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Post-ESD esophageal stricture especially after wholly circumferential ESD remains an unresolved issue without ideal strategies. Our initiative novel self-control stricture-preventing water balloon may be an alternative.Patients with esophageal neoplastic lesions expected to result in a whole circular mucosa defect after esophageal ESD from February 2018 to August 2020 were included in the study. We used a novel self-control stricture-preventing water balloon combined with oral prednisolone as preventive strategy for the enrolled patients.Thirty-seven patients (9 females and 28 males, patients aged 52 to 82 years) finished the 12-week treatment including steroid treatment and balloon placement. The median size of longitudinal diameter was 7 cm (range from 4 to 14 cm). All the lesions achieved curative resection and the median procedure time was 110 min (range 50 to 180 min). Balloons were found migration in 4 patients. As a result, there were 3 patients (8.1%) experienced stricture. Generally, patients could tolerate to balloons, only with mild uncomfortableness, such as occasional sore throat, cough, and retrosternal pain. In addition, during the follow-up period, no significant adverse events associated to oral steroid administration were observed and no recurrence was found.Our novel self-control stricture-preventing water balloon based on the oral steroid therapy is effective and safe. This strategy well prevents esophageal stricture after complete circumferential ESD.

Endoscopic submucosal dissection (ESD) of superficial squamous epithelial lesions at the pharynx is still a challenge for most endoscopists due to the limited working space and inexperience. The aim of this study was to evaluate the outcomes of ESD for superficial pharyngeal carcinomas.A total of 30 superficial carcinomas at the pharynx in 27 consecutively treated patients were included. The rates of en bloc resection, complete resection, major complications, local recurrence, and metastasis were evaluated retrospectively as the therapeutic outcomes.The en bloc and complete resection rates were respectively 100% and 93.3%. No bleeding, perforation, or dyspnea during or after the ESD procedure occurred. There was 1 patient with emphysema. The median hospital stay was 6 days. During the follow-up period of 1 year, 1 patient had neck lymph node metastasis.ESD is effective and safe for resection of superficial carcinomas at the pharynx, with a high complete resection rate and favorable outcomes.

Background & Aims: Cisplatin (DDP)-based chemotherapy is commonly adopted as the first-line treatment for patients with oesophageal squamous cell carcinoma (OSCC), but the high rate of drug resistance limits its clinical application, and the underlying mechanisms remain unclear. The aims of this study is to elucidate the role of abnormal signal transmission and metabolism in chemoresistance of OSCC under oxygen-deprived microenvironment, and try to find targeted drugs that enhance the sensitivity of DDP chemotherapy. Methods: Upregulated genes in OSCCs were determined by RNA-seq, public database, IHC, rt-qPCR and Western blotting (WB). The clinicopathological significance of IGF1R, ASS1, PYCR1 in OSCC were analyzed using Tissue Micriarray (TMA). Metabolic abnormalities were determined by untargeted metabolomics analysis. The DDP resistance role of IGF1R, ASS1, PYCR1 in OSCC was investigated in vitro and in vivo. Results: Generally, tumor cells are in a hypoxic microenvironment. By genomic profiling, we identified IGF1R as one of RTKs, were upregulated in OSCCs under low oxygen condition. Clinically, enhanced IGF1R expression was associated with higher stages and poor prognosis in OSCC patients, and it’s inhibitor linsitinib, showed synergistic effects on DDP therapy in vivo and in vitro.Since hypoxia conditions frequently lead to metabolic reprogramming, we further integrated metabolomic analysis to find that abnormal IGF1R pathways promoted the expression of metabolic enzymes argininosuccinate synthetase 1 (ASS1) and pyrroline-5-carboxylate reductase 1 (PYCR1) via transcriptional activity of cMYC. Deeply, enhanced expression of ASS1 promoted arginine metabolism for biological anabolism, whereas PYCR1 activated proline metabolism for redox balance, which maintained the proliferation ability of OSCC cells during DDP treatment under hypoxia condition. Conclusions: Enhanced expression of ASS1 and PYCR1 via IGF1R pathways rewired arginine and proline metabolism, promoting DDP resistance in OSCC under low oxygen conditions. Linsitinib targeting IGF1R signaling may provides promising combination therapy options for OSCC patients with DDP resistance.

In this paper we propose a novel clustering method for functional data based on the principal curve clustering approach. By this method functional data are approximated using functional principal c...

Background: Since lung cancer (LC) has a poor prognosis worldwide, this study focuses on constructing the immune-related lncRNAs (IRlncRNAs) model for improving survivability among lung cancer patients.Methods: This work identified immune-related differentially expressed genes (IRDEGs) in cancer compared with healthy tissues based on The Cancer Genome Atlas (TCGA)-derived expression profiles. Prognostic genes were later screened by univariate Cox regression, thereafter, multivariate Cox regression was performed to establish a prognostic risk model. After evaluating risk scores of all cases, the risk model was used to perform a clinical correlation analysis.Results: This work established a 6 immune-related genes (IRGs)-based signature. It suggested the poor survival of high-risk patients, with the area under the receiver operating characteristic (ROC) curve (AUC) value being 0.776. Besides, high-risk IRGs like IPO5P1 and AC090559.1 were associated with significant malignant clinical manifestations. Further, IRlncRNAs were related to cell cycle and DNA damage repair through KEGG enrichment analysis.Conclusion: Our as-constructed signature might be the model to effectively predict LC survival. Moreover, tumor immunity analysis helped to develop efficient clinical treatments.

Background Rheumatoid arthritis (RA) is an inflammatory disease, which seriously affects human joints. This study aimed to detect the changes in the expression of long non-coding RNA growth arrest-specific transcript 5 (GAS5) in peripheral blood mononuclear cells (PBMCs) derived from patients with RA and healthy controls (HC), as well as analyze the correlation between GAS5 and clinical indicators of RA. Also, the role and mechanism of GAS5 in regulating the AMP-activated protein kinase (AMPK) pathway in RA was further assessed. Methods The PBMCs were isolated from the RA patients. Next, GAS5 expression was detected in RA PBMCs by quantitative real-time polymerase chain reaction, and its diagnostic value on RA was determined by receiver operating characteristic curves (ROC). The levels of interleukin (IL)-6 and IL-17 were detected via enzyme-linked immunosorbent assay. The expressions of total and phosphorylated AMPK as well as p38MAPK were determined with Western blot. Results GAS5 was down-regulated in RA PBMCs, and consequently serves as a potential diagnostic marker for RA (sensitivity, 90%; specificity, 80%; area under the curve, 0.89). Further, GAS5 negatively regulated erythrocyte sedimentation rate, C-reactive protein, Disease Activity Score of 28 joints and antibodies against cyclic citrullinated peptide, as well as the IL-6 and IL-17 levels of RA PBMCs. Similarly, GAS5 was observed to activate the AMPK pathway. Conclusion GAS5 activated the AMPK pathway, while it negatively regulated the expression of cytokines IL-6 and IL-17.

Background Esophageal squamous cell carcinoma (ESCC) is notorious for the rapid progression especially early tumor metastasis due to the unclear mechanism. Recently, ETV5 attracts much attention for its potential role as an oncogenic transcription factor involved in multiple cancers. However, no one reported the mechanism behind the association between ETV5 expression and Esophageal squamous cell carcinoma (ESCC) progression. Therefore, in this study, we aimed to investigate the role of ETV5 in ESCC. Methods The Cancer Genome Atlas (TCGA) and GEO database was used to explore ETV5 expression in ESCC. ECA109, KYSE150 and TE1 cell lines were used in the experiments. The Cell Counting Kit 8 (CCK8), migration, invasion, wound healing assays were exerted to evaluate proliferation, migration and invasion of ESCC cells. RNA sequencing was performed to find downstream genes regulated by ETV5. Real-time PCR, Western blotting, Chromatin immunoprecipitation (CHIP) and Dual luciferase reporter assays were used to assess the underlying mechanism. Immunohistochemistry was used to evaluate the relationship between ETV5 expression, clinicopathological parameters and patient prognosis. Tumor metastasis was investigated in BALB/c nude mice. Results ETV5 was observed upregulated in ESCC both from online database and our ESCC tissues and ETV5 was associated with tumor staging. Knockdown of ETV5 or its downstream genes SKA1 and TRPV2 significantly suppress ESCC cells migration and invasion, respectively. Additionally, in vivo study showed knockdown of ETV5 inhibited tumor metastasis. Further experiments unveiled ETV5 could transcriptionally upregulate the expression of SKA1 and TRPV2 and further activate MMPs in ESCC progression. Conclusion ETV5 promoted metastasis of ESCC by activating MMPs through augmenting the transcription of SKA1 and TRPV2. ETV5 was likely to be a novel diagnostic marker and therapeutic target in ESCC treatment.

Objectives To investigate why patients with terminal illness and their families in Shanghai choose the hospice ward and their decision-making process. Methods This was a mixed-method study consisting of a cross-sectional survey and a descriptive qualitative study. Medical decision-makers for patients hospitalized in hospice wards were recruited between September 2019 and July 2021. A medical decision-maker is a family member who makes medical decisions for a patient. All 146 participants completed a self-developed 10-item questionnaire that included five items about their demographic characteristics and five items about the decision-making process. The semi-structured interviews were conducted with nine participants to understand the family’s decision-making process when they chose a hospice ward. The interviews were analyzed using qualitative content analysis. Results The mean age of the 146 participants was 57.6 years old. Of the decision-makers, 56.85% were the patients’ children. Family-dominated discussions involving other family members were the main decision-making mode (84.93%). Patient participation in the decision-making process was reported in 43.15% of families. The participation of doctors (17.81%) and nurses (2.05%) were reported in a small number of families. The most common reason for choosing the hospice ward was the inability to find any other hospital for the patients (82.19%). The most common ways to learn about the service were neighbors and friends (38.36%) and social media (28.77%). Two themes and six categories emerged from the interviews. The first theme was reasons for choosing hospice wards. The reasons included being unable to care for the patients at home, staying in a hospice ward could reduce the psychological stress for home care, being unable to be admitted into tertiary/secondary hospitals, and thinking a hospice ward was a suitable place for the family. The second theme was the decision process of choosing a hospice ward. This theme included the following two categories, i.e., ways to learn about the hospice ward and family-discussion decision mode. Conclusion To most families having dying patients, a hospice ward is a reasonable and balanced choice after the families experience huge care stress and practical difficulties. The participation of patients should be encouraged in the family discussion so that their wishes can be known. More efforts will be needed to guide the families with dying patients to make reasonable medical choices. Social media can be a good way to improve public awareness of hospice services in the future. Meanwhile, healthcare providers should be more involved in the decision-making process.

Hyperuricaemia, which results from the overproduction and underexcretion of uric acid, has been linked with chronic renal dysfunction, cardiovascular diseases, diabetes and metabolic syndrome. However, available clinical drugs cannot simultaneously target the production and excretion of uric acid. Norathyriol, a natural xanthone, was expected to have the dual actions. We previously reported that norathyriol possessed potent anti-hyperuricaemic activity related to the inhibition of uric acid production. Here, we investigated the uricosuric actions in hyperuricaemic animals and explored the possible molecular mechanisms associated with renal urate transporters and xanthine oxidase (XO). The results showed that norathyriol (0.5–4.0 mg/kg) dose- and time-dependently decreased serum urate levels in uric acid-induced hyperuricaemic mice and markedly increased the fractional excretion of urate in oxonate-induced hyperuricaemic rats, demonstrating a promotion of urate excretion in the kidney. Further evidence showed that norathyriol markedly increased renal mRNA and protein expression of the secretory organic anion transporter 1 (OAT1) in hyperuricaemic mice and strengthened its transport function in vitro. Moreover, norathyriol also upregulated the mRNA expression of the secretory transporters OAT3, ATP-binding cassette transporter G2 and multidrug resistance protein 4, but not their protein expression. Changes in the expression of the reabsorptive transporters were not observed. This is the first report that norathyriol has uricosuric effects by targeting OAT1. Moreover, norathyriol significantly inhibited XO activity in an uncompetitive manner. Taken together, these findings suggest that norathyriol has the potential to be developed as a new anti-hyperuricaemic agent with dual actions that activate OAT1 and inhibit XO activity.

Using the word as a basic unit may undermine Chinese event detection model’s performance because of the inaccurate word boundaries generated by segmentation tools. Besides, word embeddings are contextual independent and cannot handle the polysemy of event triggers, which may prevent us from obtaining the desired performance. To address these issues, we propose a BiLSTM-CRF (Bidirectional Long Short-Term Memory Conditional Random Field) model using contextualized representations, which regards event detection task as a character-level sequence labeling problem and uses contextualized representations to disambiguate event triggers. Experiments show that our proposed method sets a new state-of-the-art, which proves Chinese characters could replace words for the Chinese event detection task. Besides, using contextualized representation reduces the false positive case, which verifies that this kind of representation could remedy the weakness of the word embedding technique. Based on the results, we believe that character-level models are worth exploring in the future.

Cancer cells develop under nutrient and oxygen deficient microenvironment caused by insufficient vascularization. Reprogramming metabolism meets the needs of the rapid growth of cancer cells in nutrient stress conditions. But the precise mechanism of metabolic abnormalities in esophageal squamous cell carcinoma (ESCC) remains largely unclear. Using omics technology, we measured the changes of metabolic enzymes and pathways on ESCC under the microenvironment of hypoxia and nutrient deficiency. Consequently, the expression of argininosuccinate synthetase 1 (ASS1) and pyrroline-5-carboxylate reductase 1 (PYCR1) was enhanced and may promoted the proliferation and migration of ESCC by its catalyzed metabolites. Clinically, high levels of ASS1 and PYCR1 were significantly associated with advanced stages and metastasis, even early stage compared to intraepithelial neoplasia. In mechanism, IGF1R regulated ASS1 and PYCR1 by affecting IGF1R - Ras/MAPK - c-MYC axis. In vivo, ASS1 and PYCR1 could promote tumor growth and chemotherapeutic resistance. In summary, enhanced ASS1 and PYCR1 induces ESCC tolerance to nutrient stress and maintains cancer development and IGF1R-cMYC axis is the key factor upregulating ASS1 and PYCR under harsh conditions. The study also provides a molecular aspect for developing biomarkers of ESCC and therapeutic benefits of targeting IGF1R/ASS1/PYCR1 axis. Funding Information: This study was supported by grants from The Top- level Clinical Discipline Project of Shanghai Pudong (PWYgf2018-04), National Natural Science Foundation of China (82073224, 82072684 and 81872351) and Shanghai Committee of Science and Technology (18140900100) Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: This study was approved by the institutional review board of Shanghai East Hospital, School of Medicine, Tongji University. The in vivo study was approved by the animal care and use committee of Tongji University.

OBJECTIVE: To investigate the effects of etomidate on electrophysiological properties and nicotinic acetylcholine receptors (nAChRs) of ventral horn neurons in the spinal cord. METHODS: The spinal cord containing lumbosacral enlargement was isolated from 19 neonatal SD rats aged 7-12 days. The spinal cord were sliced and digested with papain (0.18 g/30 mL artificial cerebrospinal fluid) and incubated for 40 min. At the ventral horn, acute mechanical separation of neurons was performed with fire-polished Pasteur pipettes, and perforated patch-clamp recordings combined with pharmacological methods were employed on the adherent healthy neurons. In current-clamp mode, the spontaneous action potential (AP) of the ventral horn neurons in the spinal cord was recorded. The effects of pretreatment with different concentrations of etomidate on AP recorded in the ventral horn neurons were examined. In the voltage-clamp mode, nicotine was applied to induce inward currents in the ventral horn neurons, and the effect of pretreatment with etomidate on the inward currents induced by nicotine were examined with different etomidate concentrations, different holding potentials and different use time. RESULTS: The isolated ventral horn neurons were in good condition with large diverse somata and intact processes. The isolated spinal ventral horn neurons (n=21) had spontaneous action potentials, and were continuously perfused for 2 min with 0.3, 3.0 and 30.0 μmol/L etomidate. Compared with those before administration, the AP amplitude, spike potential amplitude and overshoot were concentration-dependently suppressed (P < 0.01), and spontaneous discharge frequency was obviously reduced (P < 0.01, n=12). The APs of the other 9 neurons were completely abolished by etomidate at 3.0 or 30 μmol/L. At the same holding potential (VH=-70 mV), pretreatment with 0.3, 3.0 or 30.0 μmol/L etomidate for 2 min concentration-dependently suppressed the current amplitude induced by 0.4 mmol/L nicotine (P < 0.01, n=7). At the holding potentials of - 30, - 50, and - 70 mV, pretreatment with 30.0 μmol/L etomidate for 2 min voltage-dependently suppressed the current amplitude induced by 0.4 mmol/L nicotine (P < 0.01, n=6 for each holding potential). During the 6 min of 30.0 μmol/L etomidate pretreatment, the clamped cells were exposed to 0.4 mmol/L nicotine for 4 times at 0, 2, 4, and 6 min (each exposure time was 2 s), and the nicotinic current amplitude decreased gradually as the number of exposures increased. But at the same concentration, two nicotine exposures (one at the beginning and the other at the end of the 6 min pretreatment) resulted in a significantly lower inhibition rate compared with 4 nicotine exposures (P < 0.01, n=6). CONCLUSION: etomidate reduces the excitability of the spinal ventral neurons in a concentration-dependent manner and suppresses the function of nAChR in a concentration-, voltage-, and use-dependent manner.

With the advancement in endoscopic technology, the discovery of novel endoscopic techniques such as endoscopic full-thickness resection (EFTR) provides new contents for natural orifice transluminal endoscopic surgery (NOTES) and endoscopic therapeutic options for patients with gastrointestinal lesions. Here, we present transcolonic endoscopic appendectomy as an expansion of full thickness resection with extraluminal dissection of the appendix for minimally invasive treatment of the sessile serrated lesions (SSLs) deeply involving the appendiceal orifice; final closure is done by endoloop and clip placement. The procedure was successful in four patients with good follow-up results at the 3 months colonoscopic control. Generally, transcolonic endoscopic appendectomy extends endoscopic resection technique and will promisingly replace combined endoscopic and laparoscopic surgery technique. This technique should be studied further. SSLs are colorectal lesions with malignant potential1 and should be removed as accurately as possible.2 In dilemma, more than half of the appendiceal adenomas are SSLs3 4 and therapeutic methods are controversial: endoscopic resection, extended laparoscopic appendectomy or combined laparoscopic appendectomy is traditionally optional.1 Surgical resection remains the standard and endoscopic resection is sometimes performed as an alternative to surgical intervention. However, conventional endoscopic resection of SSLs involving the appendiceal orifice has very critical limitations: endoscopic resection into the appendiceal orifice deeply itself carries a risk of appendicitis and it cannot guarantee a negative deep margin for lesions growing into the lumen of the appendix.2 To overcome these disadvantages, we present a novel NOTES technique, transcolonic endoscopic appendectomy, for the SSL involving the appendiceal orifice. This technique takes advantage of EFTR technique, which includes the endoscopic full-thickness incision and defect closure techniques. Here, we report a series of patients with the SSLs deeply involving the appendiceal orifice removed by transcolonic endoscopic appendectomy technique (figure 1). Patient demographics, procedure details, outcomes, histology and follow-up after …

Anorectal malignant melanoma (ARMM) is a rare disease accounting for less than 1% of primary anorectal malignancies. Here we first present a case of early primary anorectal malignant melanoma completely resected by endoscopic submucosal dissection (ESD). A 43-year-old woman visited our hospital because of suspected anal melanoma found by routine colonoscopy in her local hospital. Following series of tests including CT, MRI, and whole-body PET-CT did not show any evidence of metastasis. The lesion was removed by the method of ESD in en bloc and no delayed bleeding or perforation occurred. The result of histopathologic examinations confirmed to be malignant melanoma. No recurrence or distant metastases were found during follow-up time (the latest follow-up was 2 years after ESD). The present case showed endoscopic submucosal dissection that can be an effective and safe alternative treating early primary anorectal malignant melanoma.

Gaussian process regression (GPR) has been shown to be a powerful and effective non- parametric method for regression, classification and interpolation, due to many of its desirable properties. However, most GPR models consider univariate or multivariate covariates only. In this paper we extend the GPR models to cases where the covariates include both functional and multivariate variables and the response is multidimen- sional. The model naturally incorporates two different types of covariates: multivari- ate and functional, and the principal component analysis is used to de-correlate the multivariate response which avoids the widely recognised difficulty in the multi-output GPR models of formulating covariance functions which have to describe the correla- tions not only between data points but also between responses. The usefulness of the proposed method is demonstrated through a simulated example and two real data sets in chemometrics.

Ras‑associated protein 1A (Rap1A) is a member of the Ras subfamily of small GTP‑binding proteins and is found to promote metastasis in several types of cancer. However, the functional role and molecular mechanism of action in Rap1A in esophageal squamous cell carcinoma (ESCC) is not fully understood. In the present study, Rap1A was found to be upregulated in ESCC tissues and its expression was correlated with cancer stage. Functional studies revealed that Rap1A could promote ESCC metastasis by stimulating cell migration and invasion in vivo and in vitro. Further study indicated that the transcriptional factor SP1 increased Rap1A expression via promoter binding and transcription activation. Furthermore, Rap1A promoted epithelial‑to‑mesenchymal transition, possibly through the AKT signaling pathway. Hence, the findings of the present study indicated that Rap1A may be a potential prognostic marker or therapeutic target for ESCC.

We performed this study to better elucidate the correlations between vascular endothelial growth factor (VEGF) gene polymorphisms and congenital heart diseases (CHD). Eligible articles were searched in PubMed, Medline, Embase and CNKI. Eighteen studies were finally included in our meta-analysis. A significant association with the risk of CHD was detected for the rs1570360 polymorphism in additive comparison in overall analyses. Further subgroup analyses according to ethnicity of study participants and type of disease demonstrated that the rs833061 polymorphism was significantly correlated with the risk of CHD in Asians under additive genetic model, and the rs3025039 polymorphism was significantly correlated with the risk of Tetralogy of Fallot (TOF) in dominant, recessive and allele models. In conclusion, our findings indicated that rs1570360 and rs833061 polymorphisms may affect the risk of CHD. In addition, the rs3025039 polymorphism may serve as a genetic biomarker of TOF.

Microtubule (MT) regulation is involved in both neuronal function and the maintenance of neuronal structure, and MT dysregulation appears to be a general downstream indicator and effector of age‐related neurodegeneration. But the role of MTs in natural aging is largely unknown. Here, we demonstrate a role of MT regulators in regulating longevity. We find that loss of EFA‐6, a modulator of MT dynamics, can delay both neuronal aging and extend the lifespan of C. elegans. Through the use of genetic mutants affecting other MT‐regulating genes in C. elegans, we find that loss of MT stabilizing genes (including ptrn‐1 and ptl‐1) shortens lifespan, while loss of MT destabilizing gene hdac‐6 extends lifespan. Via the use of tissue‐specific transgenes, we further show that these MT regulators can act in the nervous system to modulate lifespan. Through RNA‐seq analyses, we found that genes involved in lipid metabolism were differentially expressed in MT regulator mutants, and via the use of Nile Red and Oil Red O staining, we show that the MT regulator mutants have altered fat storage. We further find that the increased fat storage and extended lifespan of the long‐lived MT regulator mutants are dependent on the DAF‐16/FOXO transcription factor. Our results suggest that neuronal MT status might affect organismal aging through DAF‐16‐regulated changes in fat metabolism, and therefore, MT‐based therapies might represent a novel intervention to promote healthy aging.