The estrogen/miR-338-3p/ADAM17 axis enhances the viability of breast cancer cells via suppressing NK cell's function.

Natural killer (NK) cells are the critical elements of the innate immune response and implicated in rapidly recognizing and eliminating cancer cells. However, the tumor-suppressive ability of NK cells is often impaired in several cancer types. The critical roles of microRNAs have been elucidated by increasing evidences, while the regulation of miR-338-3p in anti-tumor activation of NK cells and its relationship with estrogen in breast cancer (BC) are still confusing. Here, miR-338-3p level was found to be significantly downregulated in BC tissues and estrogen receptor positive (ER+ ) cells, this difference was more obvious in ER+ patients or BC patients at advanced stage (TNM III and IV). MiR-338-3p level was shown to be downregulated by 17ß-estradiol in BC cells (MDA-MB-231 cells and MCF-7) in vitro. MiR-338-3p overexpression decreased disintegrin and metalloprotease-17 (ADAM17) secretion in MDA-MB-231 (ER- ) and MCF-7 (ER+ ) cells. In addition, miR-338-3p overexpression or treatment with anti-ADAM17 antibody could down-regulate granzyme B, CD16, and NKG2D in NK cells, which was reversed by human recombinant ADAM17. Furthermore, these educated NK cells could promote the viability of MDA-MB-231 or MCF-7 cells. Taken together, our results demonstrate that miR-338-3p was negatively regulated by estrogen in BC cells, impairing NK cell's activity by the up-regulation of ADAM17, and conversely promoted the viability of BC cells. Therefore, the estrogen/miR-338-3p/ADAM17 axis is critically implicated in BC pathogenesis and may provide potential targets for BC diagnosis and treatment.

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

Adjuvant albumin-bound paclitaxel combined with S-1 vs. oxaliplatin combined with capecitabine after D2 gastrectomy in patients with stage III gastric adenocarcinoma: a phase III multicenter, open-label, randomized controlled clinical trial protocol.

BACKGROUND: Surgery is the only treatment option for operable gastric cancer. The CLASSIC and ACTS-GC studies showed that the 5-year overall survival (OS) of patients with stage III gastric cancer undergoing D2 gastrectomy is still very low. Whether adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) combined chemotherapy is more effective than the XELOX standard adjuvant chemotherapy in patients with stage III gastric cancer has not been confirmed. METHODS: This is a multicenter, open-label, phase III clinical study. In this trial, 616 patients with locally advanced stage III gastric cancer that underwent curative D2 radical surgery and achieved R0 are planned to be included. Patients will be randomized 1:1 to nab-paclitaxel combined with S-1 (AS) vs. oxaliplatin combined with capecitabine (XELOX). XELOX group: Patients assigned to the XELOX group received eight 3-week cycles of oral capecitabine (1000 mg/m2) twice daily on days 1-14 of each cycle plus intravenous oxaliplatin 130 mg/m2 on day 1 of each cycle. AS group: AS group received eight 3-week cycles of oral S-1 (80-120 mg) (< 1.25 m2, 40 mg; 1.25 to < 1.5 m2, 50 mg; and > 1.5 m2, 60 mg) twice daily on days 1-14 plus intravenous nab-paclitaxel 120 mg/m2 on days 1 and 8 of each cycle. The primary endpoint was the 3-year disease-free survival (3-year-DFS) defined as the time from randomisation to the time of recurrence of the original gastric cancer, development of a new gastric cancer, or death from any cause. The secondary endpoints were the overall survival, (defined as the time from the date of randomisation to date of death from any cause) and safety (any adverse event). DISCUSSION: Compared with previous studies, this study includes nab-paclitaxel based on S-1 adjuvant chemotherapy, which is expected to achieve better efficacy and lower toxicity than the standard treatment. This study is the first clinical study to evaluate the safety and efficacy of nab-paclitaxel combined with S-1 in patients with stage III gastric cancer after D2 radical resection. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov, registration number: NCT04135781 , on October 20th, 2019.

Global profile of tRNA-derived small RNAs in gastric cancer patient plasma and identification of tRF-33-P4R8YP9LON4VDP as a new tumor suppressor.

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) have been found to play important roles in the occurrence and development of cancers. However, the tsRNA profile in gastric cancer is unknown. In this study, we aimed to identify the global tsRNA profile in plasma from gastric cancer patients and elucidate the role of tRF-33-P4R8YP9LON4VDP in gastric cancer. Differentially expressed tsRNAs in the plasma of gastric cancer patients and healthy controls were investigated using RNA sequencing. The expression levels of tRF-33-P4R8YP9LON4VDP in the plasma of gastric cancer patients, healthy controls and gastric cancer cell lines were first detected by quantitative reverse transcription-polymerase chain reaction. The effects of tRF-33-P4R8YP9LON4VDP overexpression or downregulation in gastric cancer cells on proliferation, migration, apoptosis, and cell cycle were analyzed using the Cell Counting Kit-8, scratch assay, Transwell assay, and flow cytometry, respectively. There were 21 upregulated and 46 downregulated tsRNAs found in plasma from gastric cancer patients. The significantly upregulated tsRNAs included tRF-18-S3M83004, tRF-31-PNR8YP9LON4VD, tRF-19-3L7L73JD, tRF-33-P4R8YP9LON4VDP, tRF-31-PER8YP9LON4VD, tRF-18-MBQ4NKDJ, and tRF-31-PIR8YP9LON4VD. The significantly downregulated tsRNAs included tRF-41-YDLBRY73W0K5KKOVD, tRF-18-07QSNHD2, tRF-28-86J8WPMN1E0J, tRF-29-86V8WPMN1EJ3, tRF-31-6978WPRLXN4VE, tRF-30-MIF91SS2P46I, tRF-26-MI7O3B1NR8E, tRF-30-RRJ89O9NF5W8, tRF-26-XIP2801MK8E, and tRF-35-V0J8O9YEKPRS93, In vitro studies showed that tRF-33-P4R8YP9LON4VDP inhibited proliferation of gastric cancer cells. In conclusion, tsRNAs such as tRF-33-P4R8YP9LON4VDP could serve as a novel diagnostic biomarker and target for gastric cancer therapeutics.

Krüppel-like factor 9 promotes neuroblastoma differentiation via targeting the sonic hedgehog signaling pathway.

BACKGROUND: Neuroblastoma (NB) is a deadly solid tumor of children. Krüppel-like factor 9 (KLF9) has prodifferentiation and tumor suppression functions in several types of cancers. Here, we aimed to investigate the effects of KLF9 on NB differentiation and growth and to elucidate the underlying mechanism. PROCEDURE: Sixty-five NB paraffin samples were assessed for expression levels of KLF9 and sonic hedgehog (SHH) signaling pathway proteins by immunohistochemistry. The associations between expression of KLF9 and the SHH pathway components and patients' clinicopathologic characteristics were estimated. The impacts of KLF9 on cell differentiation, proliferation, and invasion were investigated in two NB cell lines (SH-SY5Y and IMR32). Additionally, chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to elucidate the mechanism by which KLF9 regulates SHH signaling. RESULTS: Differentiating NB specimens showed significantly higher KLF9 expression levels than undifferentiated/poorly differentiated ones. Moreover, increased KLF9 expression was associated with favorable prognoses in patients with NB. A negative correlation was found between KLF9 and SHH signaling expression levels in NB specimens. In vitro assays revealed that KLF9 promoted the differentiation of NB cells and inhibited their proliferation and invasion via suppression of the SHH pathway. Furthermore, KLF9 binding sites in the SHH promoter were identified by ChIP and luciferase reporter assays. CONCLUSIONS: KLF9 exerts prodifferentiation and growth-inhibition effects on NB via suppression of the SHH pathway, suggesting a potential role of KLF9 in NB therapy.

TPM1 is a Novel Predictive Biomarker for Gastric Cancer Diagnosis and Prognosis.

BACKGROUND: Tropomyosin alpha-1 chain (TPM1) is a member of the tropomyosin family and the expression of TPM1 is found to be dysregulated in various tumors. The present study aimed to investigate the clinical performance and significance of TPM1 in gastric cancer. METHODS: First, the levels of TPM1 mRNA and protein were detected through real-time polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) respectively. The correlation between TPM1 expression and clinicopathological variables was analyzed. Then, receiver operating characteristic (ROC) curve was applied to determine the diagnostic performance of TPM1 in gastric cancer. Finally, overall survival analysis was carried out using Kaplan-Meier method in order to determine the prognostic performance of TPM1 in gastric cancer. RESULTS: Compared with the controls, TPM1 mRNA and protein expression levels were significantly downregulated in patients with gastric cancer. Downregulation of TPM1 was associated with depth of invasion and tumor node metastasis (TNM; p = 0.0030 and 0.0175, respectively). Furthermore, TPM1 might be a novel predictive biomarker for gastric cancer with an area under curve (AUC) of 0.8327. Overall survival analysis indicated that low TPM1 expression predicted poor survival (log-rank test, p = 0.0058). CONCLUSIONS: TPM1 might be a novel predictive diagnostic and prognostic biomarker for gastric cancer (95% con-fidence interval = 0.7705 - 0.8949, p < 0.0001).

Reduced expression of circRNA hsa_circ_0067582 in human gastric cancer and its potential diagnostic values.

BACKGROUND: Gastric cancer (GC) is one of the global mortality diseases and has a poor prognosis due to the lack of ideal tumor biomarkers. Circular RNAs (circRNAs) are an abundant kind of endogenous RNAs that recently are found play a crucial role in the cancer occurrence and development. Nevertheless, little is known with regard to the diagnostic values of these circRNAs for GC. In this article of research, we investigated the role of hsa_circ_0067582 in clinical diagnosis of GC. MATERIALS AND METHODS: We used divergent primers, and the expression levels of hsa_circ_0067582 in 93 fresh GC tissues and paired adjacent normal tissues from surgical patients were detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Then, a receiver operating characteristic (ROC) curve was established to assess the diagnostic significance of hsa_circ_0067582. The relationship between expression of hsa_circ_0067582 and clinicopathological factors of patients was made further explored. RESULTS: Hsa_circ_0067582 levels were significantly decreased in GC tissues contrasted with adjacent normal tissues (n = 93, P < .001). After that, we discovered that it was evidently downregulated in 81.7% (76/93) GC tissues. The area under the ROC curve (AUC) of hsa_circ_0067582 was up to 0.6937, the sensitivity was 66.67%, and the specificity was 61.29%. Moreover, the hsa_circ_0067582 levels were obviously associated with tumor diameter (P = .002) and carbohydrate antigen 19-9 (CA19-9, P = .01). Meanwhile, after operation, low-level group of hsa_circ_0067582 of GC patients was associated with better prognosis. CONCLUSION: Our data imply that hsa_circ_000067582 may be a potential biomarker for GC diagnosis and prognosis evaluation.

Exploratory laparoscopy combined with pathological examination in the diagnosis of obscure gastrointestinal bleeding in a child: a case report.

BACKGROUND: The diagnosis of obscure gastrointestinal bleeding (OGIB) which is defined as bleeding of unknown origin of the small bowel by routine evaluation in childhood is a challenge. CASE PRESENTATION: Here we report a one-year-old Chinese girl who was suspected with idiopathic pulmonary haemosiderosis (IPH) and referred to our department for further diagnosis. Finally she was diagnosed with vascular malformations (VM) by exploratory laparoscopy combined with pathological examination. CONCLUSIONS: Children OGIB could be easily misdiagnosed in the beginning, and OGIB children with active ongoing bleeding may benefit from proceeding directly to exploratory laparoscopy, followed by pathological confirmation of the diagnosis.

MicroRNA-10b promotes migration and invasion through Hoxd10 in human gastric cancer.

BACKGROUND: This study aims to investigate the effect of miR-10b overexpression on cancer cell proliferation, migration, invasion, and Hoxd10 expression. METHODS: The effect of miR-10b on proliferation, migration, and invasion of MKN-28, BGC-823, and SGC-7901 cells and the expression of Hoxd10 protein in SGC-7901 and BGC-823 cells were detected following transfection of miR-10b inhibitor or Negative Control B. Expression of Hoxd10 protein in 436 paraffin-embedded cancer tissues was also investigated. RESULTS: miR-10b was significantly upregulated in AGS, MKN-28, BGC-823, HCG-27, SGC-7901, and MKN-45 cell lines, miR-10b inhibitor significantly inhibited proliferation and migration of MKN-45, BGC-823 and SGC-7901 cells 48 h after transfection, while Hoxd10 protein in these cells lines had increased 72 h after transfection. Hoxd10 was highly expressed in gastric cancer and correlated with size of tumor, Lauren classification, depth of invasion, lymph node and distant metastasis, Tumor-Node-Metastasis (TNM) stage, and prognosis. CONCLUSIONS: miR-10b promotes migration and invasion through Hoxd10 in human gastric cancer cell lines and may play an important role in tumorigenesis, progression, and prognosis.

Characterization of the intestinal microbiome of Hirschsprung's disease with and without enterocolitis.

Hirschsprung's disease (HD) is a congenital malformation of the gastrointestinal tract characterized by the absence of the distal enteric nervous system. Hirschsprung-associated enterocolitis (HAEC) is severe life threatening complication of HD. The disease pathogenesis is still unclear, but evidences suggest that the intestinal microbiota may play important role in the development of HD and HAEC. Because microbial abundance and diversity might differ in HD patients with enterocolitis, we sought to generate comparative metagenomic signatures to characterize the structure of the microbiome in HD patients with and without enterocolitis. Our experimental design is to enroll four HD patients (two with enterocolitis and two without enterocolitis). The microbiome was characterized by 16S rRNA gene, and the data obtained will be used to taxonomically classify and compare community structure among different samples. We found that the structure of the microbiome within HAEC patients are differ from those without enterocolitis. This study helps us to understand microbial contributions to the etiology of Hirschsprung-associated enterocolitis.

Robotic distal gastrectomy using a novel pre-emptive supra-pancreatic approach without duodenal transection in the dissection of D2 lymph nodes for gastric cancer.

Background: Robot-assisted surgery has shown remarkable progress as a minimally invasive procedure for gastric cancer. This study aimed to compare the pre-emptive suprapancreatic approach without duodenal transection and the conventional approach in terms of perioperative feasibility and short-term surgical outcomes. Methods: We retrospectively analyzed all patients who underwent robotic distal gastrectomy with D2 lymph node dissection using the da Vinci Xi robotic system between December 2021 and April 2023 and categorized them into two groups for comparison. Patients treated using the pre-emptive suprapancreatic approach (observation group) were compared with those who received the conventional approach (control group). Employing one-to-one propensity score matching, we evaluated the postoperative morbidity and short-term outcomes in these two distinct groups to assess the efficacy and safety of the novel surgical technique. Results: This study enrolled 131 patients: 70 in the observation group and 61 in the control group. After propensity score matching, the operative times were significantly longer in the control group than in the observation group (229.10 ± 33.96 vs. 174.84 ± 18.37, p <0.001). The mean blood loss was lower in the observation group than in the control group (25.20 ± 11.18 vs. 85.00 ± 38.78, p <0.001). Additionally, the observation group exhibited a higher number of retrieved lymph nodes, including suprapyloric, perigastric, and superior pancreatic lymph nodes (28.69 ± 5.48 vs. 19.21 ± 2.89, p <0.001; 4.98 ± 1.27 vs. 4.29 ± 1.21, p = 0.012; 10.52 ± 2.39 vs. 5.50 ± 1.62, p <0.001; 6.26 ± 2.64 vs. 5.00 ± 1.72, p = 0.029). Drain amylase levels in the observation group were significantly lower than those in the control group (30.08 ± 33.74 vs. 69.14 ± 66.81, p <0.001). Conclusion: This study revealed that using the pre-emptive suprapancreatic approach without duodenal transection in the dissection of D2 lymph nodes for gastric cancer is a safe and feasible procedure in terms of surgical outcomes.

Linc-ROR Regulates POU5F1 and SOX2 by Competitively Binding miR-145-5p to Affect the Proliferation and Migration of Gastric Cancer Cells.

Gastric cancer is the third leading cause of cancer-related deaths worldwide, and research on gastric cancer pathogenesis is fundamental. Long intergenic non-coding RNAs (lincRNAs) control cancer initiation and progression through several mechanisms, with the competitive endogenous RNA (ceRNA) regulatory network being the most common. In this study, in situ hybridization revealed that long intergenic non-protein coding RNA-regulator of reprogramming (linc-ROR) was highly expressed in gastric cancer cells and was mainly cytoplasmic-positive. Cell counting kit-8 (CCK-8), plate colony formation, wound healing, and Transwell assay revealed that linc-ROR knockdown impedes the growth, proliferation, and migration of gastric cancer cells, while linc-ROR overexpression promoted gastric cancer cell growth, migration, and colony formation ability. Combined with previous studies, the molecular mechanism axis of linc-ROR/miR-145-5-5p/POU5F1/SOX2 was verified. The expression of linc-ROR knockdown significantly suppressed the protein expression of POU5F1 and SOX2. Co-transfection with linc-ROR siRNA reverses the carcinogenic effect of the miR-145-5p inhibitor on gastric cancer cell proliferation, cloning, and migration. These findings lay a foundation for developing novel targets for gastric cancer treatment.

An analysis of nutritional risk factors in older adults with gastrointestinal tumours.

INTRODUCTION: The aim of this study was to investigate risk factors for nutritional risk in older adults with gastrointestinal tumours. MATERIALS AND METHODS: A total of 170 eligible hospitalised older adults with gastrointestinal tumours were included. Their clinical characteristics were collected, their nutritional risk was screened by NRS 2002, and then patients were divided into a nutritional risk group and a non-nutritional risk group. The observation indicators included body mass index (BMI), muscle mass, muscle strength, and calf circumference. The third lumbar skeletal muscle index (L3 SMI) was calculated using abdominal computed tomography (CT) scan results, and grip strength/muscle strength, 6-m walking speed and calf circumference were measured. Sarcopenia was diagnosed according to the criteria of the Asian Sarcopenia Working Group (AWGS). Finally, we analysed the relationship between nutritional risk and sarcopenia and other related factors (BMI, calf circumference, L3 SMI, grip strength/muscle strength, 6-m walking speed) in older adults with gastrointestinal tumours by multivariate logistic regression analysis. RESULTS: Older adults with gastrointestinal tumours who were at nutritional risk accounted for 51.8% of patients in this study. The differences between sex, tumour stage, age, BMI, calf circumference, L3 SMI, grip strength/muscle strength, 6-m walking speed, and prevalence of sarcopenia were statistically significant in two groups (all P < 0.05). Multivariate logistic regression analysis showed that age, BMI, grip strength/muscle strength, and sarcopenia were risk factors of nutritional risk in older adults with gastrointestinal tumours (all P < 0.05). DISCUSSION: Older adults with gastrointestinal cancer had a higher proportion of nutritional risk, and L3 SMI, grip strength/muscle strength were independent risk factors for nutritional risk. In clinical practice, attention to nutritional risk screening and sarcopenia development in older adults with gastrointestinal cancer is warranted.

Ailanthone suppresses the activity of human colorectal cancer cells through the STAT3 signaling pathway.

Ailanthone (AIL) is a major quassinoid extracted from the Chinese medicinal herb, Ailanthus altissima, which has been reported to exert anti­proliferative effects on various cancer cells. The present study aimed to investigate the antitumor effects of AIL on HCT116 and SW620 colon cancer cells, and to analyze the underlying molecular mechanisms. CCK­8 assay was used to detect cell viability. Furthermore, colony formation and Transwell assays, and flow cytometry were used to examine the effects of AIL on cell proliferation, apoptosis and migration. Finally, the expression levels of cell cycle control proteins, and caspase and Bcl­2 family­related proteins involved in the regulation of apoptosis, as well as those of cell migration­ and pathway­related proteins were examined using western blot analysis. Reverse transcription­quantitative PCR was used to quantitatively analyze the changes in the JAK and STAT3 gene levels in each group. The in vitro cell function tests revealed that AIL inhibited the proliferation and migration, and induced the apoptosis and cell cycle arrest of HCT116 and SW620 cells. It was further found exerted these effects via the JAK/STAT3 signaling pathway, as well as through caspase and Bcl­2 family proteins. On the whole, the present study demonstrates that AIL suppresses the activity of colon cancer cells via the STAT3 pathway.

Microstructure and Phase Evolution of Ti-Al-C-Nb Composites Prepared by In Situ Selective Laser Forming.

In the present work, a novel Ti-Al-C-Nb composite was prepared using in situ selective laser forming (ISLF). The formation mechanism of the Ti-Al-C-Nb bulks, which were synthesized using elemental titanium, aluminum, and carbon (graphite) powders via ISLF techniques, was investigated. The results showed that the Ti3Al and TiC phases were the dominant synthesis products during the chemical reactions, and these occurred during the ISLF process. The size of the fine nanoscale crystal TiC grains could reach 157 nm at an energy level of 60 J/mm3. The porous structure of the ISLF specimens was disclosed, and an open porosity of 20-44% was determined via the scanning speed and the laser power. Both the high dynamic viscosity and the reactions of the raw powders led to the generation of a considerable number of pores, whereas the specimen processed using 45 W and 100 mm/s possessed the lowest degree of open porosity.

An analysis of melanoma epidemic characteristics and distribution in the eastern Chinese city Ningbo from 2011 to 2018.

BACKGROUND: Melanoma is a malignant tumor with poor prognosis and increasing global incidence. Little is known about the burden of melanoma in eastern Chinese cities, as the results of previous studies are inconsistent or unclear. METHODS: In this study, we collected incidence rate data from the Ningbo National Health Information Platform, diagnostic data from the Ningbo Clinicopathological Diagnosis Center, and other relevant data from the Ningbo Bureau of Statistics to evaluate temporal trends and geographic variation in melanoma incidence and to analyze the relationship between melanoma incidence and medical resource availability. RESULTS: The incidence of melanoma in Ningbo has increased significantly in the past 8 years. In 2018, melanoma incidence in Ningbo was 521.67% higher than that in 2011, which was higher than the increase in the national rate. This may be a result of our study including early melanoma, which has a faster increase rate than invasive melanoma. The incidence rate of melanoma in urban areas was significantly higher than that in rural districts. From 2011 to 2018, the incidence rate in rural districts increased by 794.15%, which was significantly higher than the incidence rate increase in urban areas (245.03%). CONCLUSIONS: All indicators relating to medical resources had a significant positive impact on melanoma incidence, indicating that the low incidence of melanoma is partly due to a lack of medical resources, which can lead to delayed treatment and increased disability-adjusted life years (DALYs). Therefore, it is necessary to continue to strengthen investment in medical resources, especially in China's rural areas and western regions where medical resources are less available.

Overabundance of Veillonella parvula promotes intestinal inflammation by activating macrophages via LPS-TLR4 pathway.

Hirschsprung's disease-associated enterocolitis (HAEC) is the most common complication of Hirschsprung's disease (HSCR). The microbiome pattern of intestinal flora in HAEC patients was significantly abnormal compared to that in HSCR patients. The overabundance of V. parvula was detected in the gut of HAEC patients. To elucidate the pathological mechanisms of the overabundance of V. parvula, we established and analyzed inflammatory models induced by LPS or single-bacterial strain transplantation in vivo. The transplantation of V. parvula induced inflammatory response in the colon of mice. Besides, we found that LPS from V. parvula can significantly impair the barrier function of colonic epithelial cells and then activate macrophages which impaired pacemaker function of interstitial cells of Cajal (ICCs). It was thus a vicious cycle, where the macrophage-related inflammation caused by V. parvula via LPS-TLR4 pathway damaged the intestinal motility, which further aggravated the intestinal flora dysbiosis and promoted the development of HAEC. Itaconic acid could break the vicious cycle by inhibiting the activation of macrophages. It could be a potential therapeutic strategy for HAEC patients with intestinal flora dysbiosis.

Clinical Experience of Intracorporeal Hand-sewn Anastomosis Following Totally Laparoscopic Pylorus-Preserving Gastrectomy for Middle-Third Early Gastric Cancer.

INTRODUCTION: Pylorus-preserving gastrectomy (PPG) has been accepted as a representative function-preserving procedure for early gastric cancer (EGC) in the middle stomach. Totally, intracorporeal laparoscopic gastrectomy can provide better aesthetics, be less invasive, and allow faster postoperative recovery. Here, we first describe the surgical procedure of totally laparoscopic pylorus-preserving gastrectomy with intracorporeal hand-sewn anastomosis (TLPPG-IHSA). METHODS: After standard procedure of lymph node dissection and middle stomach resection, we used two double-needle barbed sutures to perform a layer-to-layer manual anastomosis of the anterior and posterior walls in the abdominal cavity. Twelve patients with preoperatively diagnosed clinical EGC located in the middle third of the stomach underwent TLPPG-IHSA between August 2019 and January 2021. RESULTS: A total of 12 patients with EGC successfully underwent TLPPG-IHSA. Only one patient (8.3%) suffered postoperative gastric stasis. No complications or recurrence occurred in other patients during half a year after surgery. CONCLUSION: TLPPG-IHSA is considered technically feasible to treat EGC located in the middle third of the stomach.

Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial.

IMPORTANCE: Perioperative chemotherapy is a potential treatment for locally advanced gastric cancer. However, the optimal chemotherapy regimen remains unknown. OBJECTIVE: To investigate the safety and efficacy of S-1 plus oxaliplatin (SOX) vs fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as a perioperative chemotherapy regimen for patients with locally advanced gastric cancer. DESIGN, SETTING, AND PARTICIPANTS: In this phase 3, open-label, multicenter, randomized clinical trial, patients from 12 Chinese hospitals were enrolled between June 2011 and August 2016, with a last follow-up date of September 2019. The primary tumor was evaluated as either invading the serosa or the adjacent structures with or without metastatic lymph nodes, and with no evidence of distant metastases. Data were analyzed from December 2019 to June 2020. INTERVENTIONS: Patients were randomly assigned (1:1) to receive either 6 perioperative (2-4 preoperative and 2-4 postoperative) 3-week cycles of 130 mg/m2 oxaliplatin on day 1 and 80 to 120 mg/d S-1 orally daily for 2 weeks (SOX) or 130 mg/m2 oxaliplatin, 400 mg/m2 fluorouracil, 400 mg/m2 leucovorin, and 2400 mg/m2 fluorouracil as 46-hour infusion on day 1 (FOLFOX). MAIN OUTCOMES AND MEASURES: The primary end point was 3-year overall survival (OS). An absolute noninferiority margin of -8% was chosen. RESULTS: A total of 583 patients were enrolled; 293 were randomized to the SOX group and 290 were randomized to the FOLFOX group. Twelve patients (2.1%) refused preoperative chemotherapy (5 patients in the SOX group and 7 patients in the FOLFOX group), leaving a total of 288 patients in the SOX group (median [range] age, 61 [24 to 78] years; 197 men [68.4%]) and 283 patients in the FOLFOX group (median [range] age, 62 [24 to 80] years; 209 men [73.9%]) who received preoperative chemotherapy. The 3-year OS rate was 75.2% (95% CI, 70.3% to 80.5%) in the SOX group and 67.8% (95% CI, 62.5% to 73.5%) in the FOLFOX group. The absolute difference of 3-year OS rate between the 2 groups was 7.4% (95% CI, -0.1% to 14.9%), which was greater than the prespecified noninferiority margin (-8%) and showed the noninferiority of perioperative chemotherapy with SOX compared with FOLFOX. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, SOX was noninferior to FOLFOX as perioperative chemotherapy for patients with locally advanced gastric cancer and could be recommended as an alternative treatment for these patients in Asia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01364376.

circTADA2A Retards the Progression of Colorectal Cancer via Regulating miR-1229/BCL2L10 Signal Axis.

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer-related death around the world, becoming a severe public health problem. Mounting evidence has proven that circRNAs act as pivotal modulators in the initiation and development of CRC. Although the function of circTADA2A has been explored in osteosarcoma and breast cancer, the specific role of circTADA2A in CRC remains unknown. METHODS: Bioinformatics analysis based on GEO datasets was used to evaluate the dysregulated circRNAs in CRC. CCK-8 and transwell assays were used to detect the functions of CRC cells. qRT-PCR and Western blot were performed to evaluate the expression of RNAs and proteins. Luciferase assay and RNA pull down experiment were carried out to verify the interaction between miR and its targets. RESULTS: CircTADA2A was downregulated in CRC tissues compared with normal samples. CircTADA2A exhibited greater stability than its linear form when exposed to RNase R and actinomycin D treatment. qRT-PCR analysis validated the lower expression level of circTADA2A in CRC. The loss-of-function and gain-of-function assays indicated that circTADA2A exerted the inhibitory role in CRC cell proliferation and migration. Mechanistically, circTADA2A functioned as a sponge of miR-1229. Further experiments manifested that circTADA2A regulated BCL2L10 expression via competitively binding to miR-1229. More importantly, the tumor suppressor role of circTADA2A in the malignant behaviors of CRC cells was mediated by BCL2L10. CONCLUSION: circTADA2A suppressed cell proliferation and migration in CRC through regulation of miR-1229/BCL2L10 axis, which suggested that circTADA2A might represent a novel potential target for the treatment of CRC.