Tissue factor in cancer-associated thromboembolism: possible mechanisms and clinical applications

Venous and arterial thromboses, called as cancer-associated thromboembolism (CAT), are common complications in cancer patients that are associated with high mortality. The cell-surface glycoprotein tissue factor (TF) initiates the extrinsic blood coagulation cascade. TF is overexpressed in cancer cells and is a component of extracellular vesicles (EVs). Shedding of TF⁺EVs from cancer cells followed by association with coagulation factor VII (fVII) can trigger the blood coagulation cascade, followed by cancer-associated venous thromboembolism in some cancer types. Secretion of TF is controlled by multiple mechanisms of TF⁺EV biogenesis. The procoagulant function of TF is regulated via its conformational change. Thus, multiple steps participate in the elevation of plasma procoagulant activity. Whether cancer cell-derived TF is maximally active in the blood is unclear. Numerous mechanisms other than TF⁺EVs have been proposed as possible causes of CAT. In this review, we focused on a wide variety of regulatory and shedding mechanisms for TF, including the effect of SARS-CoV-2, to provide a broad overview for its role in CAT. Furthermore, we present the current technical issues in studying the relationship between CAT and TF.Subject terms: Molecular medicine, Cancer     

Comparing the Efficacy and Safety of Gemcitabine plus Nab-Paclitaxel versus Gemcitabine Alone in Older Adults with Unresectable Pancreatic Cancer

BackgroundGemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC.Patients and MethodsIn this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses.ResultsGnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant.ConclusionGnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.     

The SYNGAP1 3′UTR Variant in ALS Patients Causes Aberrant SYNGAP1 Splicing and Dendritic Spine Loss by Recruiting HNRNPK

Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3′ untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the SYNGAP1 3′UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the SYNGAP1 variant excessively recruited FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK), and antisense oligonucleotides (ASOs) blocking HNRNPK altered aberrant splicing and ameliorated dendritic spine loss. These data suggest that excessive recruitment of RNA-binding proteins, especially HNRNPK, as well as changes in SYNGAP1 isoforms, are crucial for spine formation in motor neurons.SIGNIFICANCE STATEMENT It is not yet known which RNAs cause the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously reported that Fused in sarcoma (FUS), a pathogenic RNA-binding protein in ALS, stabilizes synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3′ untranslated region (UTR) and maintains dendritic spine maturation. To elucidate whether this mechanism is crucial for ALS, we identified the SYNGAP1 3′UTR variant rs149438267 at the FUS binding site. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, which caused dendritic spine loss along with excessive recruitment of FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK). Our findings that dendritic spine loss is because of excess recruitment of RNA-binding proteins provide a basis for the future exploration of ALS-related RNA-binding proteins.     

Macrophage migration inhibitory factor‐CD74 interaction regulates the expression of programmed cell death ligand 1 in melanoma cells

Expression of programmed cell death ligand 1 (PD‐L1) on tumor cells contributes to cancer immune evasion by interacting with programmed cell death 1 on immune cells. γ‐Interferon (IFN‐γ) has been reported as a key extrinsic stimulator of PD‐L1 expression, yet its mechanism of expression is poorly understood. This study analyzed the role of CD74 and its ligand macrophage migration inhibitory factor (MIF) on PD‐L1 expression, by immunohistochemical analysis of melanoma tissue samples and in vitro analyses of melanoma cell lines treated with IFN‐γ and inhibitors of the MIF‐CD74 interaction. Immunohistochemical analyses of 97 melanoma tissue samples showed significant correlations between CD74 and the expression status of PD‐L1 (P < .01). In vitro analysis of 2 melanoma cell lines, which are known to secrete MIF constitutively and express cell surface CD74 following IFN‐γ stimulation, showed upregulation of PD‐L1 levels by IFN‐γ stimulation. This was suppressed by further treatment with the MIF‐CD74 interaction inhibitor, 4‐iodo‐6‐phenylpyrimidine. In the analysis of melanoma cell line WM1361A, which constitutively expresses PD‐L1, CD74, and MIF in its non‐treated state, treatment with 4‐iodo‐6‐phenylpyrimidine and transfection of siRNAs targeting MIF and CD74 significantly suppressed the expression of PD‐L1. Together, the results indicated that MIF‐CD74 interaction directly regulated the expression of PD‐L1 and helps tumor cells escape from antitumorigenic immune responses. In conclusion, the MIF‐CD74 interaction could be a therapeutic target in the treatment of melanoma patients.     

Clinical outcomes of laparoscopic and endoscopic cooperative surgery for gastric gastrointestinal stromal tumor

Background: Laparoscopic and endoscopic cooperative surgery (LECS) is a well-recognized surgical procedure for gastric gastrointestinal stromal tumor (GIST). In this report, we describe the clinical outcomes of LECS procedures for gastric GIST in our institution. Methods: We performed LECS procedures, including classical LECS, inverted LECS, closed LECS, and combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET), in 40 gastric intraluminal and intramural type GIST patients, whose tumors were ≤ 50 mm in diameter, between September 2012 and December 2020. The patient background, surgical outcomes, postoperative morbidity and mortality, as well as the tumors’ clinicopathological characteristics were analyzed retrospectively. Results: Pathological findings showed that most patients had a low or very low risk of tumor recurrence, while one patient had a high risk according to the modified-Fletcher’s classification. The median length of postoperative hospital stay was 7 days. Only one patient had severe postoperative grade III complications according to the Clavien-Dindo (C-D) classification, after closed LECS, but was treated successfully with endoscopic hemostasis for postoperative hemorrhage. The remaining patients treated with LECS did not have severe complications. During the follow-up period (median, 31 months), all patients were disease-free, with no tumor recurrence or metastases. Conclusion: LECS is a safe surgical procedure for gastric intraluminal and intramural type GIST ≤ 50 mm in diameter, with good clinical outcomes.     

Neutralizing and Epitope-Specific Antibodies against Respiratory Syncytial Virus in Maternal and Cord Blood Paired Samples

Only a few qualitative studies of neutralizing antibody titers (NATs) against respiratory syncytial virus (RSV) have focused on epitope-specific antibody (ESA) levels. Here, NATs against RSV in sera were measured using the blood of 412 mothers and cord blood (CB) of 95 of the 412 mother–child pairs. ESA levels against sites zero (Ø) and IIa of the F protein of RSV were measured in 87 of the 95 mother–child pairs. The median gestational age was 39 weeks. The NATs and ESA levels in CB were slightly higher than those in maternal blood (MB). The NATs for RSV subtype A (RSV-A) in MB and CB showed a positive correlation (r = 0.75). The ESA levels against sites Ø and IIa in MB and CB showed positive correlations, r = 0.76 and r = 0.69, respectively. In MB, the NATs and ESA levels against RSV were positively correlated, more significantly against site Ø (RSV-A: r = 0.70, RSV-B: r = 0.48) than against site IIa (RSV-A: r = 0.19, RSV-B: r = 0.31). Sufficient amounts of ESAs against sites Ø and IIa of RSV were transferred from mothers to term infants. ESA levels against site Ø contribute to NATs.     

Association between fat mass index,fat‐free mass index and hemoglobin A1c in a Japanese population: The Tohoku Medical Megabank Community‐based Cohort Study

Aims/IntroductionFat mass and fat‐free mass affect glycated hemoglobin A1c (HbA1c) levels and blood glucose levels, respectively. The aim of the present study was to examine the association between the fat mass index and fat‐free mass index with HbA1c.Materials and MethodsWe carried out a cross‐sectional study that included 3,731 men and 9,191 women aged ≥20 years, living in Miyagi Prefecture, Japan, who were not treated for diabetes. The fat mass index and fat‐free mass index were calculated as fat mass and fat‐free mass divided by the height squared, respectively. The indices were classified into sex‐specific quartiles and combined into 16 groups. An analysis of covariance was used to assess associations between the combined fat mass index and fat‐free mass index with HbA1c adjusted for potential confounders. The linear trend test was carried out by stratifying the fat mass index and fat‐free mass index, entering the number as a continuous term in the regression model.ResultsIn multivariable models, a higher fat mass index was related to higher HbA1c levels in men and women in all fat‐free mass index subgroups (P < 0.001 for linear trend). When we excluded the participants who had been identified as having diabetes, the fat‐free mass index was also related to higher HbA1c levels in most fat mass index subgroups (P < 0.05 for linear trend).ConclusionsFat mass index was positively related to HbA1c levels. The fat‐free mass index was also related to HbA1c levels when we excluded participants who had been identified as having have diabetes.