antifungal agents.

Hiatal hernia repair (HHR) during sleeve gastrectomy (SG) is recommended when hiatal hernia (HH) is found intraoperatively. However, its effect on gastroesophageal reflux disease (GERD) remains controversial. To evaluate the effect of concomitant SG and HHR on GERD in patients with obesity. Web of Science, PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov databases were searched for all studies reporting the efficacy of SG+HHR for patients with obesity and GERD up to March 2021. A total of 18 studies totaling 937 patients met the inclusion criteria. The results of meta-analysis showed that after SG+HHR, there was a significant reduction in GERD symptoms (OR: 0.20; 95% CI: 0.10 to 0.41; P < 0.00001), improvement in esophagitis (OR: 0.12, 95% CI: 0.05 to 0.26, P < 0.001), and decrease in GERD-HRQL (MD: 19.13, 95% CI: −3.74 to 34.51; P=0.01). The incidence of GERD remission after SG+HHR was 68.0% (95% CI: 55.0–80.9%), de novo GERD was 12% (95% CI: 8–16%), and HH recurrence was 11% (95% CI: 4 to 19%). SG+HHR was superior to SG alone in GERD remission (OR: 2.97, 95% CI: 1.78 to 4.95, P < 0.0001). However, there was no significant difference in de novo GERD after SG+HHR compared with SG alone. SG+HHR can positively affect weight loss, GERD resolution, esophagitis reduction, and GERD-HRQL improvement. SG+HHR seems to have a promising future in patients with obesity and GERD. However, further studies based on objective assessment are warranted to evaluate these results better.

Breast cancer (BC) is a molecular diverse disease which becomes the most common malignancy among women worldwide. There are four BC subtypes (Luminal A, Luminal B, HER2‐enriched and Basal‐like) robustly established following gene expression pattern‐based characterization, behave significant differences in terms of their incidence, risk factors, prognosis and therapeutic sensitivity. Thus, there is an urgent need to provide mechanism research, treatment strategies and/or prognosis evaluation based on the patient stratification of BC subtypes. The prostate‐derived ETS factor SPDEF was first identified as an activator of prostate specific antigen, and then, the involvements in many aspects of BC have been proposed. However, the subtype‐specific molecular function of SPDEF in BC and insights into prognostic significance have not been clearly elucidated. This study demonstrated for the first time that SPDEF may play a diversity role in the expression levels, clinicopathologic importance, biological function and prognostic evaluation in BC via bioinformatics and experimental evidence, which mainly depends on different BC subtyping. In summary, our findings would help to better understand the possible mechanisms of various BC subtypes and to find possible candidate genes for prognostic and therapeutic usage.

Objectives The aim of this study was to investigate the electrocardiographic characteristics of ventricular arrhythmias (VAs) originating near the His bundle (HB) and use the R/S ratio in lead III (RIII/SIII ratio) to predict successful ablation of para-Hisian VAs. Background Catheter ablation for idiopathic VAs near the HB is often challenging, and data are limited. Methods The present study included 134 consecutive patients undergoing catheter ablation of para-Hisian VAs. The electrocardiographic characteristics in these patients were retrospectively evaluated with successful ablation and failed ablation. Results Successful ablation was achieved in 115 (85.8%) of the 134 patients. There was no significant difference in QRS duration between the successful and the failed ablation groups. The ablation success rate was significantly lower for para-Hisian VAs with a predominantly positive R wave in lead III than those with a predominantly negative S wave in lead III. The significant factor associated with successful ablation was the RIII/SIII ratio. The RIII/SIII ratio ≤1.1 predicted the successful ablation of para-Hisian VAs with high sensitivity (80.9%) and specificity (94.7%). The RIII/SIII ratio of >1.2 had high sensitivity (100.0%) and specificity (82.8%) to predict the distance Conclusions The RIII/SIII ratio was a helpful predictor of the successful ablation of VAs originating in the vicinity of the HB. This may be useful for planning ablation of para-Hisian VAs and minimizing the risk of inadvertent atrioventricular block.

Biliary atresia (BA) is a challenging liver disease in infancy. Early diagnosis of BA is important for timely hepatoportoenterostomy. We evaluated the age‐specific diagnostic performance of transient elastography (TE) with a liver stiffness measurement (LSM) greater than 7.7 kPa in BA among infants with cholestasis. A total of 61 infants with cholestasis (5‐121 days of age) were enrolled in this prospective follow‐up study; 15 infants were BA. Four age groups were defined (≤30, 31‐60, 61‐90, and 91‐180 days). Picrosirius red staining was performed to quantify the percentage of collagen fibers in liver specimens. The utility of an LSM greater than 7.7 kPa for diagnosis of BA among infants with cholestasis was compared among age groups. In all four groups, TE showed high diagnostic power for BA using the criterion of an LSM greater than 7.7 kPa. Positive predictive values were 100%, 100%, and 100% in the groups aged 30 days or younger, 31 to 60 days, and 61 to 90 days, respectively. Respective negative predictive values were 90.9%, 94.7%, and 100%, and respective diagnostic accuracies were 92.9%, 95.2%, and 100%. The positive predictive value, negative predictive value, and diagnostic accuracy were 100%, 100%, and 100%, respectively, for LSM greater than 8.8 kPa in the group aged 91 to 180 days. The LSM was positively correlated with the percentage of collagen fibers stained by picrosirius red (P = 0.03). Conclusion: In this prospective follow‐up study, TE had good diagnostic accuracy for differentiation of BA from non‐BA cholestasis in infants with cholestasis who were 90 days of age or younger. The LSM was significantly positive correlated with the liver fibrosis status stained by picrosirius red in infants with cholestasis.

Background: SQSTM1/p62, as a selective autophagy receptor, regulates multiple signaling pathways participating in the initiation and progression of tumors. Since metastasis is still a main cause for intrahepatic cholangiocarcinoma (ICC)-associated mortality, this study aimed to explore the mechanism of p62 promoting progression of ICC.Methods: Western blotting and immunohistochemical analysis were conducted to detect the expression level of protein p62 in ICC tissues. Subsequently, loss of function experiments was applied to define the role of p62 in the progression of ICC in vitro and in vivo. Mitochondrial function and mitophagy was evaluated by measuring oxygen consumption rates (OCR) and immunofluorescence detection respectively.Results: Here we identified expression of p62 was significantly upregulated in ICC specimens compared to normal tissue. And we further illustrated that p62 expression was positively correlated with lymph-node metastasis and poor prognosis. Loss of function assays revealed that p62 not only promoted ICC cells proliferation, migration and invasive capacity in vitro, but also induced lung metastasis in xenograft mouse model. Mechanistically, high expression of p62 induced epithelial-mesenchymal transition (EMT) with upregulation of Snail1, Vimentin and down-regulation of E-Cadherin. Moreover, OCR assays and immunofluorescence cell staining demonstrated that the autophagy-dependent function of p62 may play a vital role in maintaining mitochondrial function of ICC by mitophagy.Conclusions: These data provide new evidence and feasible mechanism that abundant p62 expression promote ICC progression, suggesting a promising therapeutic target for anti-metastatic strategies in ICC patients.

Obesity is strongly linked to male infertility. Apoptotic inflammatory response caused by oxidative stress in testicular spermatogenic cells is one of the important causes of obesity-related male infertility. As bioactive peptide is secreted by the pituitary gland, pituitary adenylate cyclase activating polypeptide (PACAP) has a powerful triple role of anti-oxidation, anti-apoptosis, and anti-inflammation, and it is involved in the male reproduction regulation, but the specific mechanism remains unknown. The purpose of this study is to explore the role of PACAP in obesity-related male infertility. In cellular level experiments, mouse spermatocytes (GC-2) were treated with palmitate (PA) to establish an high-fat injury cell model in vitro and then treated with PACAP. In animal-level experiments, C57BL/6 male mice were fed with a high-fat diet (HFD) to induce obesity and subsequently treated with PACAP. The cell mechanism studies show that PACAP selectively binded to the PAC1 receptor to attenuate palmitic acid-induced mouse spermatogenic cell (GC-2) oxidative damage and apoptotic inflammatory response via the PKA/ERK/Nrf2 signaling axis. However, this mechanism was inhibited in GC-2 cells inhibiting the activity of Nrf2. The animal experiment studies show that PACAP treatment ameliorated obesity characteristics, including body weight, epididymal adipose weight, testes/body weight, serum lipids levels, and reproductive hormone levels in vivo. Additionally, PACAP was shown to improve the reproductive function of the obese mice, which was characterized by improved testis morphology and sperm parameters via Keap1/Nrf2/ARE pathway. These beneficial effects of PACAP were abolished in obese mice with testes-specific knockdown of Nrf2. Our data suggested that PACAP could ameliorate fertility in obese male mice and may be a promising candidate drug for obesity-induced male infertility.

The high‐mortality rate of cardiovascular diseases (CVDs) is associated with the myocardial ischemia and reperfusion (I/R). Recent investigations have revealed that microRNAs (miRNAs) exert vital functions in the apoptosis of cardiomyocyte cell. Nevertheless, the potential role of miR‐30a‐5p in the regulation of cardiomyocyte cell apoptosis needs to be illuminated. In the current study, we observed that hypoxia/reoxygenation (H/R) remarkably raised the level of miR‐30a‐5p but reduced the expression of E2F transcription factor 3 (E2F3) in H9c2 cardiomyocytes. In vivo, miR‐30a‐5p was found to be significantly upregulated in the hearts of rats following I/R. Downregulation of miR‐30a‐5p using anti‐miR‐30a‐5p decreased H9c2 cardiomyocytes apoptosis caused by H/R and promoted the proliferation of H9c2 inhibited by H/R. Moreover, E2F3 was a possible target gene of miR‐30a‐5p and upregulation of miR‐30a‐5p reduced the expression level of E2F3 in H9c2 cardiomyocytes. We further identified that E2F3 silencing reversed the effect of anti‐miR‐30a‐5p on the proliferation and apoptosis in H/R treated H9c2 cells. These studies suggested that downregulation of miR‐30a‐5p attenuated the impact of H/R on H9c2 cardiomyocytes through targeting E2F3.

Background To investigate the safety and activity of preoperative pembrolizumab combined with chemoradiotherapy for resectable oesophageal squamous cell carcinoma (ESCC) ( ClinicalTrials.gov number, NCT03792347). Methods Twenty resectable ESCC patients, regardless of programmed death ligand-1 status, received preoperative pembrolizumab with concurrent chemoradiotherapy (PPCT). Preoperative therapy includes carboplatin (area under the curve of 2 mg per milliliter per minute, once a week for 5 weeks), paclitaxel (50 mg/m2, once a week for 5 weeks), radiotherapy (23 fractions of 1.8 Gy, 5 fraction a week) and pembrolizumab (2 mg/kg) on days 1 and 22. Within 4–6 weeks after preoperative therapy, patients underwent surgery. The primary end-point was safety and secondary outcome measures were feasibility, pathologic complete response (pCR) rate and radiographic response. Immune signature of CD8+ T cells was evaluated in surgical specimens using immunohistochemistry and immunofluorescence. Results All patients have received PPCT successfully, except one patient who missed the last dose of chemotherapy due to leukopenia. Grade III and higher adverse events (AEs) were observed in 13 patients (13/20, 65%), and one patient had a grade V AE. The most frequent grade III AE was lymphopenia (12/13, 92%). Eighteen patients underwent surgery within 4–9 weeks after PPCT and the pCR rate was 55.6% (10/18). The percentage of transcription factor 1 positive cells was significantly higher in specimens of pCR group than those of non-pCR group (p value = 0.010). Conclusions PPCT was safe, did not delay surgery, and induced a pCR in 55.6% of resected tumours. A phase II multicentre study is undergoing for further confirmation of efficacy (NCT04435197).

Abnormalities in CD4+ T cell (Th cell) differentiation play an important role in the pathogenesis of viral myocarditis (VMC). Our previous studies demonstrated that activation of the cholinergic anti-inflammatory pathway (CAP) alleviated the inflammatory response. In addition, we observed that right cervical vagotomy aggravates VMC by inhibiting CAP. However, the vagus nerve’s effect on differentiation of CD4+ T cells has not been studied in VMC mice to date. In this study, we investigated the effects of cervical vagotomy and the α7nAChR agonist pnu282987 on CD4+ T cell differentiation in a murine myocarditis model (BALB/c) infected with coxsackievirus B3 (CVB3). Splenic CD4+ T cells from CVB3-induced mice obtained and cultured to investigate the potential mechanism of CD4+ T cell differentiation. Each Th cell subset was analyzed by flow cytometry. Our results showed that right cervical vagotomy increased proportions of Th1 and Th17 cells and decreased proportions of Th2 and Treg cells in the spleen. Vagotomy-induced upregulation of T-bet, Ror-γ, IFN-γ, and IL-17 expression while downregulating the expression of Gata3, Foxp3, and IL-4 in the heart. In addition, we observed upregulated levels of proinflammatory cytokines, aggravated myocardial lesions and cellular infiltration, and worsened cardiac function in VMC mice. Pnu282987 administration reversed these outcomes. Furthermore, vagotomy inhibited JAK2-STAT3 activation and enhanced NF-κB activation in splenic CD4+ T cells. The CD4+ T cell differentiation was related to JAK2-STAT3 and NF-κB signal pathways. In conclusion, vagus nerve modulates the inflammatory response by regulating CD4+ T cell differentiation in response to VMC.

Graphical Abstract Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with poor prognosis. In this study, we aimed to investigate the potential mechanism of latent membrane protein 1 (LMP1)-mediated tumorigenesis and provide a novel therapeutic strategy for targeting the EBV DNA genome. We found that LMP1 upregulated the expression of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1β (PGC1β) through activation of nuclear factor-κB (NF-κB). Furthermore, the activated PGC1β upregulated the expression of 8-oxoguanine DNA glycosylase (OGG1) through the coactivation of nuclear respiratory factor 1 (NRF1) and GA-binding protein α (GABPα), preventing reactive oxygen species (ROS)-mediated base incision in the EBV genome and favoring its survival. Interruption of hexokinase domain component 1 (HKDC1) by either shRNA or Tf-D-HKC8 peptide suppressed the interaction of HKDC1 with voltage-dependent anion channel 1 (VDAC1), triggering mitochondrial dysfunction and excessive generation of ROS, thus resulting in EBV suppression through ROS-mediated DNA damage. Suppression of the EBV genome inhibited the expression of the LMP1/PGC1β/HKDC1/OGG1 signaling pathway, forming a positive feed forward loop for the generation of ROS, hence inhibiting the EBV genome and subsequent EBV-associated tumor development. We concluded that LMP1 triggers EBV-associated tumorigenesis through activation of the PGC1β pathway. This study provided a novel therapeutic strategy for the treatment of EBV-associated tumors by targeting HKDC1. Supplementary Information The online version contains supplementary material available at 10.1007/s12015-020-10112-8.

Objectives. Immune checkpoint inhibitors (ICI) combined with radiotherapy (RT) have emerged as a breakthrough therapy in the treatment of various cancers. The combination has a strong rationale, but data on their efficacy and safety are still limited. Hence, we comprehensively searched the database and performed this study to elucidate the clinical manifestations of this combined strategy. Methods. We performed a meta-analysis of randomized trials that compared ICI plus RT with placebo plus RT or ICI alone for the treatment of advanced nonsmall-cell lung cancer (NSCLC) and prostate cancer. The outcomes included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and treatment-related adverse events. A fixed-effects or random-effects model was adopted depending on between-study heterogeneity. Results. Three trials involving 1584 patients were included. ICI plus RT was significantly associated with improvement of OS (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.70–0.94,P=0.004), PFS (HR = 0.64; 95% CI 0.56–0.72,P<0.00001), and DCR (relative risk [RR] = 1.38; 95% CI 1.03–1.84,P=0.03). A significant predictor for PFS with the combination of ICI and RT was age, as a significant improvement in PFS (HR = 0.49; 95% CI 0.37–0.64,P<0.00001) was observed in NSCLC patients aged under 65 years. In safety analyses, patients receiving ICI plus RT had a significantly higher incidence of dyspnea (RR = 2.43; 95% CI 1.16–5.08,P=0.02) and pneumonitis of grade 3 or higher (RR = 2.78; 95% CI 1.32–5.85,P=0.007). Conclusion. The combination of ICI and RT was associated with improved OS, PFS, and DCR. Patients under 65 years will be the dominant beneficiaries. However, the incidence of dyspnea and pneumonia of grade 3 or higher also increased, which deserves our vigilance.

Background/purpose Anastomotic stricture (AS) is a major morbidity of patients with esophageal atresia (EA) after surgical reconstruction. Our study determined the risk factors of AS after EA reconstruction. The therapeutic efficacy and complications of esophageal dilatation for children with AS were also evaluated. Methods Forty children treated for EA between January 2008 and December 2018 were included in this retrospective analysis. Esophageal dilatation was performed when AS was diagnosed. The therapeutic effect of esophageal dilatation was determined based on nutritional status, as assessed by the weight-for-age z-score. Results Sixteen EA patients developed AS. A gap >1.5 cm between the esophageal pouches (P = 0.02) in patients with EA and type A EA was a risk factor for developing AS. A mean of 7.7 sessions of esophageal dilatation were performed per patient, and no complications occurred. The nutritional status of EA children with AS after dilatation was not inferior to that of the children without AS at the 6-month follow-up. Conclusions A gap >1.5 cm between the esophageal pouches and type A EA are risk factors for AS after esophageal reconstruction. Esophageal dilatation is both safe and effective for managing strictures and improves nutritional status in EA children with AS.

Background The growth- and plasticity-associated protein-43 (GAP43) is biasedly expressed in indigestive system and nervous system. Recent study has shown that GAP43 is responsible for the development of neuronal growth and axonal regeneration in normal nervous tissue, while serves as a specific biomarker of relapsed or refractory neuroblastoma. However, its expression pattern and function in digestive system cancer remains to be clarified. Methods In this study, we examined the GAP43 status with qRT-PCR and bisulfite genomic sequencing in colorectal cancer (CRC). We investigated the effect of overexpressed GAP43 in CRC cells with RNA-seq. The RNA-seq data was analyzed with DAVID and IPA. Results GAP43 was downregulated in CRC compared to the adjacent tissues. DNA methylase inhibitor 5-Aza-CdR treatment could significantly induce GAP43, indicated that the silencing of GAP43 gene in CRC is closely related to DNA methylation. Bisulfite genomic sequencing confirmed the promoter methylation of GAP43 in CRC. To explore the transcriptional alterations by overexpressed GAP43 in CRC, we performed RNA-seq and found that upregulated genes were significantly enriched in the signaling pathways of ABC transporters and ECM-receptor interaction, while downregulated genes were significantly enriched in Ribosome signaling pathway. Further Ingenuity Pathway Analysis (IPA) showed that EIF2 signaling pathway was significantly repressed by overexpression of GAP43. Conclusion Our findings provide a novel mechanistic insight of GAP43 in CRC. Transcriptome profiling of overexpressed GAP43 in CRC uncovered the functional roles of GAP43 in the development of human CRC.

To evaluate the changes in left ventricular myocardial function in patients with colorectal cancer undergoing chemotherapy with mFOLFOX6 (oxaliplatin + 5-fluorouracil + calcium folinate) using three-dimensional speckle-tracking echocardiography (3D-STE). Data were collected from 30 patients diagnosed with colorectal cancer in our hospital treated with mFOLFOX6. We used 3D-STE to measure the following parameters of left ventricle function: global longitudinal strain (GLS), global area strain (GAS), global circumferential strain (GCS), global radial strain (GRS), and left ventricular twist (LVtw). Myocardial composite index (MCI) was calculated from measured values (MCI = GLS × LVtw). The above listed parameters were compared before and after chemotherapy. Receiver operating curves (ROC) were prepared for each parameter and analyzed to identify correlations among MCI, LVEF, GLS, and cTnT. Compared with the pre-chemotherapy state, the absolute values of MCI, LVtw, GLS, GAS, GCS, and GRS decreased with increasing cumulative doses of chemotherapeutic drugs. The absolute values of GAS, GLS, MCI, and LVtw decreased after the first cycle of chemotherapy (P