Primary Samples Research Articles

The role of Medicaid home- and community-based services in use of Medicare post-acute care.

Medicaid-funded long-term services and supports are increasingly provided through home- and community-based services (HCBS) to promote continued community living. While an emerging body of evidence examines the direct benefits and costs of HCBS, there may also be unexplored synergies with Medicare-funded post-acute care (PAC). This study aimed to provide empirical evidence on how the use of Medicaid HCBS influences Medicare PAC utilization among the dually enrolled. National Medicare claims, Medicaid claims, nursing home assessment data, and home health assessment data from 2016 to 2018. We estimated the relationship between prior Medicaid HCBS use and PAC (skilled nursing facilities [SNF] or home health) utilization in a national sample of duals with qualifying index hospitalizations. We used inverse probability weights to create balanced samples on observed characteristics and estimated multivariable regression with hospital fixed effects and extensive controls. We also conducted stratified analyses for key subgroups. The primary sample included 887,598 hospital discharges from community-dwelling duals who had an eligible index hospitalization between April 1, 2016, and September 30, 2018. We found HCBS use was associated with a 9 percentage-point increase in the use of home health relative to SNF, conditional on using PAC, and a meaningful reduction in length of stay for those using SNF. In addition, in our primary sample, we found HCBS use to be associated with an overall increase in PAC use, given that the absolute increase in home health use was larger than the absolute decrease in SNF use. In other words, the use of Medicaid-funded HCBS was associated with a shift in Medicare-funded PAC use toward home-based settings. Our findings indicate potential synergies between Medicaid-funded HCBS and increased use of home-based PAC, suggesting policymakers should cautiously consider these dynamics in HCBS expansion efforts.

Nuclear factor-κB activation by transforming growth factor-β1 drives tumour microenvironment-mediated drug resistance in neuroblastoma.

Intrinsic and extrinsic factors in the tumour microenvironment (TME) contribute to therapeutic resistance. Here we demonstrate that transforming growth factor (TGF)-β1 produced in the TME increased drug resistance of neuroblastoma (NB) cells. Human NB cell lines were tested in vitro for their sensitivity to Doxorubicin (DOX) and Etoposide (ETOP) in the presence of tumour-associated macrophages (TAM) and mesenchymal stromal cells/cancer-associated fibroblasts (MSC/CAF). These experiments were validated in xenotransplanted and primary tumour samples. Drug resistance was associated with an increased expression of efflux transporter and anti-apoptotic proteins. Upregulation was dependent on activation of nuclear factor (NF)-κB by TGF-β-activated kinase (TAK1) and SMAD2. Resistance was reversed upon pharmacologic and genetic inhibitions of NF-κB, and TAK1/SMAD2. Interleukin-6, leukaemia inhibitory factor and oncostatin M were upregulated by this TGF-β/TAK1/NF-κB/SMAD2 signalling pathway contributing to drug resistance via an autocrine loop activating STAT3. An analysis of xenotransplanted NB tumours revealed an increased presence of phospho (p)-NF-κB in tumours co-injected with MSC/CAF and TAM, and these tumours failed to respond to Etoposide but responded if treated with a TGF-βR1/ALK5 inhibitor. Nuclear p-NF-κB was increased in patient-derived tumours rich in TME cells. The data provides a novel insight into a targetable mechanism of environment-mediated drug resistance.

Multi-omics analysis of macrophage-associated receptor and ligand reveals a strong prognostic signature and subtypes in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a significant contributor to morbidity and mortality worldwide. The interaction between receptors and ligands is the primary mode of intercellular signaling and plays a vital role in the progression of HCC. This study aimed to identify the macrophage-related receptor ligand marker genes associated with HCC and further explored the molecular immune mechanisms attributed to altered biomarkers. Single-cell RNA sequencing data containing primary and recurrent samples were downloaded from the China National GeneBank. Cell types were first identified to explore differences between immune cells from different sample sources. CellChat analysis was used to infer and analyze intercellular communication networks quantitatively. Three molecular subtypes were constructed based on the screened twenty macrophage-associated receptor ligand genes. Bulk RNA-Seq data were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. After the screening, the minor absolute shrinkage and selection operator (LASSO) regression model was employed to identify key markers. After collecting peripheral blood and clinical information from patients, an enzyme-linked immunosorbent assay (ELISA) was used to detect the correlation between key markers and IL-10, one of the macrophage markers. After developing a new HCC risk adjustment model and conducting analysis, it was found that there were significant differences in immune status and gene mutations between the high-risk and low-risk groups of patients based on macrophage-associated receptor and ligand genes. This study identified SPP1, ANGPT2, and NCL as key biological targets for HCC. The drug-gene interaction network analysis identified wortmannin, ribavirin, and tarnafloxin as potential therapeutic drugs for the three key markers. In a clinical cohort study, patients with immune checkpoint inhibitor (ICI) resistance had significantly higher expression levels of OPN, ANGPT2, NCL, and IL-10 than patients with ICI-responsiveness. These three key markers were positively correlated with the expression level of IL-10. The signature based on macrophage-associated receptor and ligand genes can accurately predict the prognosis of patients with HCC and the sensitivity to immunotherapy. These results may help guide the development of targeted prevention and personalized treatment of HCC.

CD20-bispecific antibodies improve response to CD19-CAR T-cells in lymphoma in-vitro and CLL in-vivo models.

Anti-CD19 chimeric antigen receptor T-cells (CD19-CAR) represent an effective treatment for relapsed/refractory B-cell malignancies but incomplete responses often result in early disease progression. We here assessed potential benefits of co-administering CD20-targeting bispecific antibodies (CD20-BsAb) with CD19-CAR, aiming to enhance immunotherapeutic efficacy. Addition of CD20-BsAb to co-cultures of CD19-CAR and primary samples of B-cell malignancies, comprising malignant B- and endogenous T-cells, significantly improved killing of malignant cells alongside enhanced expansion of both endogenous T-cells and CD19-CAR. CD20-BsAb induced an increase in proliferation and activation of endogenous T-cells and CD19-CAR. In an immunocompetent mouse model of CLL, relapse after initial treatment response frequently occurred after CD19-CAR monotherapy. Combination with injections of CD20-BsAb significantly enhanced treatment response and resulted in improved eradication of malignant cells. Higher efficacy was accompanied by improved T-cell expansion upon CD20-BsAb administration and resulted in longer survival, with 80% of mice being cured with no detectable malignant cell population within eight weeks of therapy initiation. Collectively, our in-vitro and in-vivo data demonstrate enhanced therapeutic efficacy of CD19-CAR when combined with CD20-BsAb in B-cell malignancies. Activation and proliferation of both infused CAR T-cells as well as endogenous T-cells may contribute to improved disease control.

P.102 Integration of Ultrasensitive electroluminescent immunoassay and cell-free DNA methylation analysis for the non-invasive discrimination of adult diffuse gliomas

Background: Gliomas are highly aggressive brain tumors with nearly universal recurrence rate. Despite this, the ability to accurately predict tumor recurrence relies solely on serial MRI imaging, highlighting the need for prognostic biomarkers. Due to the low accuracies of individual serum markers, we have proposed the use of an integrated, multi-platform approach to biomarker discovery. Methods: A cohort of 107 glioma plasma samples, including 30 pairs, underwent plasma proteomic, consisting of a panel of serum proteins (FABP4, GFAP, NFL, Tau and MMP3,4 &7) quantified through ultrasensitive electrochemiluminescence multiplexed immunoassays, and plasma DNA methylation analysis, captured through cell-free methylated DNA immunoprecipitation and high-throughput sequencing. Results: Unsupervised hierarchal clustering revealed robust separation of primary and recurrent tumors through plasma proteomics, associated with a distinct plasma methylation signature. NFL, Tau and MMP3 levels differed between primary and recurrent samples; pair-wise analysis revealed increased in NFL and Tau concentrations upon recurrence. Tau levels predicted outcome independent of WHO Grade and IDH status. A predictive model created through the integration of the proteomic and methylation signatures revealed an AUC of 0.83. Conclusions: The combination of DNA methylation and plasma proteomics showcases that an integrative approach may improve the ability of these techniques for the serial monitoring of gliomas patients.

Chimeric Antigen Receptor T Cell with an Inducible Caspase 9 Suicide Gene Eradicates Uveal Melanoma Liver Metastases via B7-H3 Targeting

Uveal melanoma (UM) is the most common intraocular malignant tumor. Despite successful treatment of the primary tumor, about 50% of patients will recur with systemic disease for which there are no effective treatment strategies. Here we investigated the preclinical efficacy of a chimeric antigen receptor (CAR) T cell-based immunotherapy targeting B7-H3. B7-H3 expression on primary and metastatic human UM samples and cell lines was assessed by RNA sequencing, flow cytometry, and immunohistochemistry. Antitumor activity of CAR T cells targeting B7-H3 was tested in vitro with UM cell lines, metastatic UM patient-derived organotypic tumor spheroids (PDOTS), and in immunodeficient and humanized murine models. B7-H3 is expressed at high levels on >95% UM tumor cells in vitro and in vivo. We generated a B7-H3 CAR with an inducible caspase-9 (iCas9) suicide gene controlled by the chemical inducer of dimerization AP1903, which effectively kills UM cells in vitro and eradicates UM liver metastases in murine models. Delivery of iCas9.B7-H3 CAR T cells in experimental models of UM liver metastases demonstrates a durable anti-tumor response, even upon tumor re-challenge or in the presence of a significant metastatic disease burden. We demonstrate effective iCas9.B7-H3 CAR T cell elimination in vitro and in vivo in response to AP1903. Our studies demonstrate more effective tumor suppression with iCas9.B7-H3 CAR T cells as compared to a B7-H3-targeted humanized monoclonal antibody. These studies support a phase I clinical trial with iCas9.B7-H3 CAR T cells to treat patients with metastatic UM.

The HER2 flip-HER2 amplification of tumor cells in the cerebrospinal fluid of breast cancer patients with leptomeningeal disease: implications for treating the LM tumor with anti-HER2 therapy

IntroductionCNSide is a platform that detects and characterizes tumor cells in the cerebrospinal fluid (CSF) of patients with leptomeningeal disease (LMD). The platform was validated per College of American Pathologists (CAP) and Clinical Laboratories Improvement Amendment (CLIA) guidelines and run as a commercial Laboratory Developed Test (LDT) at Biocept in San Diego, CA. The platform allows CSF tumor cell (CSF-TC) enumeration and biomarker characterization by fluorescent in situ hybridization (FISH). MethodsWe performed a multicenter retrospective chart review of HER2 FISH CNSide test results that were commercially ordered on 26 patients by physicians for LMD breast cancer patients between April 2020 and October 2022.ResultsWe show that HER2 is amplified on CSF tumor cells in 62% (16/26) of LMD breast cancer patients. 10/26 (38%) patients had discordant HER2-positivity between the primary tumor tissue and CSF-TC; of these, 35% (9/26) of the patients displayed HER2 amplification on the CSF-TCs, however were categorized as HER2 negative on the primary tumor. Of the 27% (7/26) patients with a HER2 positive primary tumor, one patient showed a HER2 negative LMD tumor. Two patients, 8% (2/26) had a HER2 equivocal primary tumor; of these, one demonstrated a HER2 negative, and one a HER2 positive LMD tumor. Serial analysis (at least 4 longitudinal tests) of HER2 status of the CSF-TC throughout therapy was available for 14 patients and demonstrated that HER2 status of the LMD changed in 29% (4/14) during their treatment course and impacted care decisions. ConclusionsOur data suggests that CSF-TC HER2 FISH analysis in LMD breast cancer patients may be discordant to the primary tumor sample and the discovery of HER2 positivity in the CSF may open doors to anti-HER2 targeted therapy options for LMD patients.

Inducible CXCL12/CXCR4–dependent extramedullary hematopoietic niches in the adrenal gland

AbstractAdult hematopoietic stem and progenitor cells (HSPCs) reside in the bone marrow (BM) hematopoietic niche, which regulates HSPC quiescence, self-renewal, and commitment in a demand-adapted manner. Although the complex BM niche is responsible for adult hematopoiesis, evidence exists for simpler, albeit functional and more accessible, extramedullary hematopoietic niches. Inspired by the anecdotal description of retroperitoneal hematopoietic masses occurring at higher frequency upon hormonal dysregulation within the adrenal gland, we hypothesized that the adult adrenal gland could be induced into a hematopoietic-supportive environment in a systematic manner, thus revealing mechanisms underlying de novo niche formation in the adult. Here, we show that upon splenectomy and hormonal stimulation, the adult adrenal gland of mice can be induced to recruit and host functional HSPCs, capable of serial transplantation, and that this phenomenon is associated with de novo formation of platelet–derived growth factor receptor α–expressing stromal nodules. We further show in CXCL12–green fluorescent protein reporter mice that adrenal glands contain a stromal population reminiscent of the CXCL12-abundant reticular cells, which compose the BM HSPC niche. Mechanistically, HSPC homing to hormonally induced adrenal glands was found dependent on the CXCR4–CXCL12 axis. Mirroring our findings in mice, we found reticular CXCL12+ cells coexpressing master niche regulator FOXC1 in primary samples from human adrenal myelolipomas, a benign tumor composed of adipose and hematopoietic tissue. Our findings reignite long-standing questions regarding hormonal regulation of hematopoiesis and provide a novel model to facilitate the study of adult-specific inducible hematopoietic niches, which may pave the way to therapeutic applications.

Seasonal variation in D2/3 dopamine receptor availability in the human brain.

Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic dopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized. Based on a historical database of healthy human brain [11C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. Daylength at the time of scanning was used as a predictor for brain regional non-displaceable binding of the radiotracer, while controlling for age and sex. Daylength was negatively correlated with availability of D2/3 dopamine receptors in the striatum. The largest effect was found in the left caudate, and based on the primary sample, every 4.26h (i.e., one standard deviation) increase of daylength was associated with a mean 2.8% drop (95% CI -0.042 to -0.014) of the receptor availability. Seasonally varying D2/3 receptor signaling may also underlie the seasonality of mood, feeding, and motivational processes. Our finding suggests that in future studies of brain dopamine signaling, especially in high-latitude regions, the effect of seasonality should be considered.

MYC Inhibition Potentiates CD8+ T Cells Against Multiple Myeloma and Overcomes Immunomodulatory Drug Resistance

Abstract Purpose: Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are cornerstone therapies in Multiple Myeloma (MM), yet patients inevitably become refractory. IMiDs exert cytotoxicity through inducing Cereblon-dependent proteasomal degradation of IKZF1 and IKZF3, resulting in downregulation of the oncogenic transcription factors IRF4 and MYC. To date, clinical IMiD resistance independent of CRBN or IKZF1/3 has not been well-explored. Here, we investigated the roles of IRF4 and MYC in this context. Experimental Design: Using bone marrow aspirates from patients with IMiD naïve or refractory MM, we examined IKZF1/3 protein levels and IRF4/MYC gene expression following ex vivo pomalidomide treatment via flow cytometry and qPCR. We also assessed ex vivo sensitivity to the MYC inhibitor, MYCi975, using flow cytometry. Results: We discovered that while pomalidomide frequently led to IKZF1/3 degradation in MM cells, MYC gene expression was unaffected by pomalidomide in most IMiD refractory samples. We subsequently demonstrated that MYCi975 exerted strong anti-MM effects in both IMiD naïve and refractory samples. Unexpectedly, we identified CD8+ T cells from patients with MM as crucial effectors of MYCi975-induced cytotoxicity in primary MM samples, and we discovered MYCi975 enhanced the cytotoxic functions of memory CD8+ T cells. We lastly observed synergy between MYCi975 and pomalidomide in IMiD refractory samples, suggesting restoring MYC downregulation can re-sensitize refractory MM to IMiDs. Conclusion: Our study supports the concept that MYC represents an Achille’s heel in MM across disease states and that MYCi975 may be a promising therapeutic for patients with MM, particularly in combination with IMiDs.

Claudin-18 status and its correlation with HER2 and PD-L1 expression in gastric cancer with peritoneal dissemination

Abstract Background Gastric cancer with peritoneal dissemination (PD) has a dismal prognosis, and current treatments have shown little efficacy. CLDN18.2-targeted therapies have shown promising efficacy against gastric cancers that express high levels of CLDN18. Because of the limited information regarding CLDN18.2 status in PD, we analyzed PD-positive gastric cancers for CLDN18 status in both primary and PD, along with HER2 and PD-L1 combined positive score (CPS). Methods Immunohistochemical analyses were performed on 84 gastric cancer cases using paired primary and PD tissue samples. Results At 40% cut-off, CLDN18 was positive in 57% (48/84) primary tumors and in 44% (37/84) PDs. At 75% cut-off, 28.6% (24/84) primary tumors and 20.2% (17/84) PDs were CLDN18-positive. The concordance rate between primary tumors and PD was 79.8% at 40% cut-off and 75% at 75% cut-off. When comparing biopsy and surgical specimens, the concordance rates were 87.5% at 40% cut-off and 81.3% at 75% cut-off. Within a tumor, the superficial area tended to have a higher CLDN18-positive rate than the invasive front (P = 0.001). Although HER2 -positivity was only 11.9% in this cohort, CLDN18 positivity in HER2-negative tumors (n = 74) was relatively high: 60.8% at 40% cut-off and 28.4% at 75% cut-off. Among double-negative (HER2 − and PD-L1 CPS < 1) tumors, CLDN18 positivity was 67.6% at 40% cut-off and 26.5% at 75% cut-off. Conclusions CLDN18 expression is generally maintained in PD and is relatively high even in double-negative tumors, making it a promising therapeutic target for PD-positive gastric cancer.

AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML.

T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human-engineered cytotoxic CD4+ T cells. Single-cell RNA-seq of primary AML samples and CD4+ T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4+ T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing by primary ex vivo-isolated CD8+ T cells in vitro, and engineered CD4+ T cells in vitro and in vivo. While AML heterogeneity implies that multiple factors may determine their sensitivity to T cell killing, these data show that ICAM1 acts as an immune trigger, allowing T cell killing, and could play a role in AML patient survival in vivo.

Blockage of BCL-XL overcomes venetoclax resistance across BCL2+ lymphoid malignancies irrespective of BIM status

AbstractVenetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which calls for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient–derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL1L11/BIM status.

Increased H19/miR-675 Expression in Adult T-Cell Leukemia Is Associated with a Unique Notch Signature Pathway.

The Notch pathway is a key cancer driver and is important in tumor progression. Early research suggested that Notch activity was highly dependent on the expression of the intracellular cleaved domain of Notch-1 (NICD). However, recent insights into Notch signaling reveal the presence of Notch pathway signatures, which may vary depending on different cancer types and tumor microenvironments. Herein, we perform a comprehensive investigation of the Notch signaling pathway in adult T-cell leukemia (ATL) primary patient samples. Using gene arrays, we demonstrate that the Notch pathway is constitutively activated in ATL patient samples. Furthermore, the activation of Notch in ATL cells remains elevated irrespective of the presence of activating mutations in Notch itself or its repressor, FBXW7, and that ATL cells are dependent upon Notch-1 expression for proliferation and survival. We demonstrate that ATL cells exhibit the expression of pivotal Notch-related genes, including notch-1, hes1, c-myc, H19, and hes4, thereby defining a critical Notch signature associated with ATL disease. Finally, we demonstrate that lncRNA H19 is highly expressed in ATL patient samples and ATL cells and contributes to Notch signaling activation. Collectively, our results shed further light on the Notch pathway in ATL leukemia and reveal new therapeutic approaches to inhibit Notch activation in ATL cells.

Therapeutic Potential of Antibody Targeting Neuronal Pentraxin Receptor in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis despite advances in multidisciplinary treatments and immune checkpoint inhibitors. We previously reported that neural pentraxin receptor (NPTXR), a transmembrane protein mainly expressed in the brain and involved in synaptic transmission, is implicated in gastric cancer malignancy. This study evaluated the expression and function of NPTXR in ESCC, the therapeutic potential of monoclonal antibody (mAb) against NPTXR, and its prognostic value in ESCC patients. The study involved analyzing the NPTXR expression in 21 ESCC cell lines and total 371 primary ESCC tissue samples using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. The impact of NPTXR on the malignant behavior of ESCC was examined using small interfering RNA-mediated knockdown and a subsequent assessment of cell proliferation, apoptosis, and adhesion. This study further investigated the efficacy of anti-NPTXR mAb in vitro and associations between the expression of NPTXR messenger RNA (mRNA) and protein with clinicopathological factors and the prognosis. NPTXR was overexpressed in several ESCC cell lines and primary ESCC tissues. Knockdown of NPTXR in ESCC cells resulted in reduced proliferation, increased apoptosis, and decreased cell adhesion. The mAb against NPTXR significantly inhibited ESCC cell proliferation in vitro. A high NPTXR expression in patient tissues was correlated with a worse overall survival, suggesting its potential as a prognostic biomarker. NPTXR influences the malignant behavior of ESCC cells. Anti-NPTXR mAb may be a promising therapeutic agent, and its expression in ESCC tissues may serve as a prognostic biomarker.

Association of low Angiomotin-p130 and high YAP1 nuclear expression with adverse prognosis in epithelial ovarian cancer.

The aim of our study was to examine the association of Angiomotin (Amot-p130) and Yes-associated protein 1 (YAP1) expressions and their prognostic significance in epithelial ovarian cancer (EOC). A total of 100 primary EOC samples were obtained for immunohistochemical analysis of Amot-p130 and YAP1 expressions. Correlation analysis was performed between Amot-p130 or YAP1 and clinical factors. The overall survival time was calculated. Low Amot-p130 and high YAP1 nuclear expression were identified in 34 and 56 of 100 EOC tissues, respectively. Both low Amot-p130 and high YAP1 nuclear expression were associated with advanced tumor stage, high-grade carcinoma, and non-response to chemotherapy (p<0.05). They were also associated with shorter overall survival time (p<0.05) by log-rank test. A marker of low Amot-p130 and high YAP1 expression was associated with high-grade ovarian carcinoma, late-stage disease, non-response to chemotherapy, and shorter overall survival time (p<0.05). Low Amot-p130 and high YAP1 nuclear expression can provide additional prognostic information for patients with EOC. A marker of low Amot-p130 and high YAP1 expression may be a potent predictor of poor prognosis in patients with epithelial ovarian cancer.

Extreme-emission-line galaxies in the MUSE Hubble Ultra Deep Field Survey

We aim to apply a methodology to build a sample of extreme-emission-line galaxies (EELGs) using integral field spectroscopy data. In this work, we followed the spectroscopic criteria corresponding to EELG selection and used the MUSE Hubble Ultra-Deep field survey, which includes the deepest spectroscopic survey ever performed. Objects in the primary (extended) sample were detected requiring a rest-frame equivalent width of EWo geqslant 300 leq EWo leq 300 ) in any of the emission lines of OII OIII or Halpha . A detailed closer inspection of the spectra of the candidates selected has been performed on a one-by-one basis in order to confirm their classification. For this sample, the line fluxes, physical properties, and chemical abundances of the EELGs have been derived, as well as their spatially resolved structure and kinematics. Four (five) of the galaxies in the primary (extended) sample, sim 57$&lt;!PCT!&gt;$ (sim 83$&lt;!PCT!&gt;$), were spatially resolved. Three (none) of them present a clear pattern compatible with rotation. We show how our entire EELG sample shares the same loci defined by high-redshift galaxies (z approx 6-8) for the mass-metallicity relation, illustrating their role as local analogs.

Accounting for sample overlap in economics meta‐analyses: The generalized‐weights method in practice

AbstractMeta‐analyses in economics frequently exhibit considerable overlap among primary samples. If not addressed, sample overlap leads to efficiency losses and inflated rates of false positives at the meta‐analytical level. In previous work, we proposed a generalized‐weights (GW) approach to handle sample overlap. This approach effectively approximates the correlation structure between primary estimates using information on sample sizes and overlap degrees in the primary studies. This paper demonstrates the application of the GW method to economics meta‐analyses, addressing practical challenges that are likely to be encountered. We account for variations in data aggregation levels, estimation methods, and effect size metrics, among other issues. We derive explicit covariance formulas for different scenarios, evaluate the accuracy of the approximations, and employ Monte Carlo simulations to demonstrate how the method enhances efficiency and restores the false positive rate to its nominal level.

Mutation characteristics and molecular evolution of ovarian metastasis from gastric cancer and potential biomarkers for paclitaxel treatment

Ovarian metastasis is one of the major causes of treatment failure in patients with gastric cancer (GC). However, the genomic characteristics of ovarian metastasis in GC remain poorly understood. In this study, we enroll 74 GC patients with ovarian metastasis, with 64 having matched primary and metastatic samples. Here, we show a characterization of the mutation landscape of this disease, alongside an investigation into the molecular heterogeneity and pathway mutation enrichments between synchronous and metachronous metastasis. We classify patients into distinct clonal evolution patterns based on the distribution of mutations in paired samples. Notably, the parallel evolution group exhibits the most favorable prognosis. Additionally, by analyzing the differential response to chemotherapy, we identify potential biomarkers, including SALL4, CCDC105, and CLDN18, for predicting the efficacy of paclitaxel treatment. Furthermore, we validate that CLDN18 fusion mutations improve tumor response to paclitaxel treatment in GC with ovarian metastasis in vitro and vivo.

Drivers of Urban Agriculture and their Influence on the Socio-Economic Status of the Urban Farmers in Uganda, A Case Study of Kampala and Mbarara Cities

The study analyzed the influence of forms and drivers of urban Agriculture on the socio-economic status of the farmers in Kampala and Mbarara Cities. The specific objective of the study was to examine the influence drivers of urban agriculture on the socio-economic status of farmers. The study adopted a cross-sectional research design using multiple data collection methods. A multistage cluster sampling technique involving simple random sampling to get both primary and secondary sampling units, snowball to get target respondents and purposive sampling for key informants and focus group members was used. Data were collected using social survey questionnaires for households, focus group discussions checklist (FGDs), key informant interview guides and observations, from a sample of 384 respondents. The study found a strong association between drivers of UA and the socioeconomic status of the urban farmers in Kampala and Mbarara Cities. Household socio-economic status has substantially correlated with the drivers of the urban farmers and out of 9 items considered only 5 was significant which include access to capital (x2 = 1.175, p&lt; 0.047), access to agriculture extension services (x2 = 3.634, p&lt; 0.026), access to financial grants (x2 = 5.190, p&lt;0.001), access to markets (x2 = 6.993, p&lt; 0.001), value addition(x2 = 3.718, p&lt;0.014). The study confirmed a significant relationship between drivers of urban agriculture and the socio-economic status of urban farmers. Urban agriculture drivers like access to capital and financial grants, nature of market access and value addition had a significant influence on household socio-economic status.