Lysosome-Targeting Bacterial Outer Membrane Vesicles for Tumor Specific Degradation of PD-L1.

Increased expression of immune check point genes, such as PD-L1, is one of the main reasons for immunosuppression, especially for colon cancer. Development of novel therapeutic strategies is of great importance to improve the prognosis. In this study, outer membrane vesicles (OMV) derived from Gram-negative bacteria are engineered to immune checkpoint blockade nanosystem for efficient elicitation of anti-tumor immunity. Briefly, the OMVs are engineered with Lyp1-Traptavidin (S52G, R53D mutant of streptavidin) fusion protein displayed on the surface. The Lyp-1 endows the OMV with the capacity to target tumor tissues, while the Traptavidin ensures easy decoration of biotinylated anti-PD-L1 and biotinylated M6P (mannose 6-phosphate). The simultaneously anchored anti-PD-L1 and M6P (ligand for cation-independent mannose 6-phosphate receptor) on the engineered OMVs coordinately direct the membrane PD-L1 to lysosome for degradation, and thus unleash the anti-tumor immunity. With syngeneic tumor model, the engineered OMVs are confirmed to boost immunity, inhibit cancer growth, and thus prolong survival. Together, A proposed OMV-based modular nanosystem that enables assembly of biotinylated anti-PD-L1 and M6P on the surface for tumor-targeted immune checkpoint blockade.

Clinical value of circulating tumour cells in evaluating the efficacy of continuous hepatic arterial infusion among colorectal cancer patients.

Few studies have been conducted to evaluate the efficacy of HAIC using circulating tumour cells (CTCs). In this study, a total of 100 patients who received HAIC treatment and CTC detection were selected. The results showed that after HAIC treatment, the levels of CTC, carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) decreased. Postoperative progression-free survival (PFS) rates between patients with positive and negative preoperative CTC results, and for CA19-9, CEA were significantly different. The positive rate of CTCs was 61% before chemotherapy and 23% after chemotherapy, and the correlation coefficient between the two was 0.385. Those whose CTC values increased after chemotherapy had shorter PFS rates. CTCs are an independent predictor of recurrence. Patients with CTC-positive results are more susceptible to recurrence. The CTC count in peripheral blood has a close bearing on the postoperative chemotherapy efficacy of patients with CRC and affects patients' PFS.

Discovery of a potent Gilteritinib-based FLT3-PROTAC degrader for the treatment of Acute myeloid leukemia.

Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin-proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.

YTHDC1 promotes the malignant progression of gastric cancer by promoting ROD1 translocation to the nucleus.

RNA-binding proteins (RBPs) make vital impacts on tumor progression and are important potential targets for tumor treatment. Previous studies have shown that RBP regulator of differentiation 1 (ROD1), enriched in the nucleus, is abnormally expressed and functions as a splicing factor in tumors; however, the mechanism underlying its involvement in gastric cancer (GC) is unknown. In this study, ROD1 is found to stimulate GC cell proliferation and metastasis and is related to poor patient prognosis. In vitro experiments showed that ROD1 influences GC proliferation and metastasis through modulating the imbalance of the level of the oncogenic gene OIP5 and the tumor suppressor gene GPD1L. Further studies showed that the N6-methyladenosine (m6A) "reader" protein YTHDC1 can interact with ROD1 and regulate the balance of the expression of the downstream molecules OIP5/GPD1L by promoting the nuclear enrichment of ROD1. Therefore, YTHDC1 stimulates GC development and progression through modulating nuclear enrichment of the splicing factor ROD1.

Discovery of a Novel CSF-1R Inhibitor with Highly Improved Pharmacokinetic Profiles and Superior Efficacy in Colorectal Cancer Immunotherapy.

Blocking CSF-1/CSF-1R pathway has emerged as a promising strategy to remodel tumor immune microenvironment (TME) by reprogramming tumor-associated macrophages (TAMs). In this work, a novel CSF-1R inhibitor C19 with a highly improved pharmacokinetic profile and in vivo anticolorectal cancer (CRC) efficiency was successfully discovered. C19 could effectively reprogram M2-like TAMs to M1 phenotype and reshape the TME by inducing the recruitment of CD8+ T cells into tumors and reducing the infiltration of immunosuppressive Tregs/MDSCs. Deeper mechanistic studies revealed that C19 facilitated the infiltration of CD8+ T cells by enhancing the secretion of chemokine CXCL9, thus significantly potentiating the anti-CRC efficiency of PD-1 blockade. More importantly, C19 combined with PD-1 mAb could induce durable antitumor immune memory, effectively overcoming the recurrence of CRC. Taken together, our findings suggest that C19 is a promising therapeutic option for sensitizing CRC to anti-PD-1 therapy.

Discovery of a Novel Orally Bioavailable FLT3-PROTAC Degrader for Efficient Treatment of Acute Myeloid Leukemia and Overcoming Resistance of FLT3 Inhibitors.

Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis-targeting chimeras (PROTACs) represent a promising approach to eliminate the resistance of FLT3 inhibitors. However, due to the poor druggability of PROTACs, the development of orally bioavailable FLT3-PROTACs faces great challenges. Herein, a novel orally bioavailable FLT3-ITD degrader A20 with excellent pharmacokinetic properties was discovered through reasonable design. A20 selectively inhibited the proliferation of FLT3-ITD mutant acute myeloid leukemia (AML) cells and potently induced FLT3-ITD degradation through the ubiquitin-proteasome system. Notably, oral administration of A20 resulted in complete tumor regression on subcutaneous AML xenograft models. Furthermore, on systemic AML xenograft models, A20 could completely eliminate the CD45+CD33+ human leukemic cells in murine and significantly prolonged the survival time of mice. Most importantly, A20 exerted significantly improved antiproliferative activity against drug-resistant AML cells compared to existing FLT3 inhibitors. These findings suggested that A20 could serve as a promising drug candidate for relapsed or refractory AML.

Recent advances in IgG4-related autoimmune pancreatitis.

The incidence of IgG4-related autoimmune pancreatitis (IgG4-AIP) is high in Asia and other countries, and unnecessary treatment is often undertaken due to both missed diagnosis and misdiagnosis in clinical practice. Although IgG4-AIP has attracted increasing attention, the details of IgG4-AIP pathogenesis and systemic immune response, including its relationship to tumor pathogenesis, are still unclear. In recent years, research on serum immunological detection, pathological features, clinical manifestations, diagnosis and treatment measures for IgG4-AIP has gradually increased. It is of great importance to summarize and discuss the latest progress regarding IgG4-AIP disease.

Short- and long-term outcomes of laparoscopic versus open gastrectomy after neoadjuvant chemotherapy: A case-control study using a propensity score matching method.

Background: Neoadjuvant chemotherapy (NACT) is increasingly becoming the recommended treatment for locally advanced gastric cancer (LAGC) with promising results. According to previous reports, few studies have evaluated the benefits of laparoscopic gastrectomy (LG) after NACT. Methods: 135 patients from our center who underwent gastrectomy with NACT were available, including 41 patients of LG and 94 OG between July 2018 and July 2022. To reduce selection bias, we used the nearest neighbor method and set caliper = 0.2 for 3:1 matching between LG and OG groups for propensity score matching method (PSM). After PSM, the matched 41 patients with LG and 80 patients with OG formed the cohort, respectively. Univariate and multivariate Cox analyses were performed on all variables to determine independent risk factors associated with survival. Results: LG had a longer operating time compared to OG [260.00 min (220.00 min, 300.00 min) vs. 200.00 min (160.00 min, 260 min), P < 0.001]. The estimated blood loss, metastatic lymph nodes (LN), total LN examined, postoperative hospital stays, blood transfusion (P>0.05) and the incidence of postoperative complications did not show statistical differences from the OG group (P = 0.084). The type of surgery (LG vs. OG) did not show a significant risk propensity in the univariate and multivariate Cox analysis (HR = 0.69, P = 0.36, 95 % CI: 0.31-1.53). Through the Kaplan-Meier curves, a certain trend showed that the LG group had a better long-term survival outcomes than the OG group, although there was no statistical difference between two groups (P>0.05). Conclusion: LG is a promising treatment option for LAGC patients receiving NACT and had an acceptable safety and efficacy compared to OG.

Multidrug-resistant Klebsiella Pneumoniae Infection Led to Resection of the Graft in a Small Bowel Transplant Recipient: A Case Report and Review of the Literature.

BACKGROUND: Infection due to multidrug-resistant Klebsiella pneumoniae is a common cause of graft resection after small bowel transplantation. We report a failed case in which the intestinal graft was resected 18 days after the operation due to postoperative infection with multidrug-resistant K pneumoniae and a literature review of other common causes of small bowel transplantation failure have been reported. METHODS: A female, 29 years of age, underwent partial living small bowel transplantation for short bowel syndrome. After the operation, the patient was infected with multidrug-resistant K pneumoniae, even though various anti-infective regimens were employed. It further developed into sepsis and disseminated into intravascular coagulation, leading to exfoliation and necrosis of the intestinal mucosa. Finally, the intestinal graft had to be resected to save the patient's life. RESULTS: Multidrug-resistant K pneumoniae infection often affects the biological function of intestinal grafts and can even lead to necrosis. Other common causes of failure, including postoperative infection, rejection, post-transplantation lymphoproliferative disorder, graft-vs-host disease, surgical complications, and other related diseases, were also discussed throughout the literature review. CONCLUSIONS: Pathogenesis due to diverse and interrelated factors makes the survival of intestinal allografts a great challenge. Therefore, only by fully understanding and mastering the common causes of surgical failure can the success rate of small bowel transplantation be effectively improved.

Comparison of thoracoabdominal versus abdominal-transhiatal surgical approaches in Siewert type II adenocarcinoma at the esophagogastric junction: Protocol for a prospective multicenter randomized controlled trial.

Background: Siewert type II adenocarcinoma of the esophagogastric junction (Siewert II AEG) can be resected by the right thoracoabdominal surgical approach (RTA) or abdominal-transhiatal surgical approach (TH) under minimally invasive conditions. Although both surgical methods achieve complete tumor resection, there is a debate as to whether the former method is superior to or at least noninferior to the latter in terms of surgical safety. Currently, a small number of retrospective studies have compared the two surgical approaches, with inconclusive results. As such, a prospective multicenter randomized controlled trial is necessary to validate the value of RTA (Ivor-Lewis) compared to TH. Methods: The planned study is a prospective, multicenter, randomized clinical trial. Patients (n=212) with Siewert II AEG that could be resected by either of the above two surgical approaches will be included in this trial and randomized to the RTA group (n=106) or the TH group (n=106). The primary outcome will be 3-year disease-free survival (DFS). The secondary outcomes will include 5-year overall survival (OS), incidence of postoperative complications, postoperative mortality, local recurrence rate, number and location of removed lymph nodes, quality of life (QOL), surgical Apgar score, and duration of the operation. Follow-ups are scheduled every three months for the first 3 years after the surgery and every six months for the next 2 years. Discussion: Among Siewert II AEG patients with resectable tumors, this is the first prospective, randomized clinical trial comparing the surgical safety of minimally invasive RTA and TH. RTA is hypothesized to provide better digestive tract reconstruction and dissection of mediastinal lymph nodes while maintaining a high quality of life and good postoperative outcome. Moreover, this trial will provide a high level of evidence for the choice of surgical procedures for Siewert II AEG. Clinical trial registration: Chinese Ethics Committee of Registering Clinical Trials, identifier (ChiECRCT20210635); Clinical Trial.gov, identifier (NCT05356520).

Prognostic model based on m6A-associated lncRNAs in esophageal cancer.

Background: This research aimed to build an m6A-associated lncRNA prognostic model of esophageal cancer that can be used to predict outcome in esophageal cancer patients. Methods: RNA sequencing transcriptome data and clinical information about patients with esophageal cancer were obtained according to TCGA. Twenty-four m6A-associated genes were selected based on previous studies. m6A-associated lncRNAs were determined through Pearson correlation analysis. Three m6A-associated lncRNA prognostic signatures were built through analysis of the training set using univariate, LASSO, and multivariate Cox regression. To validate the stabilization of the risk signature, Kaplan-Meier and ROC curve analyses were performed on the testing and complete sets. The prognoses of EC patients were predicted quantitatively by building a nomogram. GSEA was conducted to analyze the underlying signaling pathways and biological processes. To identify the underlying mechanisms through which the lncRNAs act, we constructed a PPI network and a ceRNA network and conducted GO and KEGG pathway analyses. EC samples were evaluated using the ESTIMATE algorithm to compute stromal, immune, and estimate scores. The ssGSEA algorithm was used to quantitatively infer immune cell infiltration and immune functions. The TIDE algorithm was performed to simulate immune evasion and predict the response to immunotherapy. Results: We identified and validated an m6A-associated lncRNA risk model in EC that could correctly and reliably predict the OS of EC patients. The ceRNA network, PPI network, and GO and KEGG pathway analyses confirmed and the underlying mechanisms and functions provided enlightenment regarding therapeutic strategies for EC. Immunotherapy responses were better in the low-risk subgroup, and PD-1 and CTLA4 checkpoint immunotherapy benefited the patients in the low-risk subgroup. Conclusions: We constructed a new m6A-related lncRNA prognostic risk model of EC, based on three m6A-related lncRNAs: LINC01612, AC025166.1 and AC016876.2, that can predict the prognoses of EC patients.

Study protocol for feasibility and safety of adopting early oral feeding in post total laparoscopic total gastrectomy (overlap esophagojejunostomy): A multicentre randomized controlled trial.

Background: Total laparoscopic total gastrectomy (TLTG) for gastric cancer, especially with overlap esophagojejunostomy, has been verified that it has advantages of minimally invasion, less intraoperative bleeding, and faster recovery. Meanwhile, early oral feeding (EOF) after the operation has been demonstrated to significantly promote early rehabilitation in patients, particularly with distal gastrectomy. However, due to the limited application of TLTG, there is few related research proving whether it is credible or safe to adopt EOF after TLTG (overlap esophagojejunostomy). So, it is urgent to start a prospective, multicenter, randomized clinical trials to supply high level evidence. Methods/design: This study is a prospective, multicenter, randomized controlled trial with 200 patients (100 in each group). These eligible participants are randomly allocated into two different groups, including EOF group and delay oral feeding (DOF) group after TLTG (overlap esophagojejunostomy). Anastomotic leakage will be carefully observed and recorded as the primary endpoints; the period of the first defecation and exhaust, postoperative length of stay and hospitalization expenses will be recorded as secondary endpoints to ascertain the feasibility and safety of adopting EOF after TLTG (overlap esophagojejunostomy). Discussion: Recently, the adoption of TLTG was limited due to its difficult anastomotic procedure, especially in vivo esophagojejunostomy. With the innovation and improvement of operating techniques, overlap esophagojejunostomy with linear staplers simplified the anastomotic steps and reduced operational difficulties after TLTG. Meanwhile, EOF had received increasing attention from surgical clinicians as a nutrition part of enhanced recovery after surgery (ERAS), which had shown better results in patients after distal gastrectomy. Considering the above factors, we implemented EOF protocol to evaluate the feasibility and safety of adopting EOF after TLTG (overlap esophagojejunostomy), which provided additional evidence for the development of clinical nutrition guidelines. Clinical trial registration: [www.chictr.org.cn], identifier [ChiECRCT20200440 and ChiCTR2000040692].

Influence of Comprehensive Nursing Intervention Combined with WeChat Platform Propaganda and Education of ERAS Concept on Postoperative Functional Recovery of Patients with Gallbladder Polyps.

To analyze the effect of comprehensive nursing intervention based on ERAS's concept in laparoscopic gallbladder polyp (GP) surgery on patients' postoperative quality of life and nursing job satisfaction. Ninety patients with polyps were included in this article until October 2021. In this format, the 45 cases are divided into governing bodies and committees according to their processing time. As recommended by the ERAS committee, the committee provides daily and patient care, as well as training on the WeChat platform. The pain level (visual analogue scale (VAS) score), the quality of life (life quality index (GLQI) score), and the incidence of complications were compared between the two groups before and after the intervention. The VAS score of the control group at 2 h after operation was lower than that of the control group, and the difference was statistically significant (P < 0.05). After the intervention, the GLQI scores of the two groups were higher than those before the intervention, and the GLQI scores of the control group were higher than those of the control group, with significant differences (all P < 0.05). Studies have shown that comprehensive nursing intervention applied to patients with gallbladder polyps can reduce postoperative pain with less complications and can also improve nursing satisfaction, which is worthy of clinical promotion.

Surgical treatment for cryptoglandular and Crohn's perianal fistulas: Protocol of an umbrella review.

INTRODUCTION: A high prevalence of cryptoglandular and Crohn's perianal fistulas has been reported worldwide, and several surgical options are available for the management of anal fistula, with varying clinical efficacy. However, currently, the available evidence for the effectiveness of these surgical approaches are lacking and of concern in terms of the credibility and strength. The purpose of this study is to evaluate the credibility of the published systematic reviews and meta-analyses that assess the efficacy and safety of the surgical options for cryptoglandular and Crohn's perianal fistulas through an umbrella review. METHODS AND ANALYSIS: A systematic search in PubMed, Embase and Cochrane library will be performed from inception to December 2020 without any language restriction. We will include systematic reviews and meta-analyses that investigate the efficacy and safety of surgical approaches in the management of cryptoglandular and Crohn's perianal fistulas. Two reviewers will independently screen search results through reading the titles or abstracts. Relevant information will be extracted from each eligible systematic review or meta-analysis. Based on random effects model summary estimates along with their p values, 95% prediction intervals, between-study heterogeneity, small-study effects and excess significance, we will classify the evidence from convincing (class I) to weak (class IV). Findings will be summarized using quantitative synthesis combined with a narrative approach. Cryptoglandular and Crohn's perianal fistulas will be summarized separately. Two authors will independently perform the literature search, data extraction, and quality assessment of each included systematic review and meta-analysis. Any unresolved conflicts or doubts will be resolved by discussion or by consulting a senior author. The risk of bias of the systematic reviews will be assessed using a 16-item Assessment of Multiple Systematic Reviews 2 (AMSTAR2) checklist. The strength of evidence for the included systematic reviews will be classified as "high", "moderate", "low", or "critically low" quality. ETHICS AND DISSEMINATION: Ethics approval is not required as we will collect data from the published systematic reviews and meta-analyses without using individual patient data. The results of this umbrella review will be published in a peer-reviewed journal and will be presented at an anorectal disease conference. PROSPERO REGISTRATION NUMBER: CRD42020200754.

Construction and Characterization of KRAS Immune Lipid Magnetic Balls for Colorectal Cancer Circulating Tumor Cells.

OBJECTIVE: The purpose of this study was to prepare and characterize a lipid magnetic ball modified with KRAS antibodies on the surface and to isolate circulating tumor cells of colorectal cancer with KRAS mutations. METHODS: The microemulsion method was used to form lipid bilayers to encapsulate Fe3O4 nanoparticles with superparamagnetism to form lipid magnetic balls, and KRAS antibodies were formed on the surface to form KRAS immune lipid magnetic balls. RESULTS: Compared with traditional EpCAM antibody-modified lipid magnetic balls, it can effectively improve the capture ability of colorectal cancer circulating tumor cells with KRAS mutation, the capture rate reaches 92.9%, and the capture results are consistent with clinical diagnosis and pathology. CONCLUSION: Our results showed that KRAS antibody-modified lipid magnetic balls can be used in the diagnosis and treatment of KRAS colorectal cancer.

Development of screening tools to predict the risk of recurrence and related complications following anal fistula surgery: protocol for a prospective cohort study.

INTRODUCTION: Postoperative recurrence and related complications are common and related to poor outcomes in patients with anal fistula (AF). Due to being associated with short-term and long-term cure rates, perioperative complications have received widespread attention following AF surgery. This study aims to identify a set of predictive factors to develop risk prediction models for recurrence and related complications following AF surgery. We plan to develop and validate risk prediction models, using information collected through a WeChat patient-reported questionnaire system combined with clinical, laboratory and imaging findings from the perioperative period until 3-6 months following AF surgery. METHODS AND ANALYSIS: This is a prospective hospital-based cohort study using a linked database of collected health data as well as the follow-up outcomes for all adult patients who suffered from AF at a tertiary referral hospital in Shanghai, China. We will perform logistic regression models to predict anal fistula recurrence (AFR) as well as related complications (eg, wound haemorrhage, faecal impaction, urinary retention, delayed wound healing and unplanned hospitalisation) during and after AF surgery, and machine learning approaches will also be applied to develop risk prediction models. This prospective study aims to develop the first risk prediction models for AFR and related complications using multidimensional variables. These tools can be used to warn, motivate and empower patients to avoid some modifiable risk factors to prevent postoperative complications early. This study will also provide alternative tools for the early screening of high-risk patients with AFR and related complications, helping surgeons better understand the aetiology and outcomes of AF in an earlier stage. ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Board of Shuguang Hospital affiliated with Shanghai University of Traditional Chinese Medicine (approval number: 2019-699-54-01). The results of this study will be submitted to international scientific peer-reviewed journals or conferences in surgery, anorectal surgery or anorectal diseases. TRIAL REGISTRATION NUMBER: ChiCTR1900025069; Pre-results.

Area-specific economic status should be regarded as a vital factor affecting the occurrence, development and outcome of cervical cancer.

For patients with cervical cancer, despite the incidence and mortality rates have been declining in recent years, due to its huge population base, cervical cancer has always been a serious public health problem. Our research placed emphasis on the indices greatly associated with overall area-specific social economic status, making up for the defects of traditional research which only pay attention to the situation of some specific disease or patients' individual social status. A total of 39160 women identified cervical cancer were concluded in our study from the Surveillance, Epidemiology, and End Results (SEER) 18 Program data between 1980 and 2014. With improving the area-specific social economic factors in recent years, the occurrence and prognosis of cervical cancer showed different variation patterns respectively. Some states like California and Georgia for their better economic status and more healthcare investment by local medical institution, population there showed a lower prevalence, incidence, more timely diagnosis, effective treatment, and better prognosis. According to our study, we aimed to give a scientific interpretation on how the area-specific social economic factors affect the disease situation at the macro level and help local medical institution make advisable decisions for controlling cervical cancer.

Transcriptome Based System Biology Exploration Reveals Homogeneous Tumorigenicity of Alimentary Tract Malignancy.

Malignancies of alimentary tract include esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and rectum adenocarcinoma (READ). Despite of their similarities in cancer development and progression, there are numerous researches concentrating on single tumor but relatively little on their common mechanisms. Our study explored the transcriptomic data of digestive tract cancers from The Cancer Genome Atlas database, yielding their common differentially expressed genes including 1,700 mRNAs, 29 miRNAs, and 362 long non-coding RNAs (lncRNAs). There were 12 mRNAs, 5 miRNAs, and 16 lncRNAs in the core competitive endogenous RNAs network by RNA-RNA interactions, highlighting the prognostic nodes of SERPINE1, hsa-mir-145, and SNHG1. In addition, the weighted gene co-expression network analysis (WGCNA) illustrated 20 gene modules associated with clinical traits. By taking intersections of modules related to the same trait, we got 67 common genes shared by ESCA and READ and screened 5 hub genes, including ADCY6, CXCL3, NPBWR1, TAS2R38, and PTGDR2. In conclusion, the present study found that SERPINE1/has-mir-145/SNHG1 axis acted as promising targets and the hub genes reasoned the similarity between ESCA and READ, which revealed the homogeneous tumorigenicity of digestive tract cancers at the transcriptome level and led to further comprehension and therapeutics for digestive tract cancers.