Poor Therapy Outcome Research Articles

Comprehensive analysis identifies YKT6 as a potential prognostic and diagnostic biomarker in lung adenocarcinoma

BackgroundLung cancer is the most common cause of cancer-related death worldwide. The most prevalent histological subtype of lung cancer is lung adenocarcinoma (LUAD), with incidence rising each year. Treating LUAD remains a significant issue due to a lack of early diagnosis and poor therapy outcomes. YKT6 is a member of the SNARE protein family, whose clinical value and biological function in LUAD has yet to be established.MethodsTCGA, HPA and UALCAN were used to analyze YKT6 mRNA and protein levels, the correlation between YKT6 expression and clinicopathological features and prognosis. YKT6 mRNA and protein expression were verified by qRT-PCR, immunohistochemistry (IHC) and tissue microarrays (TMA). Additionally, lung cancer cell lines were chosen for YKT6 silencing to explore the effects on cell proliferation and migration. The cBioPortal was used to select YKT6-related genes. Protein-protein interaction (PPI) network was created based on STRING database and hub genes were screened, with their expression levels and prognosis values in LUAD analyzed accordingly. YKT6-related genes were enriched by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses.ResultsIn LUAD, YKT6 was distinctly highly expressed with relation to clinical features of staging, smoking, lymph node metastasis, and TP53 mutation. Elevated YKT6 expression was linked to adverse prognosis, serving as an independent unfavorable prognostic factor. Moreover, YKT6 presented high diagnostic value in LUAD patients (AUC = 0.856). Experimental validation indicated that freshly collected LUAD tissues showed significantly high mRNA expression of YKT6. IHC and TMA verified increased YKT6 protein level in LUAD. Knockdown of YKT6 inhibited cell proliferation and promoted apoptosis, with mitigated capability of migration and invasion. The top ten hub genes screened by PPI network were highly expressed in LUAD, and significantly associated with poor prognosis. GO and KEGG analyses showed that YKT6-related genes were mainly involved in cell cycle.ConclusionElevated YKT6 expression is related to poor prognosis of LUAD patients. YKT6 can serve as a novel biomarker for LUAD diagnosis and prognosis. Cell proliferation, migration and invasion was impaired with increased apoptosis upon YKT6 silencing in lung cancer cells. In summary, this study comprehensively uncovered that YKT6 could be identified as a potential prognostic and diagnostic biomarker in LUAD.

Morphological Prediction of CPAP Associated Acute Respiratory Instability.

Multiple mechanisms are involved in the pathogenesis of obstructive sleep apnea (OSA). Elevated loop gain is a key target for precision OSA care and may be associated with treatment intolerance when the upper airway is the sole therapeutic target. Morphological or computational estimation of LG is not yet widely available or fully validated - there is a need for improved phenotyping/endotyping of apnea to advance its therapy and prognosis. This study proposes a new algorithm to assess self-similarity as a signature of elevated loop gain using respiratory effort signals and presents its use to predict the probability of acute failure (high residual event counts) of continuous positive airway pressure (CPAP) therapy. Effort signals from 2145 split-night polysomnography studies from the Massachusetts General Hospital were analyzed for SS and used to predict acute CPAP therapy effectiveness. Logistic regression models were trained and evaluated using 5-fold cross-validation. Receiver operating characteristic (ROC) and precision-recall (PR) curves with AUC values of 0.82 and 0.84, respectively, were obtained. Self-similarity combined with the central apnea index (CAI) and hypoxic burden outperformed CAI alone. Even in those with a low CAI by conventional scoring criteria or only mild desaturation, SS was related to poor therapy outcomes. The proposed algorithm for assessing SS as a measure of expressed high loop gain is accurate, non-invasive, and has the potential to improve phenotyping/endotyping of apnea, leading to more precise sleep apnea treatment strategies.

The Matrix Protein Tropoelastin Prolongs Mesenchymal Stromal Cell Vitality and Delays Senescence During Replicative Aging.

Cellular senescence leads to the functional decline of regenerative cells such as mesenchymal stromal/stem cells (MSCs), which gives rise to chronic conditions and contributes to poor cell therapy outcomes. Aging tissues are associated with extracellular matrix (ECM) dysregulation, including loss of elastin. However, the role of the ECM in modulating senescence is underexplored. In this work, it is shown that tropoelastin, the soluble elastin precursor, is not only a marker of young MSCs but also actively preserves cell fitness and delays senescence during replicative aging. MSCs briefly exposed to tropoelastin exhibit upregulation of proliferative genes and concurrent downregulation of senescence genes. The seno-protective benefits of tropoelastin persist during continuous, long-term MSC culture, and significantly extend the MSC replicative lifespan. Tropoelastin-expanded MSCs further maintain youth-associated phenotype and function compared to age-matched controls, including preserved clonogenic potential, minimal senescence-associated beta-galactosidase activity, maintained cell sizes, reduced expression of senescence markers, suppressed secretion of senescence-associated factors, and increased production of youth-associated proteins. This work points to the utility of exogenously-supplemented tropoelastin for manufacturing MSCs that robustly maintain regenerative potential with age. It further reveals the active role of classical structural ECM proteins in driving cellular age-associated fitness, potentially leading to future interventions for aging-related pathologies.

Droplet Microfluidics for Current Cancer Research: From Single-Cell Analysis to 3D Cell Culture.

Cancer is the second leading cause of death worldwide. Differences in drug resistance and treatment response caused by the heterogeneity of cancer cells are the primary reasons for poor cancer therapy outcomes in patients. In addition, current in vitro anticancer drug-screening methods rely on two-dimensional monolayer-cultured cancer cells, which cannot accurately predict drug behavior in vivo. Therefore, a powerful tool to study the heterogeneity of cancer cells and produce effective in vitro tumor models is warranted to leverage cancer research. Droplet microfluidics has become a powerful platform for the single-cell analysis of cancer cells and three-dimensional cell culture of in vitro tumor spheroids. In this review, we discuss the use of droplet microfluidics in cancer research. Droplet microfluidic technologies, including single- or double-emulsion droplet generation and passive- or active-droplet manipulation, are concisely discussed. Recent advances in droplet microfluidics for single-cell analysis of cancer cells, circulating tumor cells, and scaffold-free/based 3D cell culture of tumor spheroids have been systematically introduced. Finally, the challenges that must be overcome for the further application of droplet microfluidics in cancer research are discussed.

Abstract B023: Paracrine enhancement of tumor cell proliferation provides indirect stroma-mediated chemoresistance via acceleration of tumor recovery between chemotherapy cycles

Abstract The ability of tumors to survive therapy reflects both cell-intrinsic and microenvironmental mechanisms. Across many cancers, including triple-negative breast cancer (TNBC), a high stroma/tumor ratio correlates with poor survival. In many contexts, this correlation can be explained by the direct reduction of therapy sensitivity by stroma-produced paracrine factors. We sought to explore whether this direct effect contributes to the link between stroma and poor responses to chemotherapies. Our in vitro studies with panels of TNBC cell line models and stromal isolates failed to detect a direct modulation of chemoresistance. At the same time, consistent with prior studies, we observed treatment-independent enhancement of tumor cell proliferation by fibroblast-produced secreted factors. Using spatial statistics analyses, we found that proximity to stroma is often associated with enhanced tumor cell proliferation in vivo. Based on these observations, we hypothesized an indirect link between stroma and chemoresistance, where stroma-augmented proliferation potentiates the recovery of residual tumors between chemotherapy cycles. To evaluate the feasibility of this hypothesis, we developed a spatial agent-based model of stroma impact on proliferation/death dynamics. The model was quantitatively parameterized using inferences from histological analyses and experimental studies. We found that the observed enhancement of tumor cell proliferation within stroma-proximal niches can enable tumors to avoid elimination over multiple chemotherapy cycles. Therefore, our study supports the existence of a novel, indirect mechanism of environment-mediated chemoresistance that might contribute to the negative correlation between stromal content and poor therapy outcomes. Citation Format: Daria Miroshnychenko, Tatiana Miti, Pragya Kumar, Anna Miller, Mark Laurie, Nathalia Giraldo, Marilyn M. Bui, Philipp M. Altrock, David Basanta, Anriy Marusyk. Paracrine enhancement of tumor cell proliferation provides indirect stroma-mediated chemoresistance via acceleration of tumor recovery between chemotherapy cycles [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B023.

Antibiotics Resistance among Nosocomial Burkholderia cepacia Isolates Detected in Sebha, Libya

Background: B. cepacia complex (Bcc) is an emerging pathogenic organism that can cause many nosocomial infections among hospitalized patients. Inadequate laboratory facilities for B. cepacia complex detection and subsequently inappropriate treatment are considered a major cause for poor therapy outcomes.
 Methods: This project was aimed to investigate phenotype production of ESBL, AmpC, and Carbapenemase among 47 B. cepacia complex isolated from different Sebha health care facilities.
 Results: Our data showed that 44.68% were ESBL producers, 57.44% were AmpC producers, while only 29.78% produced carbapenemase. In this study, antibiotics susceptibility of Bcc isolates was variable, 100 % resistant to Ticarcillin/clavulanic acid, 85 % resistant to sulfamethoxazoletrimethoprim, 76 % resistant to Ticarcillin/clavulanic Chloramphenicol, 57 % to Ceftazidime, and 55 % to Tetracyclines, 44% to Ciprofloxacin and 31% to Meropenem.
 Conclusion: In conclusion, this study shows that Bcc species have a higher resistance level attributed to several mechanisms. This high resistance needs careful antimicrobial prescribing regulations, and urgent implementation of infection prevention control is necessary.

Ferritinophagy-mediated apoptosis and paraptosis induction involved MAPK and PI3K/AKT pathway in mechanism of an iron chelator

Melanoma cells were more resistant to ferroptosis with still poor therapy outcomes. Sensitizing melanoma cell to the ferroptosis inducer was a crucial strategy for treatment of melanoma. In the present study, 2,2′-di-pyridylketone hydrazone dithiocarbamate s-butyric acid (DpdtbA) displayed superior inhibitory activity than ferroptosis inducer Erastin in melanoma cells, which prompt us to explore the underlying mechanism. The analyses from flow cytometry and Western blot showed that the growth inhibition of DpdtbA against SK-MEL-28 and A375 cells involved apoptosis induction and G1 phase arrest. Surprisingly, the cytoplasmic vacuoles were found upon the treatment; transmission electron microscopy and endoplasmic reticulum (ER) staining revealed that the cytoplasmic vacuoles were in ER; while down-regulation of alix and requirement of protein synthesis suggested there was an occurrence of paraptosis. However, both NAC and 3-MA could significantly attenuate the cytoplasmic vacuolization and growth inhibition, hinting that both ROS and autophagy involved the paraptosis induction. The additional evidence revealed that there was an occurrence of continuous ferritinophagy, which was responsible for the ROS production. Downregulation of NCOA4 clearly attenuated the apoptosis and paraptosis induction. In addition, activation of MAPK involved regulation of paraptosis, but only ERK and JNK had role in the formation of cytoplasmic vacuoles and growth inhibition. Furthermore, a ROS dependent regulation of PI3K/AKT pathway was also involved. Taken together, our result firstly demonstrated that a continuous ferritinophagy contributed to the apoptosis and paraptosis induction, highlighting that the lysosomal labile iron pool had a crucial role in control of melanoma cell fate.

Athletes with Eating Disorders: Analysis of Their Clinical Characteristics, Psychopathology and Response to Treatment.

Eating disorders (ED) have frequently been described among athletes. However, their specific features and therapy responses are lacking in the literature. The aims of this article were to compare clinical, psychopathological and personality traits between ED patients who were professional athletes (ED-A) with those who were not (ED-NA) and to explore differences in response to treatment. The sample comprised n = 104 patients with ED (n = 52 ED-A and n = 52 matched ED-NA) diagnosed according to DSM-5 criteria. Evaluation consisted of a semi-structured face-to-face clinical interview conducted by expert clinicians and a psychometric battery. Treatment outcome was evaluated when the treatment program ended. ED-A patients showed less body dissatisfaction and psychological distress. No differences were found in treatment outcome among the groups. Within the ED-A group, those participants who performed individual sport activities and aesthetic sports presented higher eating psychopathology, more general psychopathology, differential personality traits and poor therapy outcome. Individual and aesthetic sports presented more severity and worse prognosis. Although usual treatment for ED might be similarly effective in ED-A and ED-NA, it might be important to develop preventive and early detection programs involving sports physicians and psychologists, coaches and family throughout the entire athletic career and afterwards.

EIF4A3 serves as a prognostic and immunosuppressive microenvironment factor and inhibits cell apoptosis in bladder cancer.

EIF4A3 (Eukaryotic translation initiation factor 4A3 (EIF4A3) was recently recognized as an oncogene; however, its role in BLCA (bladder cancer) remains unclear. We explored EIF4A3 expression and its prognostic value in BLCA in public datasets, including the TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus). Thereafter, the association between EIF4A3 expression and the infiltration of immune cells and immune-checkpoint expression was determined using TIMER2 (Tumor Immune Estimation Resource 2) tool. Additionally, the impact of EIF4A3 on cellular proliferation and apoptosis events in BLCA cell lines was determined by siRNA technology. In this study, EIF4A3 was found to be significantly upregulated in BLCA, upregulated expression of EIF4A3 was related to poor prognosis, advanced histologic grade, subtype, pathological stage, white race, and poor primary therapy outcome. The immune infiltration analysis revealed that EIF4A3 expression was negatively associated with CD8+ and CD4+ T cells and positively with myeloid-derived suppressor cells, macrophage M2, cancer-associated fibroblasts, and Treg cells. Moreover, EIF4A3 was coexpressed with PD-L1 (programmed cell death 1-ligand 1) and its expression was higher in patients responding to anti-PD-L1 therapy. EIF4A3 knockdown significantly inhibited proliferation and promoted apoptosis in 5,637 and T24 cells. In summary, BLCA patients with elevated EIF4A3 expression had an unfavorable prognosis and immunosuppressive microenvironment, and EIF4A3 may facilitate BLCA progression by promoting cell proliferation and inhibiting apoptosis. Furthermore, our study suggests that EIF4A3 is a potential biomarker and therapeutic target for BLCA.

Abstract 4666: PDX, mini-brain co-cultures and patient-derived tumor organoids: Preclinical models to study the prion protein in glioblastoma biology

Abstract Glioblastoma (GBM), supported by a subpopulation of glioblastoma stem cells (GSCs), stands among the most harmful tumors. Its invasive and aggressive behavior has been correlated with poor therapy outcomes and reduced patient survival, which remains difficult to model and treat due to its cellular and molecular heterogeneity. GSCs are responsible for the malignant features of this cancer, including increased recurrence rates and resistance to therapy. Efforts have been employed to understand the molecular and cellular mechanisms underlying GSCs biology. The cellular prion protein (PrPC), encoded by the PRNP gene, is a key player in GBM biology, and our group has proposed PrPC as a scaffold protein that integrates signaling platforms involved in GSCs maintenance. A deeper understanding of the intracellular pathways modulated by PrPC is essential to identify novel targets for GBM treatment. We have analyzed bulk-RNA sequencing (RNA-seq) data from patient-derived xenografts (PDX) and in vitro preclinical experimental models. RNA-seq analyses identified differentially expressed genes (DEGs) associated with adhesion and migration signaling pathways in PDX cells with high PRNP expression (PRNP−HIGH). Morphological characterization of PDX samples with PRNP−HIGH levels showed an increase in morphologically undifferentiated cell groups, that are more commonly found in younger GBM patients. Furthermore, molecular profiling using Exome data showed that groups PRNP−HIGH present enhanced global patterns of gene mutations. Due to the importance of experimental models to translate basic science into clinical applications, we are establishing emerging models to study PrPC function in GBM biology: glioblastoma organoids (GBO) from patient’s surgically resected GBM tumors; and brain organoids derived from human-induced pluripotent stem cells. We noticed a morphological and molecular reproducibility of the cytoarchitecture of brain organoids and GBO, similar to that described in the literature, indicating consistency in 3D structures, despite the variability between patients. Furthermore, brain organoids will be co-cultured with GSCs, providing platforms for studying the interaction between tumor cells and brain parenchyma. The establishment of these models will improve our comprehension of the role of PrPC in GSCs maintenance and provide additional tools to understand GBM biology and predict tumor progression and response to treatment. Citation Format: Maria Clara da Silva Souza, Barbara P. Coelho, Camila F. Fernandes, Tiago G. Dos Santos, Stefan Knorst, Cibele Masotti, Maria Rita S. Passos-Bueno, Marilene H. Lopes. PDX, mini-brain co-cultures and patient-derived tumor organoids: Preclinical models to study the prion protein in glioblastoma biology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4666.

Existential Isolation as a Correlate of Mental Health Problems, Predictor of Treatment Outcome, and Moderator of a Patient-Therapist Match Effect

Introduction: Ample research has established that interpersonal isolation—the objective separateness from others—is a correlate of maladaptive psychological outcomes. However, existential isolation (EI)—the feeling of aloneness in one's subjective experience—has received less empirical attention. From the limited existing research, higher EI has been associated with greater severity of mental health concerns and more negative beliefs about treatment. Yet, these investigations have largely been conducted with non-clinical samples. Further, virtually no studies have examined EI as a predictor of current psychotherapy outcomes. Moreover, given their risk of holding negative treatment beliefs, it is plausible that therapy would be most effective if more existentially isolated individuals experienced being well matched to their therapist. This study extended EI research to a clinical sample and provided a novel test of EI as a direct predictor of outcome and moderator of a patient-therapist match system in naturalistic psychotherapy. Method: Data derived from a randomized trial comparing the effectiveness of prospectively matching patients (N = 218) to therapists (N = 48) with empirical strengths in treating the patient's specific presenting problem(s) versus case assignment as usual (Constantino et al., 2021). Patients rated EI at baseline and mental health outcomes repeatedly through treatment. We conducted correlations to examine baseline EI-symptom associations and multilevel modeling to test EI as a predictor of symptom change and moderator of the known beneficial match effect on outcome. Results: As predicted, higher EI was associated with greater depression, anxiety, and distress at baseline, as well as poorer therapy outcome across and at the end of treatment. In the expected direction, though not to a statistically significant level, the positive match effect was stronger for patients with higher versus lower EI. Discussion: We discuss research and practice implications at the intersection of social and clinical psychology.

Hesperidin potentially interacts with the catalytic site of gamma-secretase and modifies notch sensitive genes and cancer stemness marker expression in colon cancer cells and colonosphere

Gamma secretase (GS) produces Notch Intracellular Domain (NICD) by trans-membrane cleavage of notch receptor. The NICD enters the nucleus and activates the notch signaling pathway (NSP) by activating notch-responsive gene transcription. Hyperactivation of NSP is related to cancer aggressiveness, therapy resistance, and poor therapy outcome, and decreased overall disease-free survival in patients. Till date, none of the GS inhibitors (GSI) has been clinically approved due to their toxicity in patients. Thus in the present study, we explored the GS catalytic site binding potential of hesperidin (natural flavone glycoside) and its effect on notch responsive gene expression in HCT-116 cells. Molecular docking, MM-GBSA binding energy calculations, and molecular dynamics (MD) simulation experiments were performed to study the GS catalytic site binding potential of hesperidin. The compound showed better GS catalytic site binding potential at the active site compared to experimentally validated GSI, N-N-(3, 5-Difluorophenacetyl)-L-alanyl-S-phenylglycine t-butyl ester (DAPT) in molecular docking and MM-GBSA experiments. MD simulation results showed that hesperidin forms stable and energetically favorable complex with gamma secretase in comparison to standard inhibitor (DAPT)-GS complex. Further, in vitro experiments showed that hesperidin inhibited cell growth and sphere formation potential in HCT-116 cells. Further, hesperidin treatment altered notch responsive genes (Hes1, Hey1, and E-cad) and cancer stemness/self-renewal markers expression at transcription levels. In conclusion, hesperidin produces toxicity in HCT-116 cells and decreases colonosphere formation by inhibiting transcription of notch signaling pathway target genes and stemness markers. Communicated by Ramaswamy H. Sarma

CDCA4 as a novel molecular biomarker of poor prognosis in patients with lung adenocarcinoma.

BackgroundBecause of the high incidence and poor prognoses of lung adenocarcinoma (LUAD), it is essential to identify cost-effective treatment options and accurate and reliable prognostic biomarkers. CDCA4 upregulation has been identified in many cancers. However, the prognostic importance of CDCA4 and its role in LUAD remain unknown.MethodsCDCA4 expression was assessed through IHC, Western blotting (WB) and RT-PCR. The Cancer Genome Atlas (TCGA) provided data from 513 patients to study the expression and prognostic relevance of CDCA4 in LUAD. This study used gene set enrichment analyses (GSEA), gene ontology and KEGG pathway analyses for elucidating potential mechanisms underpinning the function of CDCA4 in LUAD. We also investigated correlations between immune infiltration and CDCA4 expression with single specimen GSEA (ssGSEA).ResultsAccording to database analysis and identification of patient tissue samples, CDCA4 expression in tumour tissues surpassed that in normal tissues (P< 0.001). Increased CDCA4 expression was positively correlated with a higher T, N, pathologic stage and poor primary therapy outcome. In addition, the Kaplan–Meier plotter exhibited that an elevated CDCA4 expression was related to worse disease-specific survival(DSS) and overall survival (OS) (DSS HR= 5.145, 95% CI=3.413-7.758, P<0.001; OS HR=3.570, 95% CI=2.472-5.155, P<0.001). Then multivariate COX regression analyses indicated that the CDCA4 gene was an independent risk consideration for prognoses. GO and KEGG results showed that CDCA4 and its neighbouring genes were enriched in the cell cycle and DNA replication. As determined by GSEA, CDCA4 was related to various immune-related signalling pathways (SPs), Homologous recombination, DNA replication and the cell cycle. SsGSEA analysis showed a significant association between CDCA4 expression and Th2 cells, mast cells, eosinophils and Th17 cells.ConclusionsCDCA4 expression is increased in LUAD and is a potential predictive biomarker and therapeutic target.

HIV-related stigma, disclosure and social support: experiences among young pregnant and postpartum women living with HIV in South Africa

ABSTRACT Young pregnant and postpartum women living with HIV (WLHIV) are at high risk of poor antiretroviral therapy (ART) outcomes, which may be driven partly by HIV-related stigma. We conducted in-depth interviews with 20 pregnant and postpartum WLHIV aged 19–24 years to understand how different forms of HIV-related stigma manifest in their lives, as well as their experiences of HIV-status disclosure and social support. Participants described profound levels of perceived stigma in their community, including gossip from other young women and judgement from older adults. Consequently, participants disclosed to a limited number of people to avoid being stigmatised, and disclosure to peers was especially uncommon. However, disclosure in certain situations was described as leading to emotional support and support for ART adherence, and disclosure to older WLHIV resulted in participants having a role model. Finally, participants expressed varied ways in which they accept, speak about, and live with their HIV diagnosis. These data provide a rich understanding of the experiences of HIV-related stigma in this population and point to the need for psychosocial interventions focussed on acceptance and coping with an HIV-positive diagnosis despite profound levels of perceived stigma, as well as navigating decisions around the targets and timing of disclosure. Trial registration: ClinicalTrials.gov identifier: NCT04036851.

Examining the Relationship Between Psychosocial Factors with Knowledge of HIV-Positive Status and Antiretroviral Therapy Exposure Among Adolescent Girls and Young Women Living with HIV in South Africa.

Adolescent girls and young women (AGYW) living with HIV have poor antiretroviral therapy (ART) outcomes. We examined the relationship between psychosocial factors with knowledge of HIV-positive status and antiretroviral therapy exposure among AGYW living with HIV in South Africa. Participants 15-24years responded to a survey including socio-demographics, psychosocial factors, and HIV testing. Blood was collected to determine HIV status and ART exposure. Multivariable analyses were conducted using R. Of 568 participants with HIV, 356 had knowledge of their HIV-positive status. Social support from family [aOR 1.14 (95% CI 1.04-1.24)] or from a special person [aOR 1.12 (95% CI 1.02-1.23)] was associated with knowledge of HIV-positive status. Resilience [aOR 1.05 (95% CI 1.01-1.08)] was the only psychosocial factor associated with a higher odds of ART exposure. Social support and resilience may increase knowledge of HIV-positive status and ART exposure among South African AGYW.

Comparison of the somatic mutations between circulating tumor DNA and tissue DNA in Chinese patients with non-small cell lung cancer

Non-invasive liquid biopsies of circulating tumor DNA (ctDNA) is a rapidly growing field in the research of non-small cell lung cancer (NSCLC). In this study, factors affecting the concordance of mutations in paired plasma and tissue and the detection rate of ctDNA in real-world Chinese patients with NSCLC were identified. Peripheral blood and paired formalin-fixed paraffin-embedded tumor tissue samples from 125 NSCLC patients were collected and analyzed by sequencing 15 genes. Serological biomarkers were tested by immunoassay. The overall concordance between tumor and plasma samples and the detection rate of somatic mutations in ctDNA was 69.2% and 78.4%, respectively. The concordance and detection rate raised with clinical stage were stage I: 14.3%, 14.3%; stage II: 53.3%, 60.0%; stage III: 71.4%, 78.1%; stage IV: 74.1%, 85.2%. With increased tumor diameter, the concordance and detection rate raised from 33.33% to 71.64% and 33.33% to 80.8%, respectively. For patients with partial response, stable disease, progressive disease, and who were treatment-naïve, the concordance and detection rates were 0.0%, 62.7%, 75.2, 73.6%, and 16.7%, 61.9%, 83.3%, 86.5%, respectively. Serological markers: CEA, CA125, NSE, and CYFRA21-1 were significantly higher for patients with detectable somatic alterations in ctDNA than in those who were ctDNA negative (17.08 ng/mL vs. 3.95 ng/mL, 21.63 U/mL vs. 18.27 U/mL, 17.68 U/mL vs. 14.14 U/mL, and 6.55 U/mL vs. 3.81 U/mL, respectively). Advanced-stage, treatment naïve or poor therapy outcome, and large tumor size were associated with a high concordance and detection rate. Patients with detectable mutations in ctDNA had a higher level of carcinoembryonic antigen, CA125, NSE, and CYFRA21-1.

Evaluating the frequency, prognosis and survival of RUNX1 and ASXL1 mutations in patients with acute myeloid leukaemia in northeastern Iran.

To evaluate the frequency and prognosis of runt‐related transcription factor 1 (RUNX1) and additional sex combs like‐1 (ASXL1) mutations in acute myeloid leukaemia (AML) patients in northeastern Iran. This cross‐sectional study was performed on 40 patients with AML (including 35 patients with denovo AML and five patients with secondary AML) from February 2018 to February 2021. All patients were followed up for 36 months. We evaluated the frequency and survival rate of RUNX1 and ASXL1 mutations in AML patients. To detect mutations, peripheral blood samples and bone marrow aspiration were taken from all participants. One male patient (2.5%) had RUNX1 mutations and four cases (10%; 3 females vs. 1 male) had ASXL1 mutations. The survival rates of AML patients after 1, 3, 6, 9, 12, 24 and 36 months were 98%, 90%, 77%, 62%, 52%, 27% and 20%, respectively. There was a significant relationship between the occurrence of ASXL1 mutations and the survival of patients with AML (p = 0.027). Also, there was a significant relationship between the incidence of death and haemoglobin levels in patients with AML (p = 0.045). Thus, with an increase of one unit in patients' haemoglobin levels, the risk of death is reduced by 16.6%. Patients with AML had a high mortality rate, poor therapy outcome and low survival rate. ASXL1 and RUNX1 mutations are associated with a worse prognosis in patients with newly diagnosed AML. Also, we witnessed that the prevalence of ASXL1 to RUNX1 mutations was higher in northeastern Iran compared with other regions.

Evaluation of flow cytometric expressions of CD96 and CD123 on leukemic stem cells in patients with adult acute myeloid leukemia and their utility as prognostic markers

Background Acute myeloid leukemia (AML) is a disease associated with a risk of relapse or refractoriness to the frontline agents. This is attributable to the quiescent leukemic stem cells (LSC). We aimed to determine the expression status of CD96 and CD123 on the surface of LSC in adult patients with AML and their relationship to prognosis. Patients and methods A total of 40 adult patients with de novo AML and 40 age-matched and sex-matched controls were recruited from Center ‘X,’ City ‘Y,’ Country ‘Y’ from June 2017 to February 2018, with 1-year follow-up. Bone marrow samples were collected for flow cytometric analysis using CD34, CD38, CD96, and CD123 monoclonal antibodies. For cases, samples were obtained at diagnosis and on day 28 after chemotherapy, whereas for controls, samples were taken once. Results CD96 and CD123 expressions are significantly higher in patients with AML as compared with controls. CD96 expression is associated with higher initial bone marrow and peripheral blood blast percentages. Day28 CD96 expression is positively correlated with its expression on day 0 and with CD123 expression at diagnosis, with P values of less than 0.001 and 0.034, respectively. Both markers were much more frequently expressed on LSCs in differentiated AML as compared with ill-differentiated subtypes (P&lt;0.05). Both markers are linked to poor therapy outcome, with inferior progression-free survival among CD96-positive and CD123-positive cases at day 28 (P=0.035 and 0.041, respectively). Conclusions CD96 and CD123 represent potential targetable markers for the future development of therapeutic armamentarium for AML.

CAF-Associated Paracrine Signaling Worsens Outcome and Potentially Contributes to Chemoresistance in Epithelial Ovarian Cancer.

BackgroundHigh-grade serous ovarian cancer (HGSOC) is the predominant and deadliest form of ovarian cancer. Some of its histological subtypes can be distinguished by frequent occurrence of cancer-associated myofibroblasts (CAFs) and desmoplastic stroma reaction (DSR). In this study, we want to explore the relationship between therapy outcome and the activity of CAF-associated signaling pathways in a homogeneous HGSOC patient collective. Furthermore, we want to validate these findings in a general Epithelial ovarian cancer (EOC) cohort.MethodsThe investigation cohort consists of 24 HGSOC patients. All of them were treated with platinum-based components and clinical follow-up was available. The validation cohort was comprised of 303 patients. Sequencing data (whole transcriptome) and clinical data were extracted from The Cancer Genome Atlas (TCGA). RNA of HGSOC patients was isolated using a Maxwell RSC instrument and the appropriate RNA isolation kit. For digital expression analysis a custom-designed gene panel was employed. All genes were linked to various DSR- and CAF- associated pathways. Expression analysis was performed on the NanoString nCounter platform. Finally, data were explored using the R programming environment (v. 4.0.3).ResultIn total, 15 CAF-associated genes were associated with patients’ survival. More specifically, 6 genes (MMP13, CGA, EPHA3, PSMD9, PITX2, PHLPP1) were linked to poor therapy outcome. Though a variety of different pathways appeared to be associated with therapy failure, many were related to CAF paracrine signaling, including MAPK, Ras and TGF-β pathways. Similar results were obtained from the validation cohort.DiscussionIn this study, we could successfully link CAF-associated pathways, as shown by increased Ras, MAPK and PI3K-Akt signaling to therapy failure (chemotherapy) in HGSOC and EOCs in general. As platinum-based chemotherapy has been the state-of-the-art therapy to treat HGSOC for decades, it is necessary to unveil the reasons behind resistance developments and poor outcome. In this work, CAF-associated signaling is shown to compromise therapy response. In the validation cohort, CAF-associated signaling is also associated with therapy failure in general EOC, possibly hinting towards a conserved mechanism. Therefore, it may be helpful to stratify HGSOC patients for CAF activity and consider alternative treatment options.

The clinical and molecular cardiometabolic fingerprint of an exploratory psoriatic arthritis cohort is associated with the disease activity and differentially modulated by methotrexate and apremilast.

Objectives(1) To evaluate clinical and molecular cardiovascular disease (CVD) signs and their relationship with psoriatic arthritis (PsA) features and (2) to identify a clinical patient profile susceptible to benefit from methotrexate (MTX) and/or apremilast regarding CVD risk.MethodsThis cross‐sectional study included 100 patients with PsA and 100 age‐matched healthy donors. In addition, an exploratory cohort of 45 biologically naïve patients treated for 6 months with apremilast, MTX or combined therapy according to routine clinical practice was recruited. Extensive clinical and metabolic profiles were obtained. Ninety‐nine surrogate CVD‐related molecules were analysed in plasma and peripheral blood mononuclear cells (PBMCs). Hard cluster analysis was performed to identify the clinical and molecular phenotypes. Mechanistic studies were performed on adipocytes.ResultsCardiometabolic comorbidities were associated with disease activity and long‐term inflammatory status. Thirty‐five CVD‐related proteins were altered in the plasma and PBMCs of PsA patients and were associated with the key clinical features of the disease. Plasma levels of some of the CVD‐related molecules might distinguish insulin‐resistant patients (MMP‐3, CD163, FABP‐4), high disease activity (GAL‐3 and FABP‐4) and poor therapy outcomes (CD‐163, LTBR and CNTN‐1). Hard cluster analysis identified two phenotypes of patients according to the rates of cardiometabolic comorbidities with distinctive clinical and molecular responses to each treatment.Conclusions(1) Novel CVD‐related proteins associated with clinical features could be emerging therapeutic targets in the context of PsA and (2) the pleiotropic action of apremilast could make it an excellent choice for the management of PsA patients with high CVD risk, targeting metabolic alterations and CVD‐related molecules.