Receptor-interacting Protein Kinase 2 Is an Immunotherapy Target in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy because of its aggressive nature and the paucity of effective treatment options. Almost all registered drugs have proven ineffective in addressing the needs of patients with PDAC. This is the result of a poor understanding of the unique tumor-immune microenvironment (TME) in PDAC. To identify druggable regulators of immunosuppressive TME, we performed a kinome- and membranome-focused CRISPR screening using orthotopic PDAC models. Our data showed that receptor-interacting protein kinase 2 (RIPK2) is a crucial driver of immune evasion of cytotoxic T-cell killing and that genetic or pharmacologic targeting of RIPK2 sensitizes PDAC to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy, leading to prolonged survival or complete regression. Mechanistic studies revealed that tumor-intrinsic RIPK2 ablation disrupts desmoplastic TME and restores MHC class I (MHC-I) surface levels through eliminating NBR1-mediated autophagy-lysosomal degradation. Our results provide a rationale for a novel combination therapy consisting of RIPK2 inhibition and anti-PD-1 immunotherapy for PDAC. SIGNIFICANCE: PDAC is resistant to almost all available therapies, including immune checkpoint blockade. Through in vivo CRISPR screen, we identified that RIPK2 plays a crucial role in facilitating immune evasion by impeding antigen presentation and cytotoxic T-cell killing. Targeting tumor-intrinsic RIPK2 either genetically or pharmacologically improves PDAC to anti-PD-1 immunotherapy. See related commentary by Liu et al., p. 208 . This article is featured in Selected Articles from This Issue, p. 201.

Ion Mobility-Derived Collision Cross-Sections Add Extra Capability in Distinguishing Isomers and Compounds with Similar Retention Times: The Case of Aphidicolanes.

The hyphenation of ion mobility spectrometry with high-resolution mass spectrometry has been widely used in the characterization of various metabolites. Nevertheless, such a powerful tool remains largely unexplored in natural products research, possibly mainly due to the lack of available compounds. To evaluate the ability of collision cross-sections (CCSs) in characterizing compounds, especially isomeric natural products, here we measured and compared the traveling-wave IMS-derived nitrogen CCS values for 75 marine-derived aphidicolanes. We established a CCS database for these compounds which contained 227 CCS values of different adducts. When comparing the CCS differences, 36 of 57 pairs (over 60%) of chromatographically neighboring compounds showed a ΔCCS over 2%. What is more, 64 of 104 isomeric pairs (over 60%) of aphidicolanes can be distinguished by their CCS values, and 13 of 18 pairs (over 70%) of chromatographically indistinguishable isomers can be differentiated from the mobility dimension. Our results strongly supported CCS as an important parameter with good orthogonality and complementarity with retention time. CCS is expected to play an important role in distinguishing complex and diverse marine natural products.

Neoadjuvant Chemohormonal Therapy in Prostate Cancer Before Radical Prostatectomy: A Systematic Review and Meta-Analysis.

Objective: This meta-analysis was to investigate the effects of neoadjuvant chemohormonal therapy (NCHT) on patients with prostate cancer (PCa) before radical prostatectomy (RP) and attempt to provide meaningful evidence. Methods: A systematic search was performed using the PubMed, Web of Science, and Cochrane Library databases in February 2022 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relevant studies were critically screened and we extracted the data of demography, postoperative pathology, and survival to calculate the pooled effect sizes. Subgroup analyses and sensitivity analyses were used to explore the source of heterogeneity. Results: Six identified studies involving 1717 subjects were included according to the selection criteria. There was no significant difference between NCHT plus RP and RP alone groups regarding lymph node involvement (risk ratio [RR]=1.03, 95% confidence interval [CI]: 0.57-1.87, P=0.92). However, NCHT prior to RP significantly decreased the rates of positive surgical margin (PSM, RR=0.35, 95% CI: 0.22-0.55, P<0.0001) and seminal vesicle invasion (SVI, RR=0.78, 95% CI: 0.65-0.95, P=0.01), and increase pathological downstaging (RR=1.64, 95% CI: 1.17-2.29, P=0.004). Additionally, biochemical recurrence-free survival (BRFS) and overall survival (OS) were significantly prolonged under the administration of NCHT (HR=0.54, 95% CI: 0.34-0.85, P=0.008 and HR=0.67, 95% CI: 0.48-0.94, P=0.02, respectively). Conclusions: Compared to the RP alone group, patients with NCHT plus RP showed significant improvements in PSM, SVI, pathological downstaging, BRFS, and OS, whereas further multicenter randomized controlled trials are needed to consolidate this concept.

Management and Follow-Up Practices of Women With Recurrent Stress Urinary Incontinence Following Transobturator Mid-urethral Synthetic Sling Procedure: A 6-Year Retrospective Monocentric University-Based Study.

Purpose: The purpose of this study is to evaluate the efficacy of management and follow-up practices in repeat retropubic mid-urethral synthetic sling (MUS) procedure after transobturator tape/tension-free vaginal tape-obturator (TOT/TVT-O) failure, and to clarify the possible etiology of recurrent stress urinary incontinence. Methods: The charts of all women patients who underwent tension-free vaginal tape (TVT) slings after previous failed transobturator MUS procedures between February 2012 and November 2018 at a single center were reviewed retrospectively. The transperineal ultrasound was performed to assess the pre-operative or post-operative urethral mobility and location of the slings. Furthermore, some essential evaluations were also made, mainly including medical history, physical examination, 1 h pad test, and urodynamic study. Finally, primary outcomes were evaluated according to the above items at 3, 6, and 12 months after the second operation, respectively. Results: Thirty-five patients were included in the primary transobturator MUS sling procedure. At the 6 months follow-up, 32 (91.42%) patients were socially continent and negative in 1 h pad test. The transperineal ultrasound measurement results revealed that the bladder neck descent (BND) values were significantly decreased after the repeat sling operation, and better urinary continence function was observed according to the post-operative urodynamic study. Multifactorial etiologies resulted in recurrent stress urinary incontinence (SUI), including poor surgical technique, inadequate sling tension when treating ISD, and inappropriate sling position. Then the detail of the surgical procedure varied with the results of pre-operative evaluations, affecting the validity of the second sling. Conclusion: Recurrent SUI has resulted from multi factors, pre-operative urodynamic study and transperineal ultrasound might be valuable tools to guide repeat sling operation and predict post-operative outcomes. A repeat TVT procedure may be regarded as a remedial measure for a failed transobturator MUS operation.

Combined Signature of the Urinary Microbiome and Metabolome in Patients With Interstitial Cystitis.

Interstitial cystitis (IC) is a clinical syndrome characterized by frequency, urgency, and bladder pain or pelvic pain; however, the underlying pathophysiological mechanisms and diagnostic markers are unknown. In this study, microbiome and metabolome analysis were used to explain the urine signatures of IC patients. Urine samples from 20 IC patients and 22 control groups were analyzed by using 16S rRNA sequence and liquid chromatography coupled with mass spectrometry. Four opportunistic pathogen genera, including Serratia, Brevibacterium, Porphyromonas, and Citrobacter, were significantly upregulated in IC group. The altered metabolite signatures of the metabolome may be related to sphingosine metabolism, amino acid metabolism, and fatty acid biosynthesis. Meanwhile, the associations were observed between different metabolites and microbiomes of IC. The present study suggests that the combined signatures of IC in urine microbiome and metabolome may become its prospective diagnostic markers.

Efficacy and safety of Shenling Atractylodes Powder in the treatment of ulcerative colitis: A protocol for systematic review and meta-analysis.

BACKGROUND: Ulcerative colitis (UC) is a kind of chronic non-specific ulcerative colitis, which is characterized by repeated abdominal pain, diarrhea, and mucus purulent stool. The disease is more recurrent, easy to delay, and canceration, seriously affect the quality of life, increase the economic burden of patients and society, treatment is more difficult, the World Health Organization as one of the modern refractory diseases. Shenling Atractylodes Powder in the treatment of ulcerative colitis showed a strong advantage, the effect is accurate. Therefore, this paper will systematically evaluate and meta-analyze the efficacy and safety of heat-sensitive moxibustion in the treatment of ulcerative colitis. METHODS: Eight electronic databases were searched, including the PubMed, Embase, Web of Science, Cochrane Library, China National knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biomedical Literature Database. We will search in the above electronic database from early 2021 to December without any language restrictions. Outcome indicators, including colonic mucosal symptom score Mayo colonoscopy grading, total effective rate, total incidence of adverse reactions, clinical symptom score, recurrence rate, laboratory indicators: IL-6, IL-9, TNF-α, IL-4, IL-10 inflammation-related factor levels. Rev Man5.3 software will be used for statistical analysis. The efficacy and safety results of Shenling Atractylodes Powder in the treatment of ulcerative colitis will be used as the average difference between the risk ratio of dichotomy data and the 95% co-card interval of continuous data. RESULTS: When this research program is completed, the relevant results can be obtained. ETHICS AND DISSEMINATION: This article does not need to pass the ethics committee review, because this article does not involve the ethics question, only collates the related literature research. The results of this study will be disseminated in the form of a paper to help better guide the clinical practice of heat-sensitive moxibustion in the treatment of ulcerative colitis. REGISTRATION NUMBER: INPLASY202120018.

Efficacy and safety of heat-sensitive moxibustion in the treatment of ulcerative colitis: A protocol for a systematic review and meta-analysis.

BACKGROUND: Ulcerative colitis (UC) is a chronic nonspecific intestinal inflammatory disease with unclear etiology occurring in the colonic mucosa. Its clinical manifestations are characterized by recurrent abdominal pain, diarrhea, mucous pus, and blood stool. The severity of the disease varies, and itis characterized by a high recurrence rate. Because of its long course of disease, easy to relapse, protracted and difficult to recover, seriously affect the quality of life, increase the economic burden of patients and society, and even the risk of developing cancer, it has become one of the hot issues of general concern in the medical field. Heat-sensitive moxibustion therapy has shown strong advantages in the treatment of UC, and the curative effect is accurate. therefore, this paper will carry out a systematic evaluation and meta analysis of the efficacy and safety of heat-sensitive moxibustion in the treatment of UC. METHODS: We will be searching 8 electronic databases, including PubMed, Embase, Web of Science, Cochrane Library, the China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, Wanfang Database, and Chinese Biomedical Literature Database. We will search above electronic databases from the beginning to December 2020, without any language restriction. Clinical efficacy, including total effective rate or cure rate, clinical symptom integral (abdominal pain, diarrhea, purulent stool), and recurrence rate will be accepted as the primary outcomes. The changes of cytokine Hs-CRP, IL-6, TNF-αlevels in serum, and improvement of colorectal mucosa will be used as secondary outcomes. RevMan 5.3 software will be used for statistical analysis. The result about the curative effect and safety of heat-sensitive moxibustion for UC will be presented as risk ratio for dichotomous data and mean differences with a 95% confidence interval for continuous data. RESULTS: When this research program is completed, the relevant results can be obtained. CONCLUSIONS: The results of this study will provide reliable evidence for the efficacy and safety of heat-sensitive moxibustion in the treatment of UC. INPLASY REGISTRATION NUMBER: INPLASY20201101034.

One new sesquiterpene pyridine alkaloid from the stems and leaves of Euonymus fortunei.

A new sesquiterpene pyridine alkaloid (1), along with four known compounds (2-5), were isolated from the stems and leaves of Euonymus fortunei. The new structure was determined by extensive spectroscopic analyses (IR, UV, NMR, HRESIMS and ECD). In addition, compound 3 showed a stronger anti-respiratory syncytial virus (RSV) activity with an IC50 value of 1.20 ± 0.10 µM than the positive control ribavirin with an IC50 value of 5.62 ± 0.49 µM.[Formula: see text].

Therapeutic effect of integrin-linked kinase gene-modified bone marrow-derived mesenchymal stem cells for streptozotocin-induced diabetic cystopathy in a rat model.

BACKGROUND: Diabetic cystopathy (DCP) is a chronic complication of diabetes mainly within the submucosal and muscular layers of the bladder due to the hyperglycemia-induced ischemia. As no effective therapies are currently available, the administration of optimized mesenchymal stem cells (MSCs) provides a potential treatment of DCP. Thus far, new strategy, such as genetic modification of MSCs, has been developed and has shown promising outcomes of various disorders. METHODS: This study was conducted using integrin-linked kinase (ILK) gene-modified bone marrow-derived stem cells (BMSCs) for streptozotocin (STZ)-induced diabetic cystopathy in a rat model. In total, 68 male Sprague-Dawley rats were randomized into five groups: sham control (control group, n = 10); DCP model alone (DM group, n = 10); DCP rats intravenously treated with BMSCs (BMSC group, n = 16); DCP rats accepted adenoviral vector-infected BMSCs (Ad-null-BMSC group, n = 16) and DCP rats accepted ILK adenoviral vector-infected BMSCs (Ad-ILK-BMSC group, n = 16). Diabetic rats accepted cell transplantation in the experimental group (2 rats per group) were sacrificed for the bladder tissue on the third day, 7th day, and 14th day of treatment respectively ahead of schedule. At 4 weeks after treatment, all rats in five groups accepted urodynamic studies to evaluate bladder function and were sacrificed for bladder tissue. RESULTS: Our data showed that the underactive bladder function was significantly improved in DCP rats intravenously treated with ILK gene-modified BMSCs compared to those in the DM, BMSCs, and Ad-null-BMSC group. Meanwhile, we found that gene-modified BMSC treatment significantly promoted the activation of the AKT/GSK-3ß pathway by increasing phosphorylation and led to the enhancement of survival. In addition, the expression levels of angiogenesis-related protein vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and stromal cell-derived factor-1 (SDF-1) were significantly higher in the Ad-ILK-BMSC group than that in the DM, BMSCs, and Ad-null-BMSC group as assessed by enzyme-linked immunosorbent assay and western blot. As two indicators of vascular endothelial cell markers, the expression of von Willebrand factor (vWF) and CD31 by western blot and immunofluorescent staining revealed that the percentage of the vascular area of the bladder tissue significantly increased in Ad-ILK-BMSC group compared with the BMSCs and Ad-null-BMSC group on the 14th day of treatment. Histological and immunohistochemical staining (hematoxylin and eosin (HE), vWF, Ki67, and TUNNEL) on the bladder tissue revealed statistically different results between groups. CONCLUSION: ILK gene-modified BMSCs restored the bladder function and histological construction via promoting the process of angiogenesis and protecting cells from high glucose-associated apoptosis in STZ-induced DCP rat model, which provides a potential for the treatment of patients with DCP.

Phorbol ester-type diterpenoids from the twigs and leaves of Croton tiglium.

Phytochemical investigation of the ethanol extract from the twigs and leaves of Croton tiglium led to the isolation of two new phorbol esters (1-2) and seven known ones (3-9). Their structures were elucidated by the analyses of extensive spectroscopic data (IR, MS, and 1D and 2D NMR) and comparing with related compounds. Meanwhile, compounds 1-9 were determined for their cytotoxic activities on human lung cancer cell line A549. Among them, 1-2 were inactive against the cell line A549 (IC50 > 100 µM), but compounds 3 and 7 showed weak activities.

Six New Acylphloroglucinols from Dryopteris championii.

Six new acylphloroglucinols (1 - 6) were isolated from Dryopteris championii. Their structures were established on the basis of extensive analysis of spectroscopic data and comparison with reported data. The antibacterial activities of the isolates were evaluated against Staphylococcus aureus, Escherichia coli, Bacillus subtilis, and Dickeya zeae.

SUPERFAMILY--sophisticated comparative genomics, data mining, visualization and phylogeny.

SUPERFAMILY provides structural, functional and evolutionary information for proteins from all completely sequenced genomes, and large sequence collections such as UniProt. Protein domain assignments for over 900 genomes are included in the database, which can be accessed at http://supfam.org/. Hidden Markov models based on Structural Classification of Proteins (SCOP) domain definitions at the superfamily level are used to provide structural annotation. We recently produced a new model library based on SCOP 1.73. Family level assignments are also available. From the web site users can submit sequences for SCOP domain classification; search for keywords such as superfamilies, families, organism names, models and sequence identifiers; find over- and underrepresented families or superfamilies within a genome relative to other genomes or groups of genomes; compare domain architectures across selections of genomes and finally build multiple sequence alignments between Protein Data Bank (PDB), genomic and custom sequences. Recent extensions to the database include InterPro abstracts and Gene Ontology terms for superfamiles, taxonomic visualization of the distribution of families across the tree of life, searches for functionally similar domain architectures and phylogenetic trees. The database, models and associated scripts are available for download from the ftp site.