TRIM21-mediated ubiquitylation of TAT suppresses liver metastasis in gallbladder cancer.

Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator. However, the mechanisms underlying liver metastasis remain largely unknown. Here, we report a crucial role of tyrosine aminotransferase (TAT) in liver metastasis of GBC. TAT is frequently up-regulated in GBC tissues. Increased TAT expression is associated with frequent liver metastasis and poor prognosis of GBC patients. Overexpression of TAT promotes GBC cell migration and invasion in vitro, as well as liver metastasis in vivo. TAT knockdown has the opposite effects. Intriguingly, TAT promotes liver metastasis of GBC by potentiating cardiolipin-dependent mitophagy. Mechanistically, TAT directly binds to cardiolipin and leads to cardiolipin externalization and subsequent mitophagy. Moreover, TRIM21 (Tripartite Motif Containing 21), an E3 ubiquitin ligase, interacts with TAT. The histine residues 336 and 338 at TRIM21 are essential for this binding. TRIM21 preferentially adds the lysine 63 (K63)-linked ubiquitin chains on TAT principally at K136. TRIM21-mediated TAT ubiquitination impairs its dimerization and mitochondrial location, subsequently inhibiting tumor invasion and migration of GBC cells. Therefore, our study identifies TAT as a novel driver of GBC liver metastasis, emphasizing its potential as a therapeutic target.

Acylcarnitines promote gallbladder cancer metastasis through lncBCL2L11-THOC5-JNK axis.

BACKGROUND: The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid ß-oxidation (FAO) metabolism. Different types of lipids perform various biological functions. This study aimed to determine the role of acyl carnitines in the molecular mechanisms of GBC progression. METHODS: Distribution of lipids in GBC was described by LC-MS-based lipidomics. Cellular localization, expression level and full-length of lncBCL2L11 were detected using fluorescence in situ hybridization (FISH) assays, subcellular fractionation assay and 5' and 3' rapid amplification of the cDNA ends (RACE), respectively. In vitro and in vivo experiments were used to verify the biological function of lncBCL2L11 in GBC cells. Methylated RNA Immunoprecipitation (MeRIP) was performed to detect the methylation levels of lncBCL2L11. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were used to identify lncBCL2L11 interacting proteins. Co-Immunoprecipitation (Co-IP) and Western blot assay were performed to validate the regulatory mechanism of lncBCL2L11 and THO complex. RESULTS: Acylcarnitines were significantly up-regulated in GBC tissues. High serum triglycerides correlated to decreased survival in GBC patients and promoted tumor migration. LncBCL2L11 was identified in the joint analysis of highly metastatic cells and RNA sequencing data. LncBCl2L11 prevented the binding of THOC6 and THOC5 and causes the degradation of THOC5, thus promoting the accumulation of acylcarnitines in GBC cells, leading to the malignant progression of cancer cells. In addition, highly expressed acylcarnitines stabilized the expression of lncBCL2L11 through N6-methyladenosine methylation (m6A), forming a positive feedback regulation in tumor dissemination. CONCLUSIONS: LncBCL2L11 is involved in gallbladder cancer metastasis through FAO metabolism. High lipid intake is associated with poor prognosis of GBC. Therefore, targeting lncBCL2L11 and its pathway-related proteins or reducing lipid intake may be significant for the treatment of GBC patients.

Photocatalyst-Free Activation of Sulfamoyl Chlorides for Regioselective Sulfamoyl-Oximation of Alkenes via Hydrogen Atom Transfer (HAT) and Halogen-Atom Transfer (XAT) Relay Strategy.

The use of readily available and diverse sulfamoyl chlorides for synthesizing sulfonamide compounds presents an intriguing, yet significantly underexplored strategy. Activating sulfamoyl chlorides via single-electron reduction poses challenges due to their high reduction potential. Alternatively, the SO2-Cl bond in sulfamoyl chlorides could be readily cleaved by XAT. However, the existing methodologies have been limited to either the use of photocatalyst or the monofunctionalization of activated alkenes. Here, we report a regioselective sulfamoyl-oximation of alkenes by involving the activation of sulfamoyl chlorides through a HAT and XAT relay strategy in a photocatalyst-free way. The key to this success lies in the dual roles of tert-butyl nitrite (TBN), which not only serves as the source of oximes but also acts as the HAT reagent to generate the crucial XAT reactive species. The exclusion of metal catalysts or photosensitizers for utilizing light energy renders this protocol versatile and universally applicable for synthesizing a broad range of structurally diverse oxime-containing alkyl sulfonamides.

Radical-Based cis-Selective Annulations of N,N'-Cyclic Azomethine Imines with N-Sulfonyl Cyclopropylamines.

Azomethine imines, broadly known as 1,3-dipoles, efficiently produce synthetically and biologically significant dinitrogen-fused heterocycles via predominantly concerted or ionic pathways. Herein, we describe a radical-based annulation of azomethine imines utilizing visible-light photoredox catalysis for the first time. This strategy enables the synthesis of dinitrogen-fused saturated six-membered cyclic products that have traditionally been difficult to access. Notably, our process exhibits exceptional cis diastereoselectivity, controlled by the anomeric effect. Initial mechanistic investigations reveal a tandem process comprising intermolecular radical addition and intramolecular 6-exo-trig cyclization. This work illustrates potential within the realm of visible-light-driven radical cyclization reactions involving azomethine imines.

Improved long-term outcomes after innovative preoperative evaluation and conception of precise surgery for gallbladder cancer.

BACKGROUND: Three-dimensional visualization preoperative evaluation (3D-VPE) and enhanced recovery after surgery (ERAS) have been suggested to improve outcomes of cancer surgery in patients, yet little is known regarding their clinical benefit in patients with gallbladder cancer (GBC). We hypothesized that the combination of 3D-VPE and ERAS would improve the outcome of patients undergoing surgery for GBC. OBJECTIVE: This study aimed to determine if 3D-VPE and ERAS can improve the outcomes and overall survival in patients with GBC, establishing a novel patient management strategy for GBC. METHODS: A total of 227 patients with GBC were recruited and divided into two groups: those who received traditional treatment between January 2000 and December 2010 (n = 86; the control group) and those who underwent 3D-VPE and ERAS between January 2011 and December 2017 (n = 141). Univariate and multivariate analyses were employed to assess the relationship among disease stages, lymph node invasion, and cell differentiation between the two groups. Cox regression analysis was used to investigate patient survival in these groups. RESULTS: Patients who underwent 3D-VPE and ERAS showed a significantly higher R0 resection rate (67.4% vs. 20.9%, p < 0.001) and dissected lymph node number (26.6 ± 12.6 vs. 16.3 ± 7.6 p < 0.001) compared to the control group. The median survival was 27.4 months, and the 1- and 3-year survival rates were 84.4% and 29.8%, respectively, in patients who received combined management; in the control cohort, the median survival was 12.7 months, and the 1- and 3-year survival rates were 53.5% and 15.1%, respectively. In addition, some postoperative complications and risk factors were diminished relative to the traditionally treated patients. CONCLUSION: The implementation of 3D-VPE and ERAS can significantly improve the prognosis and outcomes of patients with GBC and should be considered for wide use in clinical practice.

Indolization of N-Aryl Tertiary Amines with Diazoacetates by a Single Organophotocatalyst.

Diazoacetates are widely used to synthesize highly valuable indoles. Previous research has focused on using metal carbene reactivity or the innate nucleophilicity of the diazoacetates to create indoles through a traditional two-electron pathway. However, these strategies are constrained by the need for transition metals, oxidants, or substrate prefunctionalization. To overcome the limitations, we report herein an open-shell strategy that utilizes the radical reactivity of diazoacetates to synthesize indoles for the first time, especially for more valuable [a]-annulated indoles. Notably, this visible-light-driven transformation is enabled by a single organophotocatalyst, proceeding without metals ot additives. Preliminary mechanistic studies and density functional theory calculations disclose a relay visible-light photoredox catalytic process that probably involves several discrete photoredox catalytic cycles in a single operation with one organophotocatalyst.

Redox-Enhanced Photoelectrochemical Activity in PHV/CdS Hybrid Film.

Semiconductive photocatalytic materials have received increasing attention recently due to their ability to transform solar energy into chemical fuels and photodegrade a wide range of pollutants. Among them, cadmium sulfide (CdS) nanoparticles have been extensively studied as semiconductive photocatalysts in previous studies on hydrogen generation and environmental purification due to their suitable bandgap and sensitive light response. However, the practical applications of CdS are limited by its low charge separation, which is caused by its weak ability to separate photo-generated electron-hole pairs. In order to enhance the photoelectrochemical activity of CdS, a polymer based on viologen (PHV) was utilized to create a series of PHV/CdS hybrid films so that the viologen unit could work as the electron acceptor to increase the charge separation. In this work, various electrochemical, spectroscopic, and microscopic methods were utilized to analyze the hybrid films, and the results indicated that introducing PHV can significantly improve the performance of CdS. The photoelectrochemical activities of the hybrid films were also evaluated at various ratios, and it was discovered that a PHV-to-CdS ratio of 2:1 was the ideal ratio for the hybrid films. In comparison with CdS nanoparticles, the PHV/CdS hybrid film has a relatively lower band gap, and it can inhibit the recombination of electrons and holes, enhancing its photoelectrochemical activities. All of these merits make the PHV/CdS hybrid film as a strong candidate for photocatalysis applications in the future.

Case report: A de novo ERBB3 mutation develops in a gallbladder cancer patient carrying BRCA1 mutation after effective treatment with olaparib.

Background: Gallbladder cancer (GBC) is highly lethal and resistant to most chemotherapeutic drugs. GBC was reported to carry multiple genetic mutations such as TP53, K-RAS, and ERBB2/3. Here, we unexpectedly identified a patient with GBC harboring germline BRCA1 p.Arg1325Lys heterozygous mutation. We sought to determine if olaparib, the poly ADP-ribose polymerase inhibitor (PARPi) commonly treated for BRCA mutation, can inhibit cancer development via a therapeutic trial on this patient. Case presentation: The patient received GBC R0 resection after an 8-week olaparib treatment. After surgery and 6-month follow-up treatment with olaparib, the patient's blood carbohydrate antigen 19-9 (CA19-9) level declined from 328 to 23.6 U/ml. No recurrence in CT scanning was observed, indicating a disease-free survival of 6 months with conventional therapy. Two months later, CT examination and CA19-9 level showed cancer relapse. A blood biopsy revealed a new ERBB3 p.Gly337Arg mutation. GBC cell lines ectopically expressing BRCA1 p.Arg1325Lys together with ERBB3 p.Gly337Arg mutations were challenged with olaparib and/or afatinib, an ERBB2/3 inhibitor. The dual mutation cells were more responsive to the combined olaparib with afatinib than a single drug in the cell proliferation assay. Conclusion: Olaparib is effective in a GBC patient with a BRAC1 mutation. The efficacy of olaparib and afatinib in both cultured BRAC1 and ERBB3 mutation cell lines suggests that a combined regimen targeting BRCA1/2 and ERBB2/3 mutations may be an optimal strategy to treat GBC patients who carry both gene mutations.

Synthesis of 2-Pyrazolines with a CF3- and Alkyne-Substituted Quaternary Carbon Center via [3 + 2] Cycloaddition of ß-CF3-1,3-enynes and Diazoacetates.

Given the importance of both the CF3 group and the alkyne moiety in synthetic/medicinal chemistry, we report here the first example of efficient synthesis of 2-pyrazolines with a CF3- and alkyne-substituted quaternary carbon center. This methodology has the advantages of high functional group compatibility, the avoidance of base and open-flask conditions, easily available and easy to handle reagent, and broad substrate scope. Notably, this protocol allows for the late-stage functionalization of biologically active molecules and the gram-scale synthesis.

Hepatopancreatoduodenectomy for advanced biliary malignancies.

BACKGROUND: Hepatopancreatoduodenectomy (HPD) has been considered the only curative treatment for metastatic cholangiocarcinoma and some locally advanced gallbladder cancers (GBCs). However, HPD has not yet been included in treatment guidelines as a standard surgical procedure in consideration of its morbidity and mortality rates. The aim of this study was to evaluate the safety and effectiveness of HPD in treating biliary malignancies. METHODS: The medical records of 57 patients with advanced biliary cancer undergoing HPD from January 2009 to December 2019 were retrospectively retrieved. A case-control analysis was conducted at our department. Patients with advanced GBC who underwent HPD (HPD-GBC group) were compared with a control group (None-HPD-GBC group). Baseline characteristics, preoperative treatments, tumor pathologic features, operative results, and prognosis were assessed. RESULTS: Thirteen patients with cholangiocarcinoma and 44 patients with GBC underwent HPD at our department. Significant postoperative complications (grade III or greater) and postoperative pancreatic fistula were observed in 24 (42.1%) and 15 (26.3%) patients, respectively. One postoperative death occurred in the present study. Overall survival (OS) was longer in patients with advanced cholangiocarcinoma than in those with GBC (median survival time [MST], 31 months vs . 11 months; P   <  0.001). In the subgroup analysis of patients with advanced GBC, multivariate analysis demonstrated that T4 stage tumors ( P  = 0.012), N2 tumors ( P  = 0.001), and positive margin status ( P  = 0.004) were independently associated with poorer OS. Patients with either one or more prognostic factors exhibited a shorter MST than patients without those prognostic factors ( P  < 0.001). CONCLUSION: HPD could be performed with a relatively low mortality rate and an acceptable morbidity rate in an experienced high- volume center. For patients with advanced GBC without an N2 or T4 tumor, HPD can be a preferable treatment option.

Modular Access to 2-(Trifluoromethyl)pyrazolo[1,5-a]pyridines and Their Benzo Analogues through a Copper(I)-Catalyzed Radical Annulation.

A mechanistically distinctive copper-catalyzed radical annulation to valuable 2-(trifluoromethyl)pyrazolo[1,5-a]pyridines and their benzo analogues has been described for the first time. Notably, the newly developed complementary process allows the synthesis of 4- or 6-substituted target molecular entities as a single product, which was previously challenging to access by existing methods. The utility of this process is further demonstrated by the facile construction of four different ring systems, a gram-scale synthesis, and the late-stage functionalization of bioactive molecules.

LncRNA MNX1-AS1 sustains inactivation of Hippo pathway through a positive feedback loop with USP16/IGF2BP3 axis in gallbladder cancer.

The long non-coding RNAs (lncRNAs) have been implicated in multiple human cancers, which may offer great potential as putative targets for cancer diagnosis and treatment. However, the roles of most lncRNAs in gallbladder cancer (GBC) remain poorly understood. The objective of this research involves investigating the clinical implications and underlying mechanism of lncRNA motor neuron and pancreas homeobo×1 antisense RNA 1 (MNX1-AS1) in GBC. This study shows that MNX1-AS1 expression is elevated in the tissues of GBC patients, and is strongly associated with reduced patient survival. Functionally, MNX1-AS1 significantly stimulates the proliferation and metastasis of GBC cells in vitro and in vivo. Mechanistically, MNX1-AS1 is transcriptionally activated by TEA domain family member 4 (TEAD4), and suppresses insulin-like growing factor 2 mRNA-binding protein 3 (IGF2BP3) degradation by recruiting ubiquitin specific peptidase 16 (USP16). Furthermore, MNX1-AS1/IGF2BP3 axis inhibits the Hippo signaling pathway and subsequently activates TEAD4, thereby forming a positive feedback loop. According to our results, MNX1-AS1 facilitates tumorigenesis, progression and metastasis of GBC through a MNX1-AS1/IGF2BP3/Hippo pathway positive feedback loop, which could be both diagnostically and therapeutically helpful in GBC.

Perfluoroalkylation of Terminal Alkynes with Perfluoroalkyl Iodides Catalyzed by an Iron Salt.

The one-step, direct perfluoroalkylation of terminal alkynes with perfluoroalkyl iodides has been developed in which a simple ligandless iron salt is employed as the catalyst. Various perfluoroalkylated alkynes could be afforded in good to excellent yields with good functional group compatibility. Preliminary mechanistic studies suggest the involvement of the perfluoroalkyl radical in the catalytic cycle and the perfluoroalkylated alkenyl iodides as intermediates. The method provides straight, streamlined, and sustainable access to perfluoroalkylated acetylenes.

Management of Primary Squamous Cell Carcinoma of the Pancreas: A Case Report.

Introduction: Primary squamous cell carcinoma of the pancreas (SCCP) is a rare malignant tumor that has been reported in individual case reports only. The clinical data on primary SCCP treatment are limited. Therefore, the appropriate management strategy for this disease should be standardized. Case Presentation: We present the case of a 63-year-old man admitted to our hospital for upper left abdominal pain for 2 months without weight loss or jaundice. Enhanced computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen revealed a mixed solid and cystic lesion in the pancreatic tail, measuring 35 × 37 mm in maximum diameter with enhancement. The patient was diagnosed with primary SCCP without metastasis, based on radiological and pathological findings. He did not receive neoadjuvant therapy postoperatively and was followed up by CT and MRI for 18 months without recurrence or metastasis. Result: Complete resection is the most effective treatment for early stage primary SCCP. Abdominal MRI is an effective imaging tool for preoperative evaluation and postoperative follow-up of primary SCCP. The need for neoadjuvant therapy depends on various factors. Conclusion: Primary SCCP is a tumor with poor prognosis. Risk factor control, early accurate radiologic evaluation, and individualized treatment strategies improve the quality of life and prolong the overall survival period of patients.

Efficient and chemoselective hydrogenation of aldehydes catalyzed by well-defined PN3-pincer manganese(II) catalyst precursors: an application in furfural conversion.

Well-defined and air-stable PN3-pincer manganese(II) complexes were synthesized and used for the hydrogenation of aldehydes into alcohols under mild conditions using MeOH as a solvent. This protocol is applicable for a wide range of aldehydes containing various functional groups. Importantly, α,ß-unsaturated aldehydes, including ynals, are hydrogenated with the CC double bond/CC triple bond intact. Our methodology was demonstrated for the conversion of biomass derived feedstocks such as furfural and 5-formylfurfural to furfuryl alcohol and 5-(hydroxymethyl)furfuryl alcohol respectively.

Modified FOLFIRINOX for unresectable locally advanced or metastatic gallbladder cancer, a comparison with GEMOX regimen.

BACKGROUND: The first-line chemotherapy regimen for advanced gallbladder cancer (GBC) is gemcitabine plus platinum (GP), despite its efficacy is limited. The current investigation is a retrospective study to compare the safety and efficacy between the modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine plus oxaliplatin (GEMOX) as the first-line chemotherapy for unresectable locally advanced or metastatic GBC. METHODS: The data of patients with unresectable locally advanced or metastatic GBC, who were treated with mFOLFIRINOX or GEMOX as the first-line therapy between April 2014 and April 2018 at Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, were retrieved. This retrospective study evaluated the clinical characteristics, survival outcomes and adverse events. RESULTS: A total of 44 patients (n=25 in mFOLFIRINOX, n=19 in GEMOX) were included. There were no significant differences between groups in baseline characteristics. The median progression free survival (mPFS) was 5.0 months in the mFOLFIRINOX group and 2.5 months in the GEMOX group [P=0.021; hazard ratio (HR), 0.499; 95% CI, 0.266 to 0.937]. The median overall survival (mOS) was 9.5 months in the mFOLFIRINOX group and 7.0 months in the GEMOX group (P=0.019; HR, 0.471; 95% CI, 0.239 to 0.929). Disease control rate (DCR) was 76.0% in the mFOLFIRINOX group and 47.4% in the GEMOX group (P=0.051). The rate of grade 3-4 adverse events was 48% in the mFOLFIRINOX group and 36.8% in the GEMOX group (P=0.459). The incidence of grade 3-4 neutropenia and diarrhea were more common in the mFOLFIRINOX group, while the incidence of grade 3-4 thrombocytopenia and peripheral neuropathy were more common in the GEMOX group. CONCLUSIONS: mFOLFIRINOX might improve the poor prognosis of unresectable locally advanced or metastatic GBC, and the results need to be further verified by prospective clinical studies.