Anti-PD-1 combined with hypomethylating agent and CAG regimen bridging to allogeneic hematopoietic stem cell transplantation: a novel strategy for relapsed/refractory acute myeloid leukemia.

Introduction: The prognosis of relapsed/refractory acute myeloid leukemia (r/rAML) is dismal, and allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potential cure. Combining anti-PD-1, hypomethylating agent (HMA), and CAG (cytarabine, aclarubicin/idarubicin, granulocyte colony-stimulating factor) regimen has showed primary efficacy in r/rAML. However, pre-transplant exposure to anti-PD-1 may lead to severe graft-versus-host disease (GVHD). This preliminary study aimed to evaluate the safety and efficacy of allo-HSCT in r/rAML patients receiving the anti-PD-1+HMA+CAG regimen. Methods: Fifteen r/rAML patients (12 related haploidentical donors [HIDs], 2 matched siblings, 1 unrelated donor) received this regimen and subsequent peripheral blood HSCT. Results: Four patients with HIDs received a GVHD prophylaxis regimen consisted of Anti-thymocyte globulin and a reduced-dose of post-transplant cyclophosphamide. The median follow-up was 20.9 months (range, 1.2-34.2). The cumulative incidences of acute GVHD grade 2-4 and grade 3-4 were 40% and 13.3%, respectively. The 2-year incidence of moderate-to-severe chronic GVHD, non-relapse mortality, and relapse were 10%, 22.3%, and 22.5%, respectively. The 2-year overall survival and GVHD-free/relapse-free survival rates were 54% and 48.6%, respectively. No death or relapse was observed in the PTCy group. Conclusion: The anti-PD-1+HMA+CAG regimen bridging to allo-HSCT for r/r AML was tolerable with promising efficacy. GVHD prophylaxis with PTCy for HID-HSCT showed preliminary survival advantage.

Enhanced pharmacological activities of AKR1C3-activated prodrug AST-3424 in cancer cells with defective DNA repair.

AST-3424 is a novel and highly tumor-selective prodrug. AST-3424 is activated by AKR1C3 to release a toxic bis-alkylating moiety, AST 2660. In this study, we have investigated the essential role of DNA repair in AST-3424 mediated pharmacological activities in vitro and in vivo. We show here that AST-3424 is effective as a single therapeutic agent against cancer cells to induce cytotoxicity, DNA damage, apoptosis and cell cycle arrest at G2 phase in a dose- and AKR1C3-dependent manner in both p53-proficient H460 (RRID:CVCL_0459) and p53-deficient HT-29 cells (RRID:CVCL_0320). The combination of abrogators of G2 checkpoint with AST-3424 was only synergistic in HT-29 but not in H460 cells. The enhanced activity of AST-3424 in HT-29 cells was due to impaired DNA repair ability via the attenuation of cell cycle G2 arrest and reduced RAD51 expression. Furthermore, we utilized a BRCA2 deficient cell line and two PDX models with BRCA deleterious mutations to study the increased activity of AST-3424. The results showed that AST-3424 exhibited enhanced in vitro cytotoxicity and superior and durable in vivo anti-tumor effects in cells deficient of DNA repair protein BRCA2. In summary, we report here that when DNA repair capacity is reduced, the in vitro and in vivo activity of AST-3424 can be further enhanced, thus providing supporting evidence for the further evaluation of AST-3424 in the clinic.

Prognostic Nomograms for Patients With NF-Pan-NET After Pancreatectomy: A Retrospective Analysis Based on SEER Database.

AIMS: Surgical resection is the primary treatment option for patients diagnosed with nonfunctional pancreatic neuroendocrine tumors (NF-Pan-NETs). However, the postoperative prognostic evaluation for NF-Pan-NET patients remains obscure. This study aimed to construct an efficient model to predict the prognosis of NF-Pan-NET patients who have received surgical resection. METHODS: NF-Pan-NET patients after pancreatectomy were retrieved from the SEER database for the period of 2010 to 2019. A total of 2844 patients with NF-Pan-NET from SEER database were included in our study. After careful screening, six clinicopathological variables including age, grade, AJCC T stage, AJCC N stage, AJCC M stage, and chemotherapy were selected to develop nomograms to predict overall survival (OS) and cancer-specific survival (CSS) respectively of the patients. RESULTS: The novel models demonstrated high accuracy and discrimination in prognosticating resected NF-Pan-NET through various validation methods. Furthermore, the risk subgroups classified by the newly developed risk stratification systems based on the nomograms exhibited significant differences in both OS and CSS, surpassing the efficacy of the AJCC 8th TNM staging system. Novel nomograms and corresponding risk classification systems were developed to predict OS and CSS in patients with NF-Pan-NET after pancreatectomy. CONCLUSION: The models demonstrated superior performance compared to traditional staging systems, providing clinicians with more accurate and personalized guidance for postoperative surveillance and treatment.

Immunotherapy and liver cancer research trends and the 100 most cited articles: A bibliometric analysis.

BACKGROUND: Bibliometric analysis of liver cancer research, particularly in immunotherapy, reveals crucial insights. The US leads in liver cancer mortality but ranks fifth globally. OBJECTIVE: Scopus database analysis identified 2,349 papers, with the top 100 ranging from 127 to 4,959 citations. Notably, "Microenvironmental Regulation of Tumours Progression and Metastasis" in the Journal of Nature Medicine garnered the highest citations. METHODS: Journals like the Journal of Hepatology, Hepatology, and Nature Reports Clinical Oncology contributed significantly. Understanding molecular mechanisms and prognostic indicators is paramount for advancing combination therapies. RESULTS: For better patient outcomes, research trends in liver cancer immunotherapy point to improved treatment protocols, knowledge of the tumor microenvironment, combining therapies, predicting disease course, international cooperation, sophisticated surgical techniques, early detection, oncolytic virotherapy, and patient-centered care. CONCLUSIONS: This research underscores immunotherapy's pivotal role and encourages further exploration, offering valuable insights into liver cancer treatment trends.

Fucoidan alleviates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via Nrf2/GPX4 pathway.

Doxorubicin (Dox), a chemotherapeutic agent frequently used to treat cancer, elicits cardiotoxicity, a condition referred to as Dox-induced cardiotoxicity (DIC), and ferroptosis plays a contributory role in its pathophysiology. Fucoidan, a polysaccharide with various biological activities and safety profile, has potential therapeutic and pharmaceutical applications. This study aimed to investigate the protective effects and underlying mechanisms of fucoidan in DIC. Echocardiography, biomarkers of cardiomyocyte injury, serum creatine kinase, creatine kinase isoenzyme and lactate dehydrogenase, as well as histological staining results, revealed that fucoidan significantly reduced myocardial damage and improved cardiac function in DIC mice. Transmission electron microscopy; levels of lipid reactive oxygen species, glutathione, and malondialdehyde; ferroptosis-related markers; and regulatory factors such as glutathione peroxidase 4 (GPX4), transferrin receptor protein-1, ferritin heavy chain-1, heme oxygenase-1 in the heart tissue were measured to explore the effect of fucoidan on Dox-induced ferroptosis. These results suggested that fucoidan could inhibit cardiomyocyte ferroptosis caused by Dox. In vitro experiments revealed that silencing nuclear factor-erythroid 2-related factor 2 (Nrf2) in cardiomyocytes reduced the inhibitory effect of fucoidan on ferroptosis. Hence, fucoidan has the potential to ameliorate DIC by inhibiting ferroptosis via the Nrf2/GPX4 pathway.

Outcomes of Vaginal Repair and Vaginal Repair Combined With GnRHa Administration in the Treatment of Cesarean Section Scar Defects: A Randomized Clinical Trial.

STUDY OBJECTIVE: To prospectively investigate whether the application of vaginal repair (VR) of cesarean section scar defect (CSD) combined with a gonadotropin-releasing hormone agonist (GnRHa) achieve better clinical outcomes than VR alone. DESIGN: A randomized clinical trial. SETTING: University Hospital. PATIENTS: A total of 124 women with CSD were undergoing expectant management from December 2016 to September 2021. 61 were randomized to VR+ GnRHa and 63 to VR alone. INTERVENTION: Vaginal repair combined with GnRHa and vaginal repair alone. MEASURES AND MAIN RESULTS: The primary outcome was the duration of menstruation and thickness of the remaining muscular layer (TRM) at 6 months after surgery. Secondary outcomes included the length, width, and depth of the CSD; operation time; estimated blood loss; hospitalization time; and operative complications. Women were treated with either VR (n = 63) or VR + GnRHa (n = 61). Menstruation and TRM in patients pre vs post comparisons either with VR or VR + GnRHa are significantly improved (p <.05). Significant differences in menstruation duration and TRM occurred in patients treated with VR + GnRHa compared with those treated with VR (p <.05). Moreover, the rate of CSD after surgery in the VR group was significantly higher than that in the VR + GnRHa group (p = .033), and CSD patients in the VR + GnRHa group achieved better therapeutic effects than those in the VR group (p = .017). Patients who received VR + GnRHa had a shorter menstruation duration and a greater increment of TRM postoperatively than patients treated with VR alone (p = .021; p = .002, respectively). CONCLUSION: VR + GnRHa therapy has a greater potential to improve scar healing and reduce the number of menstruation days than VR alone for symptomatic women with CSD.

Identification of fibronectin type III domain containing 3B as a potential prognostic and therapeutic target for pancreatic cancer: a preliminary analysis.

BACKGROUND: Fibronectin type III domain containing 3B (FNDC3B), a member of the fibronectin type III domain-containing protein family, has been indicated in various malignancies. However, the precise role of FNDC3B in the progression of pancreatic cancer (PC) still remains to be elucidated. METHODS: In this study, we integrated data from the National Center for Biotechnology Information, the Cancer Genome Atlas, Genotype-Tissue Expression database, and Gene Expression Omnibus datasets to analyze FNDC3B expression and its association with various clinicopathological parameters. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, along with Gene Set Enrichment Analysis (GSEA), single sample Gene Set Enrichment Analysis (ssGSEA) and estimate analysis were recruited to delve into the biological function and immune infiltration based on FNDC3B expression. Additionally, the prognostic estimation was conducted using Cox analysis and Kaplan-Meier analysis. Subsequently, a nomogram was constructed according to the result of Cox analysis to enhance the prognostic ability of FNDC3B. Finally, the preliminary biological function of FNDC3B in PC cells was explored. RESULTS: The study demonstrated a significantly higher expression of FNDC3B in tumor tissues compared to normal pancreatic tissues, and this expression was significantly associated with various clinicopathological parameters. GSEA revealed the involvement of FNDC3B in biological processes and signaling pathways related to integrin signaling pathway and cell adhesion. Additionally, ssGSEA analysis indicated a positive correlation between FNDC3B expression and infiltration of Th2 cells and neutrophils, while showing a negative correlation with plasmacytoid dendritic cells and Th17 cells infiltration. Kaplan-Meier analysis further supported that high FNDC3B expression in PC patients was linked to shorter overall survival, disease-specific survival, and progression-free interval. However, although univariate analysis demonstrated a significant correlation between FNDC3B expression and prognosis in PC patients, this association did not hold true in multivariate analysis. Finally, our findings highlight the crucial role of FNDC3B expression in regulating proliferation, migration, and invasion abilities of PC cells. CONCLUSION: Despite limitations, the findings of this study underscored the potential of FNDC3B as a prognostic biomarker and its pivotal role in driving the progression of PC, particularly in orchestrating immune responses.

Tight regulation of a nuclear HAPSTR1-HUWE1 pathway essential for mammalian life.

The recently discovered HAPSTR1 protein broadly oversees cellular stress responses. This function requires HUWE1, a ubiquitin ligase that paradoxically marks HAPSTR1 for degradation, but much about this pathway remains unclear. Here, leveraging multiplexed proteomics, we find that HAPSTR1 enables nuclear localization of HUWE1 with implications for nuclear protein quality control. We show that HAPSTR1 is tightly regulated and identify ubiquitin ligase TRIP12 and deubiquitinase USP7 as upstream regulators titrating HAPSTR1 stability. Finally, we generate conditional Hapstr1 knockout mice, finding that Hapstr1-null mice are perinatal lethal, adult mice depleted of Hapstr1 have reduced fitness, and primary cells explanted from Hapstr1-null animals falter in culture coincident with HUWE1 mislocalization and broadly remodeled signaling. Notably, although HAPSTR1 potently suppresses p53, we find that Hapstr1 is essential for life even in mice lacking p53. Altogether, we identify novel components and functional insights into the conserved HAPSTR1-HUWE1 pathway and demonstrate its requirement for mammalian life.

Survival benefit of adjuvant chemotherapy in patients with resected gallbladder adenocarcinoma: An updated retrospective cohort analysis.

BACKGROUND: The rarity yet high malignancy of gallbladder adenocarcinoma (GBA) endows it with a distinctive nature. Radical resection remains the foremost therapeutic approach for GBA, while the impact of early recurrence and metastasis on patient prognosis necessitates the utilization of adjuvant chemotherapy (AC). Despite numerous previous studies on this topic, a consensus regarding the authentic efficacy of AC has yet to be reached. METHODS: We conducted an updated retrospective cohort analysis utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database spanning from 2010 to 2020 to explore the association between AC and survival outcomes in patients with resected GBA. RESULTS: Our study included 2782 patients from the SEER database, with further evaluation of 843 patients in each cohort following meticulous execution of a 1:1 propensity score matching. Remarkably, the AC cohort exhibited a significant survival advantage when juxtaposed against the non-AC cohort. Multivariable Cox regression analysis identified age at diagnosis, year at diagnosis, grade, AJCC T stage, AJCC N stage as well as AC as independent prognostic factors. Furthermore, our findings unveiled that poor/undifferentiated tumor histology, pathological T2 or higher category and pathological N1 category were significantly associated with improved survival when treated with AC while simultaneously observing improved survival across all age categories. CONCLUSION: These results provide additional evidence supporting the survival benefits of AC and offer guidance for personalized therapy in patients with resected GBA.

Immune checkpoints targeting dendritic cells for antibody-based modulation in cancer.

Dendritic cells (DC) are professional antigen-presenting cells which link innate to adaptive immunity. DC play a central role in regulating antitumor T-cell responses in both tumor-draining lymph nodes (TDLN) and the tumor microenvironment (TME). They modulate effector T-cell responses via immune checkpoint proteins (ICPs) that can be either stimulatory or inhibitory. Functions of DC are often impaired by the suppressive TME leading to tumor immune escape. Therefore, better understanding of the mechanisms of action of ICPs expressed by (tumor-infiltrating) DC will lead to potential new treatment strategies. Genetic manipulation and high-dimensional analyses have provided insight in the interactions between DC and T-cells in TDLN and the TME upon ICP targeting. In this review, we discuss (tumor-infiltrating) DC lineage cells and tumor tissue specific "mature" DC states and their gene signatures in relation to anti-tumor immunity. We also review a number of ICPs expressed by DC regarding their functions in phagocytosis, DC activation, or inhibition and outline position in, or promise for clinical trials in cancer immunotherapy. Collectively, we highlight the critical role of DC and their exact status in the TME for the induction and propagation of T-cell immunity to cancer.