Treatment Of Gallbladder Cancer Research Articles

Progress and controversy in minimally invasive approach to radical cholecystectomy for gallbladder cancer

Surgical treatment is one of the most important forms of treatment in patients with gallbladder cancer. With the development of minimally invasive technology, the feasibility, safety and efficacy of minimally invasive approaches such as laparoscopic or robotic-assisted radical cholecystectomy for gallbladder cancer have received continuous attention.For patients with an early T-stage (Tis or T1a), laparoscopic simple cholecystectomy is safe and economical, with a good prognosis for postoperative patients, and it has been widely accepted and performed. Radical resection of advanced gallbladder cancer requires resection of the gallbladder, its liver bed, and other neighboring invaded organs, as well as clearance of regional lymph nodes, which requires experienced gallbladder cancer treatment teams to strictly grasp the indications, select appropriate patients, and formulate a good surgical strategy to ensure the therapeutic effect. Meanwhile, robot-assisted radical resection for gallbladder cancer has been performed in a few centers and shows good clinical potential, but more high-quality studies are needed to further evaluate its value in gallbladder cancer treatment.

Deciphering the role of Enterococcus faecium cytidine deaminase in gemcitabine resistance of gallbladder cancer

Gemcitabine-based chemotherapy is a cornerstone of standard care for gallbladder cancer (GBC) treatment. Still, drug resistance remains a significant challenge, influenced by factors such as tumor-associated microbiota impacting drug concentrations within tumors. Enterococcus faecium, a member of tumor-associated microbiota, was notably enriched in the GBC patient cluster. In this study, we investigated the biochemical characteristics, catalytic activity, and kinetics of the cytidine deaminase of E. faecium (EfCDA). EfCDA showed the ability to convert gemcitabine to its metabolite 2',2'-difluorodeoxyuridine. Both EfCDA and E. faecium can induce gemcitabine resistance in GBC cells. Moreover, we determined the crystal structure of EfCDA, in its apo form and in complex with 2', 2'-difluorodeoxyuridine at high resolution. Mutation of key residues abolished the catalytic activity of EfCDA and reduced the gemcitabine resistance in GBC cells. Our findings provide structural insights into the molecular basis for recognizing gemcitabine metabolite by a bacteria CDA protein and may provide potential strategies to combat cancer drug resistance and improve the efficacy of gemcitabine-based chemotherapy in GBC treatment.

Construction of a Human Immune Library from Gallbladder Cancer Patients for the Single-Chain Fragment Variable (scFv) Antibody Selection against Claudin 18.2 via Phage Display.

Gallbladder cancer (GBC) is a very aggressive malignant neoplasm of the biliary tract with a poor prognosis. There are no specific therapies for the treatment of GBC or early diagnosis tools; for this reason, the development of strategies and technologies that facilitate or allow an early diagnosis of GBC continues to be decisive. Phage display is a robust technique used for the production of monoclonal antibodies (mAbs) involving (1) the generation of gene libraries, (2) the screening and selection of isoforms related to an immobilized antigen, and (3) the in vitro maturation of the affinity of the antibody for the antigen. This research aimed to construct a human immune library from PBMCs of GBC patients and the isolation of scFv-phage clones with specificity against the larger extracellular loop belonging to claudin 18.2, which is an important biomarker overexpressed in GBC as well as gastric cancer. The immune-library-denominated GALLBLA1 was constructed from seven GBC patients and has a diversity of 6.12 × 1010pfu mL-1. After three rounds of panning, we were able to identify clones with specificity against claudin 18.2. GALLBLA1 can contribute to the selection, isolation, and recombinant production of new human mAbs candidates for the treatment of gastrointestinal cancers.

SIRT7: A potential prognostic marker and therapeutic target in gallbladder cancer

Gallbladder cancer (GBC) is a highly aggressive malignancy with limited treatment options and poor prognosis. In this study, we aimed to investigate the role of SIRT7, a member of the sirtuin family, in GBC and its potential as a prognostic marker and therapeutic target. Through immunohistochemistry analysis of GBC tissue samples, we observed elevated levels of SIRT7, which were correlated with worse clinicopathological parameters and shorter overall survival in GBC patients. Additionally, through cellular and animal experiments, we have discovered that interfering with SIRT7 can effectively suppress the proliferation, migration, and invasive capabilities of GBC cells. Conversely, overexpressing SIRT7 yields the opposite outcome. Furthermore, interference with SIRT7 triggers cell cycle arrest and enhances apoptosis in GBC cells. Mechanistically, we found that SIRT7 inhibition led to reduced activation of the NF-κB signaling pathway, suggesting its involvement in modulating GBC cell behavior. Our findings shed light on the oncogenic role of SIRT7 in GBC and highlight its potential as a promising prognostic marker and therapeutic target. Further research is warranted to explore the therapeutic implications of targeting SIRT7 in GBC treatment.

Referral rate of patients with incidental gallbladder cancer and survival: outcomes of a multicentre retrospective study.

Treatment outcomes of incidental gallbladder cancer generally stem from tertiary referral centres, while many patients are initially diagnosed and managed in secondary care centres. Referral patterns of patients with incidental gallbladder cancer are poorly reported. This study aimed to evaluate incidental gallbladder cancer treatment in secondary centres, rates of referral to tertiary centres and its impact on survival. Medical records of patients with incidental gallbladder cancer diagnosed between 2000 and 2019 in 27 Dutch secondary centres were retrospectively reviewed. Patient characteristics, surgical treatment, tumour characteristics, referral pattern and survival were assessed. Predictors for overall survival were determined using multivariable Cox regression. In total, 382 patients with incidental gallbladder cancer were included. Of 243 patients eligible for re-resection (pT1b-pT3, M0), 131 (53.9%) were referred to a tertiary centre. The reason not to refer, despite indication for re-resection, was not documented for 52 of 112 non-referred patients (46.4%). In total, 98 patients underwent additional surgery with curative intent (40.3%), 12 of these in the secondary centre. Median overall survival was 33 months (95% c.i. 24 to 42 months) in referred patients versus 17 months (95% c.i. 3 to 31 months) in the non-referred group (P = 0.019). Referral to a tertiary centre was independently associated with improved survival after correction for age, ASA classification, tumour stage and resection margin (HR 0.60, 95% c.i. 0.38 to 0.97; P = 0.037). Poor incidental gallbladder cancer referral rates were associated with worse survival. Age, performance status, resection margin or tumour stage should not preclude referral of a patient with incidental gallbladder cancer to a tertiary centre.

Adavosertib-encapsulated metal-organic frameworks for p53-mutated gallbladder cancer treatment via synthetic lethality

Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal–organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed. The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment. Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species (ROS), which leads to a further increase in DNA damage, resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality. The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.

Hepatic arterial infusion chemotherapy combined with bevacizumab plus a PD-1 inhibitor for gallbladder cancer with hepatic oligometastasis: a real-world study.

Gallbladder cancer (GBC) is different from other biliary tract cancers in terms of molecular phenotype and microenvironment. Specific treatments for GBC need to be urgently explored. This study preliminarily investigated the clinical value of hepatic artery infusion chemotherapy (HAIC) combined with bevacizumab plus a programmed death receptor-1 (PD-1) inhibitor for treatment of GBC with hepatic oligometastasis. We retrospectively collected data on GBC patients with hepatic oligometastasis, who received this combination therapy. The clinical data, conversion rate, treatment response, adverse events (AEs), and short-term survival were summarized. The responses of primary gallbladder lesions and hepatic metastasis, and their effect on prognosis, were investigated. A total of 27 patients were included in the analysis. No grade 4 AEs were observed. The overall objective response rate (ORR) was 55.6% and the disease control rate (DCR) was 85.2%. Median overall survival (OS) time was 15.0 months and the 1-year survival rate was 64.0%. Median progression-free survival (PFS) time was 7.0 months and the 1-year PFS rate was 16.2%. Six patients (22.2%) were successfully converted to resection. Compared with primary gallbladder lesions, it appeared more difficult for patients with hepatic metastasis to achieve remission (ORR: 40.7% vs. 77.8%; P=0.012), but its response appeared to be closely related to the prognosis [median OS: 16.0 months in the complete response (CR) or partial response (PR) group vs. 11.0 months in the stable disease (SD) or progressive disease (PD) group, P=0.070; median PFS: 12.0 months in the CR or PR group vs. 6.5 months in the SD or PD group, P<0.001]. Preoperative CA19-9 of >1,900 U/mL and >5 cm metastatic lesions were associated with an unsatisfactory response, whereas a significant decrease of 18F-fluorodeoxyglucose (18F-FDG) uptake may be a marker of tumor remission. The combination of HAIC, a PD-1 inhibitor, and bevacizumab shows potential for advanced GBC with hepatic oligometastasis. The therapeutic response of hepatic metastasis had a greater influence on prognosis than that of primary gallbladder lesions.

SNORA38B promotes proliferation, migration, invasion and epithelial-mesenchymal transition of gallbladder cancer cells &lt;em&gt;via&lt;/em&gt; activating TGF-β/Smad2/3 signaling

Evidence has shown that small nucleolar RNAs (snoRNAs) participate in the tumorigenesis in multiple cancers, including gallbladder cancer (GBC). Our results showed that SNORA38B level was increased in GBC tissues compared to adjacent normal tissues. Thus, this research aimed to explore the role and molecular mechanisms of SNORA38B in GBC. SNORA38B level between normal and GBC tissues was evaluated by RT-qPCR. Cell proliferation, apoptosis, migration, and invasion were tested by EdU assay, TUNEL staining and transwell assay, respectively on human intrahepatic biliary epithelial cells (HIBEpiCs) and the GBC cell lines, NOZ and GBC-SD. Expression of proteins in GBC cells was evaluated by immunofluorescence and Western blot assays. We found that, relative to normal tissues, SNORA38B level was notably elevated in GBC tissues. SNORA38B overexpression obviously enhanced GBC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), but weakened cell apoptosis. Conversely, SNORA38B downregulation strongly suppressed the proliferation and EMT of GBC cells and induced cell apoptosis and ferroptosis, whereas these phenomena were obviously reversed by TGF-β. Meanwhile, SNORA38B downregulation notably reduced the levels of phosphorylated-Smad2 and phosphorylated-Smad3 in GBC cells, whereas these levels were elevated by TGF-β. Collectively, downregulation of SNORA38B could inhibit GBC cell proliferation and EMT and induce ferroptosis via inactivating TGF-β1/Smad2/3 signaling. These findings showed that SNORA38B may be potential target for GBC treatment.

SNHG15 promotes gallbladder cancer progression by enhancing the autophagy of tumor cell under nutrition stress

ABSTRACTGallbladder cancer (GBC) is a major malignant carcinoma of the biliary tract with extremely poor prognosis. Currently, there is no useful therapy strategies for GBC treatment, indicating the unmet mechanism researches for GBC. In this study, our data showed that SNHG15 expression significantly up-regulated and its high expression associated with poor overall survival of patients suffer from GBC. Functional experiments showed that SNHG15 depletion delayed the proliferation and enhanced the apoptosis of GBC tumor cells under the nutrition stress condition, which further confirmed in the subcutaneous xenograft model and liver metastasis model. Mechanistically, SNHG15 could interact with AMPK and facilitate the phosphorylation of AMPK to Tuberous sclerosis complex TSC2, resulting in mTOR suppression and autophagy enhancement, and finally, conferring the GBC cell sustain proliferation under nutrition stress. Taken together, our findings revealed that SNHG15 promotes GBC tumor progression by enhancing the autophagy under poor nutrition tumor microenvironment, which could be a promising targets for GBC.

Updates and advances in the concept of gallbladder cancer treatment

The gallbladder is the most common site of tumor occurrence among biliary tract cancer. Gallbladder cancer accounts for approximately 0.6% of new cancers and 0.9% of cancer-related deaths. The risk factors identified for the development of gallbladder cancer include being female,>65 years of age, asymptomatic gallstone disease,and obesity. Surgical resection is the only curative treatment for early-stage gallbladder cancer, and some intermediate or advanced gallbladder cancers can be radically cured by extended resection. However, the extent of liver resection or lymph node dissection and whether to combine it with bile duct removal, revascularisation,and multiple organ resection remain somewhat controversial. After neoadjuvant treatment, up to a third of patients with locally advanced gallbladder cancer benefit from secondary surgical treatment. Only a small proportion of patients with gallbladder cancer at high risk for recurrence will benefit from postoperative adjuvant therapy. With the advent of different target-targeted drugs and the use of genetic tests in biliary tract cancer, targeted therapy and PD-1/PD-L1 inhibitors may become the new standard of care for gallbladder cancer and need to be further explored.

Isoliquiritigenin induces HMOX1 and GPX4-mediated ferroptosis in gallbladder cancer cells.

Gallbladder cancer (GBC) is the most common malignant tumor of biliary tract. Isoliquiritigenin (ISL) is a natural compound with chalcone structure extracted from the roots of licorice and other plants. Relevant studies have shown that ISL has a strong anti-tumor ability in various types of tumors. However, the research of ISL against GBC has not been reported, which needs to be further investigated. The effects of ISL against GBC cells in vitro and in vivo were characterized by cytotoxicity test, RNA-sequencing, quantitative real-time polymerase chain reaction, reactive oxygen species (ROS) detection, lipid peroxidation detection, ferrous ion detection, glutathione disulphide/glutathione (GSSG/GSH) detection, lentivirus transfection, nude mice tumorigenesis experiment and immunohistochemistry. ISL significantly inhibited the proliferation of GBC cells in vitro . The results of transcriptome sequencing and bioinformatics analysis showed that ferroptosis was the main pathway of ISL inhibiting the proliferation of GBC, and HMOX1 and GPX4 were the key molecules of ISL-induced ferroptosis. Knockdown of HMOX1 or overexpression of GPX4 can reduce the sensitivity of GBC cells to ISL-induced ferroptosis and significantly restore the viability of GBC cells. Moreover, ISL significantly reversed the iron content, ROS level, lipid peroxidation level and GSSG/GSH ratio of GBC cells. Finally, ISL significantly inhibited the growth of GBC in vivo and regulated the ferroptosis of GBC by mediating HMOX1 and GPX4 . ISL induced ferroptosis in GBC mainly by activating p62-Keap1-Nrf2-HMOX1 signaling pathway and down-regulating GPX4 in vitro and in vivo . This evidence may provide a new direction for the treatment of GBC.

DLGAP5 promotes gallbladder cancer migration and tumor-associated macrophage M2 polarization by activating cAMP.

Although disc large associated protein family (DLGAP5) has been reported to be involved in a variety of tumor pathologic processes, its expression and mechanism in gallbladder cancer (GBC) are still uncertain. Macrophages were divided into M1 and M2 macrophages. TAM is more closely defined as M2 polarized macrophages, which plays a key role in cancer progression. To clarify the role of disc large associated protein family (DLGAP5) in gallbladder cancer (GBC) progression and investigate the mechanism. Differential genes in 10 normal paracancer tissues and 10 GBC tissues in GSE139682 from NCBI-GEO were analyzed by R language. Bioinformation analysis and clinical sample analysis were performed to detect DLGAP5 expression in GBC and its correlation with prognosis. CCK-8, EDU, transwell, wound closure, and Immunoblot were performed to detect its effects on the function of GBC cells. GST-pulldown showed the direct interact between DLGAP5 and cAMP. Macrophage polarization assay was further conducted to detect the effects of DLGAP5 on macrophage M2 polarization. The tumor growth assays were further conducted to confirm its role in mice. Biological analysis and clinical samples confirmed that DLGAP5 was increased in GBC and strongly related to poor prognosis in patients with GBC. After overexpression of DLGAP5 in GBC cell lines, such as GBC-SD and NOZ cells, cell proliferation and migration were enhanced, and macrophages were polarized to M2. However, after DLGAP5 is knocked down, there is opposite effect. Mechanistically, DLGAP5 promotes the growth and migration of GBC-SD and NOZ cells and the M2 polarization of THP-1-derived macrophages by activating cyclic adenosine monophosphate (cAMP) pathway. In vivo, GBC-SD with DLGAP5 knockdown was subcutaneously injected into nude mice. It was found that after DLGAP5 knockdown, both tumor volume and tumor were reduced, and indicators related to proliferation and M2 polarization decreased. Our study shows that DLGAP5 is significantly elevated in GBC and is strongly related to poor prognosis in patients with GBC. DLGAP5 promotes GBC proliferation, migration, and M2 polarization of macrophages through cAMP pathway, which provides a theoretical basis for the treatment of GBC and may become a promising therapeutic target.

Gallbladder cancer: current and future treatment options.

Surgery remains the preferred treatment option for early-stage gallbladder cancer (GBC). According to the anatomical position of the primary tumor, accurate preoperative stage and strict control of surgical indications, appropriate surgical strategies are selected to achieve the optimal surgical effect. However, most patients have already been at the locally advanced stage or the tumor has metastasized at the initial diagnosis. The postoperative recurrence rate and 5-year survival rate remain unsatisfactory even after radical resection for gallbladder cancer. Hence, there is an urgent need for more treatment options, such as neoadjuvant therapy, postoperative adjuvant therapy and first-line and second-line treatments of local progression and metastasis, in the whole-course treatment management of gallbladder cancer patients. In recent years, the application of molecular targeted drugs and immunotherapy has brought greater hope and broader prospects for the treatment of gallbladder cancer, but their effects in improving the prognosis of patients still lack sufficient evidence-based medicine evidence, so many problems should be addressed by further research. Based on the latest progress in gallbladder cancer research, this review systematically analyzes the treatment trends of gallbladder cancer.

ELF3 promotes gemcitabine resistance through PKMYT1/CDK1 signaling pathway in gallbladder cancer.

Gemcitabine is the standard treatment for gallbladder cancer (GBC) patients, and the development of resistance frequently limits its efficacy. However, the molecular features and mechanisms of gemcitabine resistance (Gem-R) in GBC cells remain unknown. Herein, we aimed to explore the role of ELF3 in Gem-R of GBC, including the underlying mechanisms. RNA sequencing was used to screen the essential genes related to the generation of Gem-R in GBC tissues. The correlation between Gem-R and ELF3 expression was identified in GDSC, GEO database, GBC tissues, and 3 GBC cell lines. Immunohistochemical staining, quantitative real-time polymerase chain reaction, and western blot were used to examine the expression of ELF3, PKMYT1, and CDK1. Luciferase reporter assays were used to identify the binding site of ELF3 in the PKMYT1 promoter region. CCK-8 assay and clonogenic survival assays were used to evaluate the sensitivity of gemcitabine in GBC cells. A GBC xenograft model was used to evaluate the influence of ELF3 on the therapeutic effect of gemcitabine. A consistently positive correlation between ELF3 expression and Gem-R, both in newly generated GBC RNA-seq data and in the datasets from GDSC and GEO. Gem-R in GBC cells was facilitated by ELF3 overexpression, whereas ELF3 knockdown had the opposite effect. In vivo experiments further proved that reducing ELF3 expression promoted the gemcitabine sensitivity of GBC cells and extended the survival time of mice that received orthotopic xenografted tumors. Mechanistically, ELF3 upregulated PKMYT1 expression by interacting with the DNA binding region of PKMYT1 in GBC cells, thereby promoting the phosphorylation of CDK1 and inducing Gem-R. Treatment with a combination of the PKMYT1 shRNA and gemcitabine significantly reduced the growth of GBC cells induced by overexpression of ELF3 in vitro and in vivo. ELF3/PKMYT1/CDK1 axis significantly regulates Gem-R to GBC cells and may represent a promising drug target for treating GBC patients.

Short-term efficacy of cholecystectomy plus bile duct T-tube drainage or choledochojejunostomy in the treatment of gallbladder cancer and its effects on median survival time and postoperative complications.

To explore the short-term efficacy of cholecystectomy plus bile duct T-tube drainage or choledochojejunostomy (CJ) in the treatment of gallbladder cancer (GC) and its effects on the median survival time and postoperative complications. The clinical data of 121 patients who underwent laparoscopic cholecystectomy (LC) in department of hepatobiliary surgery of the hospital from January 2018 to December 2018 were retrospectively analyzed. According to the adjuvant treatment methods, the patients were divided into 2 groups: the control group (n = 61, LC + bile duct T-tube drainage) and experimental group (n = 60, LC + CJ). The perioperative indicators, short-term efficacy, median survival time, postoperative complications and immune stress response were compared between the 2 groups of patients before and after propensity score matching. The surgical time, postoperative anal first exhaust time, and intraoperative blood loss in the experimental group were no different from those in the control group (P > .05), but the hospital stay was shorter than that in the control group (P < .05). There was no difference in the effective rate of treatment and median survival time between the 2 groups (P > .05). The total incidence rate of complications in the experimental group at 14 days after surgery was lower than that in the control group (P < .05). Day 3 after surgery, the levels of immunoglobulin M (IgM) and immunoglobulin G (IgG) of the experimental group were higher than those of the control group (P < .05), while the level of C-reactive protein (CRP) was lower than that of the control group (P < .05). Compared with bile duct T-tube drainage, LC + CJ in the treatment of GC can better shorten the postoperative hospital stay and reduce the postoperative complications and immune stress response, but and the median survival time of the 2 is similar, which can be promoted in clinical practice.

Utility of Fluorescence with Indiocyanine Green (ICG) In Laparoscopic Radical Cholecystectomy En-Bloc for the Treatment of Gallbladder Cancer

Utility of Fluorescence with Indiocyanine Green (ICG) In Laparoscopic Radical Cholecystectomy En-Bloc for the Treatment of Gallbladder Cancer

Short- and long-term outcomes of laparoscopic vs open surgery for T2 gallbladder cancer: A systematic review and meta-analysis

With the development of laparoscopic techniques, gallbladder cancer (GBC) is no longer a contraindication to laparoscopic surgery (LS). Although LS is recommended for stage T1 GBC, the value of LS for stage T2 GBC is still controversial. To evaluate the short- and long-term outcomes of LS in comparison to those of open surgery (OS) for stage T2 GBC. We searched the PubMed, Embase, Cochrane Library, Ovid, Google Scholar, and Web of Science databases for published studies comparing the efficacy of LS and OS in the treatment of stage T2 GBC, with a cutoff date of September 2022. The Stata 15 statistical software was used for analysis. Relative risk (RR) and weighted mean difference (WMD) were calculated to assess binary and continuous outcome indicators, respectively. Begg's test and Egger's test were used for detecting publication bias. A total of five studies were included, with a total of 297 patients, 153 in the LS group and 144 in the OS group. Meta-analysis results showed that the LS group was better than the OS group in terms of operative time [WMD = -41.29, 95% confidence interval (CI): -75.66 to -6.92, P = 0.02], estimated blood loss (WMD = -261.96, 95%CI: -472.60 to -51.31, P = 0.01), and hospital stay (WMD = -5.67, 95%CI: -8.53 to -2.81, P = 0.0001), whereas there was no significant difference between the two groups in terms of blood transfusion (RR = 0.60, 95%CI: 0.31-1.15, P = 0.13), complications (RR = 0.72, 95%CI: 0.39-1.33, P = 0.29), number of lymph nodes retrieved (WMD = -1.71, 95%CI: -4.27 to -0.84, P = 0.19), recurrence (RR = 0.41, 95%CI: 0.06-2.84, P = 0.36), 3-year and 5-year overall survival (RR = 0.99, 95%CI: 0.82-1.18, P = 0.89 and RR = 1.02, 95%CI: 0.68-1.53, P = 0.92; respectively), and 3-year and 5-year disease-free survival (RR = 1.01, 95%CI: 0.84-1.21, P = 0.93 and RR = 1.15, 95%CI: 0.90-1.46, P = 0.26; respectively). The long-term outcomes of LS for T2 GBC are similar to those of OS, but LS is superior to OS in terms of operative time, intraoperative bleeding, and postoperative hospital stay. Nevertheless, these findings should be validated via high-quality randomized controlled trials and longer follow-ups.

Redox-responsive engineered hybrid nanomedicine for gallbladder cancer therapy via hyaluronic acid depletion

Gallbladder cancer (GBC) is a highly fatal and most common biliary tract cancer for which there is no uniform chemotherapy regimen at present. Although several chemotherapy regimens are currently being examined in clinical trials, they are limited by the high systemic toxicity and low drug delivery efficiency. Based on the characteristics of the tumor microenvironment of GBC tumors that it is rich in hyaluronic acid (HA), herein, we design a paclitaxel (PTX)-loaded organosilica hybrid nanocarrier (named as PTX@PDHNs-HAase) modified with hyaluronidase (HAase), aiming to enhance the delivery and therapeutic efficiency of PTX in GBC tumors. Once the nanocarrier reaches the tumor site through the enhanced permeability and retention effect, HAase loaded onto the nanocarrier will degrade the excess HA presented at the GBC tumor site to cause its depletion, thereby softening the hard extracellular matrix (ECM) and facilitating further penetration of nanomedicine into the GBC tumor cells and releasing PTX under glutathione (GSH) stimulation to accomplish the chemotherapeutic effect. More importantly, PTX@PDHNs-HAase not only presents excellent therapeutic effect in vivo (tumor inhibition rate: 88.6%), but also reduces the systemic toxicity of PTX. To the best of our knowledge, this is the first exploration of the strategy to enhance the efficacy of chemotherapeutic agent for GBC tumor therapy by degrading HA to dismantle ECM for enhanced nanomedicine delivery, thus providing a promising paradigm for GBC treatment.

Long-term results and prognostic factors after surgical treatment for gallbladder cancer.

Gallbladder cancer is relatively rare and traditionally regarded as having poor prognosis. There is controversy about the effects of clinicopathological features and different surgical techniques on prognosis. The aim of this study was to investigate the effects of clinicopathological characteristics of the patients with surgically treated gallbladder cancer on long-term survival. We retrospectively analyzed the database of gallbladder cancer patients treated at our clinic between January 2003 and March 2021. Of 101 evaluated cases, 37 were inoperable. Twelve patients were determined unresectable based on surgical findings. Resection with curative intent was performed in 52 patients. The one-, three-, five-, and 10-year survival rates were 68.9%, 51.9%, 43.6%, and 43.6%, respectively. Median survival was 36.6 months. On univariate analysis, poor prognostic factors were determined as advanced age; high carbohydrate antigen 19-9 and carcinoembryonic antigen levels; non-incidental diagnosis; intraoperative incidental diagnosis; jaundice; adjacent organ/structure resection; grade 3 tumors; lymphovascular invasion; and high T, N1 or N2, M1, and high AJCC stages. Sex, IVb/V segmentectomy instead of wedge resection, perineural invasion, tumor location, number of resected lymph nodes, and extended lymphadenectomy did not significantly affect overall survival. On multivariate analysis, only high AJCC stages, grade 3 tumors, high carcinoembryonic antigen levels, and advanced age were independent predictors of poor prognosis. Treatment planning and clinical decision-making for gallbladder cancer requires individualized prognostic assessment along with standard anatomical staging and other confirmed prognostic factors.

Elongator and the role of its subcomplexes in human diseases.

The Elongator complex was initially identified in yeast, and a variety of distinct cellular functions have been assigned to the complex. In the last decade, several research groups focussed on dissecting its structure, tRNA modification activity and role in translation regulation. Recently, Elongator emerged as a crucial factor for various human diseases, and its involvement has triggered a strong interest in the complex from numerous clinical groups. The Elongator complex is highly conserved among eukaryotes, with all six subunits (Elp1-6) contributing to its stability and function. Yet, recent studies have shown that the two subcomplexes, namely the catalytic Elp123 and accessory Elp456, may have distinct roles in the development of different neuronal subtypes. This Commentary aims to provide a brief overview and new perspectives for more systematic efforts to explore the functions of the Elongator in health and disease.