The health risk of social disadvantage is transplantable into a new host.

Low socioeconomic status (SES) is a risk factor for mortality and immune dysfunction across a wide range of diseases, including cancer. However, cancer is distinct in the use of allogeneic hematopoietic cell transplantation (HCT) as a treatment for hematologic malignancies to transfer healthy hematopoietic cells from one person to another. This raises the question of whether social disadvantage of an HCT cell donor, as assessed by low SES, might impact the subsequent health outcomes of the HCT recipient. To evaluate the cellular transplantability of SES-associated health risk, we analyzed the health outcomes of 2,005 HCT recipients who were transplanted for hematologic malignancy at 125 United States transplant centers and tested whether their outcomes differed as a function of their cell donor's SES (controlling for other known HCT-related risk factors). Recipients transplanted with cells from donors in the lowest quartile of SES experienced a 9.7% reduction in overall survival (P = 0.001) and 6.6% increase in treatment-related mortality within 3 y (P = 0.008) compared to those transplanted from donors in the highest SES quartile. These results are consistent with previous research linking socioeconomic disadvantage to altered immune cell function and hematopoiesis, and they reveal an unanticipated persistence of those effects after cells are transferred into a new host environment. These SES-related disparities in health outcomes underscore the need to map the biological mechanisms involved in the social determinants of health and develop interventions to block those effects and enhance the health of both HCT donors and recipients.

Folate shapes plant root architecture by affecting auxin distribution.

Folate (vitamin B9) is important for plant root development, but the mechanism is largely unknown. Here we characterized a root defective mutant, folb2, in Arabidopsis, which has severe developmental defects in the primary root. The root apical meristem of the folb2 mutant is impaired, and adventitious roots are frequently found at the root-hypocotyl junction. Positional cloning revealed that a 61-bp deletion is present in the predicted junction region of the promoter and the 5' untranslated region of AtFolB2, a gene encoding a dihydroneopterin aldolase that functions in folate biosynthesis. This mutation leads to a significant reduction in the transcript level of AtFolB2. Liquid chromatography-mass spectrometry analysis showed that the contents of the selected folate compounds were decreased in folb2. Arabidopsis AtFolB2 knockdown lines phenocopy the folb2 mutant. On the other hand, the application of exogenous 5-formyltetrahydrofolic acid could rescue the root phenotype of folb2, indicating that the root phenotype is indeed related to the folate level. Further analysis revealed that folate could promote rootward auxin transport through auxin transporters and that folate may affect particular auxin/indole-3-acetic acid proteins and auxin response factors. Our findings provide new insights into the important role of folic acid in shaping root structure.

Evaluation of immunoregulation and immunoprotective efficacy of Glaesserella parasuis histidine kinase QseC.

QseC is a membrane sensor kinase that enables bacteria to perceive autoinducers -3, adrenaline, and norepinephrine to initiate downstream gene transcription. In this study, we found that the QseC protein of Glaesserella parasuis can serve as an effective antigen to activate the host's immune response. Therefore, we investigated the immunogenicity and host protective effect of this protein. ELISA and indirect immunofluorescence results showed that QseC protein can induce high titer levels of humoral immunity in mice and regularly generate specific serum antibodies. We used MTS reagents to detect lymphocyte proliferation levels and found that QseC protein can cause splenic lymphocyte proliferation with memory and specificity. Further immunological analysis of the spleen cell supernatant revealed significant upregulation of levels of IL-1ß, IL-4 and IFN-γ in the QseC + adjuvant group. In the mouse challenge experiment, it was found that QseC + adjuvant can provide effective protection. The results of this study demonstrate that QseC protein provides effective protection in a mouse model and has the potential to serve as a candidate antigen for a novel subunit vaccine for further research.

Ehrlichia chaffeensis Etf-3 Induces Host RAB15 Upregulation for Bacterial Intracellular Growth.

Ehrlichia chaffeensis infects human monocytes or macrophages and causes human monocytic ehrlichiosis (HME), an emerging life-threatening zoonosis. After internalization, E. chaffeensis resides in membrane-bound inclusions, E. chaffeensis-containing vesicles (ECVs), which have early endosome-like characteristics and fuse with early autophagosomes but not lysosomes, to evade host innate immune microbicidal mechanisms and obtain nutrients for bacterial intracellular growth. The mechanisms exploited by E. chaffeensis to modulate intracellular vesicle trafficking in host cells have not been comprehensively studied. Here, we demonstrate that E. chaffeensis type IV secretion system (T4SS) effector Etf-3 induces RAB15 upregulation in host cells and that RAB15, which is localized on ECVs, inhibits ECV fusion with lysosomes and induces autophagy. We found that E. chaffeensis infection upregulated RAB15 expression using qRT-PCR, and RAB15 was colocalized with E. chaffeensis using confocal microscopy. Silence of RAB15 using siRNA enhanced ECV maturation to late endosomes and fusion with lysosomes, as well as inhibited host cell autophagy. Overexpression of Etf-3 in host cells specifically induced RAB15 upregulation and autophagy. Our findings deepen the understanding of E. chaffeensis pathogenesis and adaptation in hosts as well as the function of RAB15 and facilitate the development of new therapeutics for HME.

Critical roles of mitochondrial fatty acid synthesis in tomato development and environmental response.

Plant mitochondrial fatty acid synthesis (mtFAS) appears to be important in photorespiration based on the reverse genetics research from Arabidopsis (Arabidopsis thaliana) in recent years, but its roles in plant development have not been completely explored. Here, we identified a tomato (Solanum lycopersicum) mutant, fern-like, which displays pleiotropic phenotypes including dwarfism, yellowing, curly leaves, and increased axillary buds. Positional cloning and genetic and heterozygous complementation tests revealed that the underlying gene FERN encodes a 3-hydroxyl-ACP dehydratase enzyme involved in mtFAS. FERN was causally involved in tomato morphogenesis by affecting photorespiration, energy supply, and the homeostasis of reactive oxygen species. Based on lipidome data, FERN and the mtFAS pathway may modulate tomato development by influencing mitochondrial membrane lipid composition and other lipid metabolic pathways. These findings provide important insights into the roles and importance of mtFAS in tomato development.

Whole-exome sequencing identifies FANC heterozygous germline mutation as an adverse factor for immunosuppressive therapy in Chinese aplastic anemia patients aged 40 or younger: a single-center retrospective study.

Acquired aplastic anemia (AA) is a bone marrow failure disorder characterized by pancytopenia, and immunosuppressive therapy (IST) is the optional first-line management. Several studies identified the influencing factors on IST response; however, there are still a considerable number of patients suffering from poor prognoses. In this study, we enrolled 61 AA patients aged ≤ 40 years old, and whole-exome sequencing (WES) found unexpected high FANC heterozygous germline mutations (28/61, 45.9%). Patients with FANC mutations have a significantly lower absolute reticulocyte count and CD34+ % in the bone marrow and also lower 3-, 6-, and 9-month IST response than that without mutation, which were 0% vs. 25% (P = 0.017), 26.3% vs. 42.1% (P = 0.495), and 29.4% vs. 72.2% (P = 0.011), especially in anti-thymocyte globulin combined with the cyclosporin A (ATG + CsA) group, which were 0% vs.33.4% (P = 0.143), 25% vs.83.3% (P = 0.103), and 25% vs. 100% (P = 0.003), respectively. The event-free survival in the FANCwt group was also better than that in the FANCmut group (P = 0.016) and also showed in patients who received ATG + CsA treatment (P = 0.045). In addition, all the adverse effects of FANC germline mutation were not significant in stem cell-transplanted group. Our result indicated that the WES-based detection of FANC heterozygous germline mutations may have a great meaning in predicting IST response of acquired AA. This study was registered at chictr.org.cn (# ChiCTR2100054992).

Mechanisms of cancer cell killing by metformin: a review on different cell death pathways.

Cancer resistance to anti-tumour agents has been one of the serious challenges in different types of cancer treatment. Usually, an increase in the cell death markers can predict a higher rate of survival among patients diagnosed with cancer. By increasing the regulation of survival genes, cancer cells can display a higher resistance to therapy through the suppression of anti-tumour immunity and inhibition of cell death signalling pathways. Administration of certain adjuvants may be useful in order to increase the therapeutic efficiency of anti-cancer therapy through the stimulation of different cell death pathways. Several studies have demonstrated that metformin, an antidiabetic drug with anti-cancer properties, amplifies cell death mechanisms, especially apoptosis in a broad-spectrum of cancer cells. Stimulation of the immune system by metformin has been shown to play a key role in the induction of cell death. It seems that the induction or suppression of different cell death mechanisms has a pivotal role in either sensitization or resistance of cancer cells to therapy. This review explains the cellular and molecular mechanisms of cell death following anticancer therapy. Then, we discuss the modulatory roles of metformin on different cancer cell death pathways including apoptosis, mitotic catastrophe, senescence, autophagy, ferroptosis and pyroptosis.

Impact of a novel prognostic model on allogeneic hematopoietic stem cell transplantation outcomes in patients with CMML.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.

GPC3-IL7-CCL19-CAR-T primes immune microenvironment reconstitution for hepatocellular carcinoma therapy.

BACKGROUND: Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary treatment that has become a mainstay of advanced cancer treatment. Conventional glypican-3 (GPC3)-CAR-T cells have not produced ideal clinical outcomes in advanced hepatocellular carcinoma (HCC), and the mechanism is unclear. This study aims to investigate the clinical utility of novel GPC3-7-19-CAR-T cells constructed by our team and to explore the mechanisms underlying their antitumor effects. METHODS: We engineered a novel GPC3-targeting CAR including an anti-GPC3 scFv, CD3ζ, CD28 and 4-1BB that induces co-expression of IL-7 at a moderate level (500 pg/mL) and CCL19 at a high level (15000 pg /mL) and transduced it into human T cells. In vitro, cell killing efficacy was validated by the xCELLigence RTCA system, LDH nonradioactive cytotoxicity assay and was confirmed in primary HCC organoid models employing a 3D microfluid chip. In vivo, the antitumor capacity was assessed in a humanized NSG mouse xenograft model. Finally, we initiated a phase I clinical trial to evaluate the safety and effect of GPC3-7-19-CAR-T cells in the clinic. RESULTS: GPC3-7-19-CAR-T cells had 1.5-2 times higher killing efficiency than GPC3-CAR-T cells. The tumor formation rates in GPC3-7-19-CAR-T cells treated model were reduced (3/5vs.5/5), and the average tumor volumes were 0.74 cm3 ± 1.17 vs. 0.34 cm3 ± 0.25. Of note, increased proportion of CD4+ TEM and CD8+ TCM cells was infiltrated in GPC3-7-19-CAR-T cells group. GPC3-7-19-CAR-T cells obviously reversed the immunosuppressive tumor microenvironment (TME) by reducing polymorphonuclear (PMN)-myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells infiltration and recruiting more dendritic cells (DCs) to HCC xenograft tumor tissues. In one patient with advanced HCC, GPC3-7-19-CAR-T-cell treatment resulted in tumor reduction 56 days after intravenous infusion. CONCLUSIONS: In conclusion, GPC3-7-19-CAR-T cells achieved antitumor effects superior to those of conventional GPC3-CAR-T cells by reconstructing the TME induced by the dominant CD4+ TEM and CD8+ TCM cell subsets. Most importantly, GPC3-7-19-CAR-T cells exhibited good safety and antitumor efficacy in HCC patients in the clinic. ► Novel GPC3-7-19-CAR-T cells designed with mediate level of IL-7 secretion and high level of CCL19 secretion, which could recruit more mature DCs to assist killing on GPC3+HCCs. ►DC cells recruited by CCL19 could interact with CD4+ T cells and promote the differentiation of CD4+TEFF cells into CD4+TEM and CD8+TCM subsets, leading a better anti-tumor effect on GPC3+HCCs. ►Compared with conventional GPC3-CAR-T, GPC3-7-CCL19-CAR-T cells could reverse tumor immunosuppressive microenvironment by reducing PMN-MDSC and Treg cell infiltration.

Spatial accessibility to health facilities among pregnant women with and without exposure to intimate partner violence in Uganda.

BACKGROUND: Poor physical access to health facilities could increase the likelihood of undetected intimate partner violence (IPV) during pregnancy. We aimed to determine sub-regional differences and associations between spatial accessibility to health facilities and IPV among pregnant women in Uganda. METHOD: Weighted cross-sectional analyses were conducted using merged 2016 Uganda Demographic and Health Survey and 2014 Uganda Bureau of Statistics health facility datasets. Our study population were 986 women who self-reported being currently pregnant and responded to IPV items. Outcome was spatial accessibility computed as the near point linear distance [< 5 km (optimal) vs. ≥ 5 km (low)] between women's enumeration area and health facility according to government reference cutoffs. Primary independent variable (any IPV) was defined as exposure to at least one of physical, emotional, and sexual IPV forms. Logistic regression models were sequentially adjusted for covariates in blocks based on Andersen's behavioral model of healthcare utilization. Covariates included predisposing (maternal age, parity, residence, partner controlling behavior), enabling (wealth index, occupation, education, economic empowerment, ANC visit frequency), and need (wanted current pregnancy, difficulty getting treatment money, afraid of partner, and accepted partner abuse) factors. RESULTS: Respondents' mean age was 26.1 years with ± 9.4 standard deviations (SD), mean number of ANC visits was 3.8 (± 1.5 SD) and 492/986 (49.9%) pregnant women experienced IPV. Median spatial accessibility to the nearest health facility was 4.1 km with interquartile range (IQR) from 0.2 to 329.1 km. Southwestern, and Teso subregions had the highest average percentage of pregnant women experiencing IPV (63.8-66.6%) while Karamoja subregion had the highest median spatial accessibility (7.0 to 9.3 km). In the adjusted analysis, pregnant women exposed to IPV had significantly higher odds of low spatial accessibility to nearest health facilities when compared to pregnant women without IPV exposure after controlling for enabling factors in Model 2 (aOR 1.6; 95%CI 1.2, 2.3) and need factors in Model 3 (aOR 1.5; 95%CI 1.1, 3.8). CONCLUSIONS: Spatial accessibility to health facilities were significantly lower among pregnant women with IPV exposure when compared to those no IPV exposure. Improving proximity to the nearest health facilities with ANC presents an opportunity to intervene among pregnant women experiencing IPV. Focused response and prevention interventions for violence against pregnant women should target enabling and need factors.

Intimate partner violence and antenatal care utilization predictors in Uganda: an analysis applying Andersen's behavioral model of healthcare utilization.

BACKGROUND: Optimal utilization of antenatal care (ANC) services improves positive pregnancy experiences and birth outcomes. However, paucity of evidence exists on which factors should be targeted to increase ANC utilization among women experiencing intimate partner violence (IPV) in Uganda. OBJECTIVE: To determine the independent association between IPV exposure and ANC utilization as well as the predictors of ANC utilization informed by Andersen's Behavioral Model of Healthcare Utilization. METHODS: We analyzed 2016 Uganda Demographic and Health Survey data that included a sample of 1,768 women with children aged 12 to 18 months and responded to both ANC utilization and IPV items. Our outcome was ANC utilization, a count variable assessed as the number of ANC visits in the last 12 months preceding the survey. The key independent variable was exposure to any IPV form defined as self-report of having experienced physical, sexual and/or emotional IPV. Covariates were grouped into predisposing (age, formal education, religion, problem paying treatment costs), enabling (women's autonomy, mass media exposure), need (unintended pregnancy, parity, history of pregnancy termination), and healthcare system/environmental factors (rural/urban residence, spatial accessibility to health facility). Poisson regression models tested the independent association between IPV and ANC utilization, and the predictors of ANC utilization after controlling for potential confounders. RESULTS: Mean number of ANC visits (ANC utilization) was 3.71 visits with standard deviation (SD) of ± 1.5 respectively. Overall, 60.8% of our sample reported experiencing any form of IPV. Any IPV exposure was associated with lower number of ANC visits (3.64, SD ± 1.41) when compared to women without IPV exposure (3.82, SD ± 1.64) at p = 0.013. In the adjusted models, any IPV exposure was negatively associated with ANC utilization when compared to women with no IPV exposure after controlling for enabling factors (Coef. -0.03; 95%CI -0.06,-0.01), and healthcare system/environmental factors (Coef. -0.06; 95%CI -0.11,-0.04). Predictors of ANC utilization were higher education (Coef. 0.27; 95%CI 0.15,0.39) compared with no education, high autonomy (Coef. 0.12; 95%CI 0.02,0.23) compared to low autonomy, and partial media exposure (Coef. 0.06; 95%CI 0.01,0.12) compared to low media exposure. CONCLUSION: Addressing enabling and healthcare system/environmental factors may increase ANC utilization among Ugandan women experiencing IPV. Prevention and response interventions for IPV should include strategies to increase girls' higher education completion rates, improve women's financial autonomy, and mass media exposure to improve ANC utilization in similar populations in Uganda.

Development and validation of a nomogram for predicting morbidity in surgically resected primary retroperitoneal sarcoma.

BACKGROUND: Surgery is the cornerstone of the treatment for primary retroperitoneal sarcoma (RPS). The purpose of this study was to establish a nomogram predictive model for predicting postoperative morbidity in primary RPS. METHODS: Clinicopathological data of patients who underwent radical resection from 2009 to 2021 were retrospectively analyzed. Risk factor analysis was performed using a logistic regression model, and modeling variables were selected based on Akaike Information Criterion. The nomogram prediction model was built on the basis of a binary logistic regression model and internally validated by calibration curves and concordance index. RESULTS: A total of 319 patients were enrolled, including 162 males (50.8%). 22.9% (n = 73) were over 65 years of age, and 70.2% (n = 224) had tumors larger than 10 cm. The most common histologic subtypes were well-differentiated liposarcoma (38.2%), dedifferentiated liposarcoma (25.1%) and leiomyosarcoma (7.8%). According to the Clavien-Dindo Classification, 96 (31.1%) and 31 (11.6%) patients had grade I-II complications and grade III-V complications, respectively. Age, tumor burden, location, operative time, number of combined organ resections, weighted resected organ score, estimated blood loss and packed RBC transfusion was used to construct the nomogram, and the concordance index of which was 0.795 (95% CI 0.746-0.844). and the calibration curve indicated a high agreement between predicted and actual rates. CONCLUSIONS: Nomogram, a visual predictive tool that integrates multiple clinicopathological factors, can help physicians screen RPS patients at high risk for postoperative complications and provide a basis for early intervention.

Differences in sex- and age-associated mortality in patients with anti-MDA5-positive dermatomyositis.

OBJECTIVES: The effect of sex and age on the outcomes of patients with anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (MDA5+ DM) remains unclear. This study aimed to investigate the impact of sex and age on the prognosis of patients with MDA5+ DM. METHODS: We included 251 patients (women, 156; men, 95), who were newly diagnosed with MDA5+ DM between 2014 and 2021. The outcome was 6-month all-cause mortality after the diagnosis of interstitial lung disease. Cox regression analysis was used to assess the mortality. Adjusted restricted cubic spline analysis was performed to explore the non-linear relationship between age and outcomes. RESULTS: The 6-month mortality rates of women and men were 36.5% and 46.3%, respectively. Multivariate Cox regression revealed that ≥60 years of age was significantly associated with the risk of death (hazard ratio, 2.43; 95% confidence interval, 1.02-5.78). The trend of the risk of 6-month mortality in men was relatively flat until 54 years and increased rapidly afterwards (hazard ratio, 1.14; 95% confidence interval, 1.01-1.29). In contrast, the 6-month mortality rate showed a low linear increasing trend with age among females. CONCLUSIONS: Patients with MDA5+ DM, who received contemporary treatment, had unfavourable outcomes. The 6-month mortality risk increased with age, particularly in male patients aged >54 years.

Home mortgage discrimination and incidence of triple-negative and Luminal A breast cancer among non-Hispanic Black and non-Hispanic White females in California, 2006-2015.

PURPOSE: In the United States, Black females are burdened by more aggressive subtypes and increased mortality from breast cancer compared to non-Hispanic (NH) White females. Institutional racism may contribute to these inequities. We aimed to characterize the association between home mortgage discrimination, a novel measure of institutional racism, and incidence of Luminal A and triple-negative breast cancer (TNBC) subtypes among NH Black and NH White females in California metropolitan areas. METHODS: We merged data from the California Cancer Registry on females aged 20 + diagnosed with primary invasive breast cancer between 2006 and 2015 with a census tract-level index of home mortgage lending bias measuring the odds of mortgage loan denial for Black versus White applicants, generated from the 2007-2013 Home Mortgage Disclosure Act database. Poisson regression estimated cross-sectional associations of census tract-level racial bias in mortgage lending with race/ethnicity- and Luminal A and TNBC-specific incidence rate ratios, adjusting for neighborhood confounders. RESULTS: We identified n = 102,853 cases of Luminal A and n = 15,528 cases of TNBC over the study period. Compared to NH Whites, NH Black females had higher rates of TNBC, lower rates of Luminal A breast cancer, and lived in census tracts with less racial bias in home mortgage lending. There was no evidence of association between neighborhood racial bias in mortgage lending at the time of diagnosis and either subtype among either racial/ethnic group. CONCLUSION: Future research should incorporate residential history data with measures of institutional racism to improve estimation and inform policy interventions.

Immunotherapy for liposarcoma: emerging opportunities and challenges.

Liposarcoma (LPS) is a rare adipocyte-derived malignancy accounting for 20% of all soft tissue sarcomas. Although surgery and chemotherapy are the standard treatment for LPS, the large tumor burden and high recurrence rate make it difficult to treat, especially when the disease progresses. With the progress of immunotherapies in other tumors such as melanoma and lung cancer, interest has been risen in exploring immunotherapy for LPS. This review discusses the understanding of the tumor microenvironment of LPS; the current status of immunotherapy in LPS, including immune checkpoint inhibitors, adoptive cell therapy, cancer vaccines, oncolytic viruses and combination therapies; and the future directions for exploiting strategies to make the effect of immunotherapy stronger and more durable.

Liposarcoma is a rare type of malignant tumor with no effective treatment. Immunotherapy is a new kind of treatment that functions by activating the immune system to kill tumors cells. It has gained significant progress in other cancer types. This review discusses its exploration and application in liposarcoma.

Critical role of PAFR/YAP1 positive feedback loop in cardiac fibrosis.

Aberrant activation of cardiac fibroblasts is the main cause and character of cardiac fibrosis, and inhibition of cardiac fibrosis becomes a promising treatment for cardiac diseases. Platelet-activating factor (PAF) and Hippo pathway is recently recognized as key signaling mechanisms in cardiovascular diseases. In this study we explored the potential roles of PAF and Hippo signaling pathway in cardiac fibrosis. Myocardial infarction (MI) was induced in mice by left anterior descending artery ligation. After 28 days, the mice were sacrificed, and the hearts were collected for analyses. We showed that PAF receptor (PAFR) and yes-associated protein 1 (YAP1, a key effector in the Hippo pathway) were significantly increased in the heart of MI mice. Increased expression of PAFR and YAP1 was also observed in angiotensin II (Ang II)-treated mouse cardiac fibroblasts. In mouse cardiac fibroblasts, forced expression of YAP1 increased cell viability, resulted in collagen deposition and promoted fibroblast-myofibroblast transition. We showed that PAF induced fibrogenesis through activation of YAP1 and promoted its nuclear translocation via interacting with PAFR, while YAP1 promoted the expression of PAFR by binding to and activating transcription factor TEAD1. More importantly, silencing PAFR or YAP1 by shRNA, or using transgenic mice to induce the conditional deletion of YAP1 in cardiac fibroblasts, impeded cardiac fibrosis and improved cardiac function in MI mice. Taken together, this study elucidates the role and mechanisms of PAFR/YAP1 positive feedback loop in cardiac fibrosis, suggesting a potential role of this pathway as novel therapeutic targets in cardiac fibrosis.

Effect of avatrombopag in the management of severe and refractory chemotherapy-induced thrombocytopenia (CIT) in patients with solid tumors.

Chemotherapy-induced thrombocytopenia (CIT) is a common complication in cancer patients, especially after multiple cycles of chemotherapy, which leads to the delayed treatment or reduced dosage. The treatment of CIT is limited for refractory and severe cases. Herein we reported a single-center study of avatrombopag, a type of thrombopoietin receptor agonist (TPO-RA), for the treatment of severe and refractory (S/R) CIT who failed from multi-line treatments. A total of 13 cancer patients with S/R CIT were enrolled at the First Affiliated Hospital of Zhejiang Chinese Medical University from September 2020 to February 2021. All the patients were administered oral avatrombopag at an initial dose of 60 mg/day, which could be decreased as needed, over a period of 8 weeks. Eight (8/13, 61.5%) patients responded to avatrombopag (with a platelet count ≥50 × 109/L and transfusion independent), with a median response time of 27.5 (11-50) days, and the median cumulative day of platelet response was 79 (20-167). Ten of 13 patients (76.9%) no longer required platelet transfusion at the study endpoint. The predictor of response was the level of hemoglobin (HB) at study entry, patients with an HB over 90 g/L achieved a response rate of 88.9%. In addition, platelet count showed 87.5% sensitivity and 100% specificity to predict the treatment response at a cutoff value of 25.5× 109/L at the end of the third week management. No drug-related side effects were noticed during administration. Our study showed that avatrombopag could be a novel and effective drug for the treatment of severe and refractory CIT, especially for those with hemoglobin above 90 g/L. This study was registered at chictr.org.cn as # ChiCTR2100050646.

Apolipoprotein-A is a potential prognostic biomarker for severe aplastic anemia patients treated with ATG-based immunosuppressive therapy: a single-center retrospective study.

BACKGROUND: Anti-thymoglobulin (ATG)-based immunosuppressive treatment (IST) is the standard first-line management for patients with severe AA/very severe AA (SAA/VSAA) and is not suitable for allogeneic stem cell transplantation. The response predictor was not fully investigated. OBJECTIVE: The present study attempted to explore other characteristics, such as serum lipid changes, during ATG-based IST and analyzed their significance in predicting IST response and survival. METHODS: A total of 61 newly diagnosed SAA/VSAA patients who received ATG-based IST were enrolled from January 2011 to June 2019. The blood lipid levels, immunoglobulins, and peripheral T lymphocytes were retrospectively collected, and their correlations with IST response, estimated 8.5-year overall survival (OS) and event-free survival (EFS) were analyzed. RESULTS: The overall response (OR)/complete remission (CR) at 3, 6, and 9 months was 24.6%/6.6%, 52.5%/14.8%, and 65.6%/23.0%, respectively. Based on the 9-month response effect, patients were divided into IST-response (IST-R) and IST-nonresponse (IST-NR) groups. The subgroup baseline characteristics showed that the disease severity grade, absolute neutrophil granulocyte count (ANC), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein-A (Apo-A) differed between the IST-R and IST-NR groups. Patients with lower Apo-A (< 1.205 g/L) level pretreatment had a better event-free survival (EFS), and a moderate negative correlation was established between the pretreatment Apo-A and 9-month response (P = 0.004). In addition, the T-cell subset and immunoglobulin analyses showed that the responsive patients had a low serum IgA level, which decreased further after therapy. Additionally, a moderate negative correlation was established between the 3-month IgA and 9-month response (P = 0.006). CONCLUSION: Serum Apo-A is a prognostic biomarker for newly diagnosed < 60-year-old SAA/VSAA patients who received ATG-based IST (registered at chictr.org.cn as # ChiCTR2100052979).

Unplanned reoperation after resection of retroperitoneal sarcoma: experience based on a high-volume sarcoma center.

BACKGROUND: Most retroperitoneal sarcoma (RPS) operations require combined multi-organ resection, and the proportion of unplanned reoperation is high. However, there are no relevant studies on reoperation for RPS. METHODS: Patients who underwent at least once unplanned reoperation at Shanghai Public Health Clinical Center, Fudan University, China, from August 2009 to December 2021 were retrospectively analyzed. The baseline characteristics, primary surgery, and reoperation information, postoperative complications, and survival were analyzed. RESULTS: A total of 51 patients were included. Among them, 21 (41.2%) were male and 30 (58.8%) were female. The median age was 51 (interquartile range [IQR], 49-63) years. Most (88.3%) had a history of abdominal surgery. Dedifferentiated liposarcoma, well-differentiated liposarcoma, leiomyosarcoma, and others accounted for 50.9%, 21.6%, 15.7%, and 11.8%, respectively. The conditions of the primary operation were as follows: 35 (68.6%) patients achieved complete surgical resection, 48 patients had combined organ resection, and a median of 3 (IQR, 2-4) organs was removed, of which 5 (9.9%) were combined with pancreaticoduodenectomy. The median operative time was 330 (IQR, 245-440) min, and the median estimated blood loss was 1500 (IQR, 500-2600) ml. The median postoperative hospital stay was 42 (IQR, 23-82) days. For reoperation, the most common reasons were bleeding (31.3%), complications related to intestinal anastomosis (27.4%), and intestinal perforation (19.9%). The mortality rate after reoperation was 39.2% (20/51). Twelve (23.5%) patients underwent reoperation at least twice. CONCLUSIONS: Unplanned reoperation among retroperitoneal sarcoma correlates with established measures of surgical quality.

Suppression of Sox4 protects against myocardial ischemic injury by reduction of cardiac apoptosis in mice.

Sox4 participates in the progression of embryo development and regulation of apoptosis in tumors. However, the effect and mechanism of Sox4 in myocardial infarction (MI) remains unclear. Therefore, we aimed at examining the role and molecular mechanism of Sox4 in the process of cardiomyocytes apoptosis during MI. The expression of Sox4 were obviously increased both in MI mice and in neonatal mouse cardiomyocytes treated with H2 O2 . Overexpression of Sox4 promoted cardiomyocyte apoptosis with or without H2 O2 , whereas knocking down of Sox4 alleviated H2 O2 -induced apoptosis in cardiomyocytes. Furthermore, silencing Sox4 by AAV-9 carried short hairpin RNA targeting Sox4 (AAV-9-sh-Sox4) markedly decreased cardiac infarct area, imprfoved cardiac dysfunction, and reversed apoptosis in MI mice. Mechanistically, there is a potential Sox4-binding site in the promoter region of Bim, and forced expression of Sox4 significantly promoted Bim expression in cultured cardiomyocytes with or without H2 O2 , whereas knocking down of Sox4 inhibited the expression of Bim. Further studies showed that silencing Bim attenuated Sox4-induced apoptosis in cardiomyocytes, indicating that Sox4 promoted cardiomyocytes apoptosis through regulation of Bim expression, which can be used as a potential therapeutic target for MI.