Poor Outcome In Patients Research Articles

Sinonasal mucosal melanoma in The Netherlands between 2001 and 2021: a clinical and epidemiological overview of 320 cases.

Sinonasal mucosal melanoma (SNMM) is a rare malignancy, characterised by high (local) recurrence rates and poor survival. Comprehensive understanding of tumour etiology is currently lacking, which complicates adequate tumour treatment. Besides examining trends in incidence, this study aims to assess the association between clinical characteristics, treatment practices and patient outcomes, with the objective of establishing a baseline from which SNMM management can be enhanced. All newly diagnosed SNMM cases in The Netherlands between 2001 and 2021 were included using data from The Netherlands Cancer Registry (NCR). A total of 320 patients were included. The annual incidence rate for the overall population was stable over the inclusion period with an annual percentage change (APC) of only - 0.01%. The 5-year overall survival (OS) and relative survival (RS) were 24.5 and 32.4%, respectively. Relative survival did not increase over time. The addition of adjuvant radiotherapy to surgery was not associated with a higher OS and RS compared to surgery alone. Sinonasal mucosal melanoma is a rare disease with stable incidence rates in the Netherlands between 2001 and 2021. There has been no improvement in survival over the course of the inclusion period. The study reaffirms that adjuvant radiotherapy does not seem to improve patient outcomes. Given the generally poor outcomes for SNMM patients, novel therapeutic options ought to be considered in order to improve care.

The Effect of Controlled versus Uncontrolled Hypertension on Outcomes of Carotid Revascularization Procedures.

Hypertension has been implicated as a strong predictive factor for poorer outcomes in patients undergoing various vascular procedures. However, limited research is available that examines the effect of uncontrolled hypertension on outcomes after carotid revascularization. We aimed to determine which carotid revascularization procedure yields the best outcome in this patient population. We studied patients undergoing Carotid Endarterectomy (CEA), Transfemoral Carotid Artery Stenting (TFCAS), or Transcarotid Artery Revascularization (TCAR) from April 2020 to June 2022 using data from Vascular Quality Initiative (VQI). Patients were stratified into two groups: those with controlled hypertension (cHTN) and those with uncontrolled hypertension (uHTN). Patients with cHTN were those with HTN treated with medication and a blood pressure <130/80. Patients with uHTN had a blood pressure >130/80. Our primary outcomes were in-hospital stroke, death, myocardial infarction (MI), and 30-day mortality. Our secondary outcomes were postoperative hypotension/hypertension, reperfusion syndrome, prolonged length of stay (PLOS; >1 day), stroke/death and stroke/death/MI. We used logistic regression models for the multivariate analysis. A total of 34,653 CEA (uHTN= 11,347, 32.7%), 8,199 TFCAS (uHTN=2,307, 28.1%), and 17,309 TCAR (uHTN=4,990, 28.8%) patients were included in this study. There was no significant difference in age between cHTN and uHTN patients for each carotid revascularization procedure. However, compared to cHTN, patients with uncontrolled HTN had significantly more comorbidities. Uncontrolled HTN was associated with an increased risk of combined in-hospital stroke/death/MI following CEA (aOR=1.56 [95% CI: 1.30-1.87]; p<0.001), TFCAS (aOR=1.59 [95% CI: 1.21-2.08]; p<0.001) and TCAR (aOR=1.39 [95% CI: 1.12-1.73]; p=0.003) compared to controlled HTN. Additionally, uHTN was associated with PLOS following all carotid revascularization methods. For the sub-analysis of patients with uHTN, TFCAS was associated with an increased risk of stroke (aOR=1.82 [95% CI: 1.39-2.37]; p<0.001), in-hospital death (aOR=3.73 [95% CI: 2.25-6.19]; p<0.001), reperfusion syndrome (aOR=6.24 [95% CI: 3.57-10.93]; p<0.001), and extended LOS (aOR=1.87 [95% CI: 1.51-2.32]; p<0.001) compared to CEA. There was no statistically significant difference between the outcomes of TCAR compared to CEA. The results from this study show that patients with uncontrolled hypertension are at a higher risk of stroke and death postoperatively compared to patients with controlled hypertension; highlighting the importance of treating HTN before undergoing elective carotid revascularization. Additionally, in patients with uHTN, TFCAS yields the worst outcomes while CEA and TCAR proved to be the safer interventions. Uncontrolled hypertensive patients with symptomatic carotid disease treated with CEA or TCAR have better outcomes compared to those treated with TFCAS.

MAPPING THYROID HORMONE ACTION IN THE HUMAN BRAIN.

Normal brain development, mood, and cognitive functions depend on thyroid hormone (TH) action. However, little is known about how TH mediates its actions in the human brain. This is because of limited access to human brains deprived of TH during fetal and early postnatal life, as well as from adults with altered thyroid status. One way to partially bypass these limitations is by using magnetic resonance imaging and spectroscopy, two neuroimaging techniques that provide detailed, non-invasive information on human brain structure and function. Another way is using human-induced pluripotent stem cells (hiPSCs)-derived three-dimensional in vitro systems, known as brain organoids, which allow for studying fundamental aspects of the early stages of human brain development. This narrative review focuses on neuroimaging and brain organoid studies. Neuroimaging of human brains performed in individuals with different thyroid conditions provides information on the volume, myelination, blood flow, neural activity, and connectivity of different areas. Such studies show that a suboptimal thyroid status can impact human brain development and its normal function throughout life. This is true not only for patients with sporadic congenital hypothyroidism, during pregnancy or early after birth, but also for adult patients with hypo- or hyperthyroidism and for patients carrying mutations that manifest as impaired sensitivity to TH-and even for normal individuals during aging. Studies using brain organoids generated from iPSCs of healthy individuals or patients with thyroid genetic conditions provide insights into how TH can impact the early development of the human cerebral cortex. The developmental alterations in children born to mothers with different degrees of gestational hypothyroidism or who developed hypothyroidism early in life are remarkable, affecting multiple brain regions and pathways, including the cerebral cortex, hippocampus, cerebellum, interhemispheric and corticospinal tracts, and associative nuclei. The data connecting such changes to poor neurological outcomes in adult patients with hypothyroidism represent an objective link between thyroid-specific functional brain alterations and behavior. Growing brain organoids require TH, proving critical for human neuro- and oligodendrogenesis. These models proved useful in screening drugs with potential therapeutics for patients with genetic thyroid diseases.

Multimodal data integration for enhanced longitudinal prediction for cardiac and cerebrovascular events following initial diagnosis of obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS), a prevalent condition, often coexists with intricate metabolic issues and is frequently associated with negative cardiovascular outcomes. We developed a longitudinal prediction model integrating multimodal data for cardiovascular risk stratification of patients with an initial diagnosis of OSAS. We reviewed the data of patients with new-onset OSAS who underwent diagnostic polysomnography between 2018-19. Patients were treated using standard treatment regimens according to clinical practice guidelines. Over a median follow-up of 32 months, 98/729 participants (13.4%) experienced our composite outcome. At a ratio of 7:3, cases were randomly divided into development (n = 510) and validation (n = 219) cohorts. A prediction nomogram was created using six clinical factors - sex, age, diabetes mellitus, history of coronary artery disease, triglyceride-glucose index, and apnea-hypopnea index. The prediction nomogram showed excellent discriminatory power, based on Harrell's C-index values of 0.826 (95% confidence interval (CI) = 0.779-0.873) for the development cohort and 0.877 (95% CI = 0.824-0.93) for the validation cohort. Moreover, comparing the predicted and observed major adverse cardiac and cerebrovascular events in both development and validation cohorts indicated that the prediction nomogram was well-calibrated. Decision curve analysis demonstrated the good clinical applicability of the prediction nomogram. Our findings demonstrated the construction of an innovative visualisation tool that utilises various types of data to predict poor outcomes in Chinese patients diagnosed with OSAS, providing accurate and personalised therapy. Chinese Clinical Trial Registry ChiCTR2300075727.

Screening for Financial Toxicity Among Patients with Cancer: A Systematic Review.

Despite the pervasiveness and adverse impacts of financial toxicity (FT) in cancer care, there are no definitive measures for FT screening that have been widely integrated into clinical practice. The aim of this review is to evaluate current methods of assessing FT among patients with cancer and confirm factors associated with higher risk of FT. A systematic review was performed according to PRISMA guidelines. We included peer-reviewed studies that cross-sectionally, longitudinally, or prospectively measured the self-reported financial impact of patients undergoing cancer care in the United States. Out of 1085 identified studies, 51 met final inclusion criteria. Outcomes evaluated included FT measures/tools, time and setting of screening, FT prevalence, and sociodemographic or clinical patient-level associated factors. Our findings demonstrate that there is wide variability in FT screening practices including in the timing (diagnosis vs treatment vs survivorship), setting (clinic-based, online, telephone/mail), utilized tools (21 unique tools, 7 previously validated), and interpretations of screening results (varying FT score cutoffs defining high vs. low FT). Younger age, lower income, lower education, non-white race, employment status change, advanced cancer stage, and systemic/radiation therapy, were among factors associated with worse FT across the studies. FT screening remains heterogenous within the United States. With the ever-escalating cost of cancer care, and the strong association between FT and poor patient outcomes, universal and routine FT screening is imperative in cancer care. Further research and multifaceted interventions identifying best practices for FT screening are needed.

Exploring the Efficacy of Selected Allografts in Chronic Wound Healing: Evidence from Murine Models and Clinical Data for a Proposed Treatment Algorithm.

Chronic wounds can lead to poor outcomes for patients, with risks including amputation and death. In the United States, chronic wounds affect 2.5% of the population and cost up to $28 billion per year in primary healthcare costs. Allograft tissues (dermal, amnion, and amnion/chorion) have shown efficacy in improving healing of chronic, recalcitrant wounds in human patients, as evidenced by multiple clinical trials. Their mechanisms of actions have been relatively understudied, until recently. Research in murine models has shown dermal allografts promote re-epithelialization, amnion allografts promote granulation tissue formation and angiogenesis, and amnion/chorion allografts support all stages of wound healing. These findings not only confirm effectiveness, but they shed light on mechanisms of action responsible for their therapeutic utility in patients. Despite the promise of allografts in chronic wound care, a gap exists in understanding which allografts are most effective during each wound healing stage. The variable efficacy among each type of allograft suggests a mechanistic approach towards a proposed clinical treatment algorithm, based on wound characteristics and patient's needs, may be beneficial. Recent advances in allografts provide a framework for further investigations on how allograft selection can be based on specific needs of individual patients. This requires additional research to identify which allografts support the best outcomes during each stage of the wound healing process as well as utility in specific wound types. Longitudinal human studies investigating the long-term impacts of allografts, particularly in the remodeling phase, are also essential to developing a deeper understanding of their role in sustained wound repair and recovery.

Molecular Mechanisms of Tumorgenesis and Metastasis of Long Non-coding RNA (lncRNA) NEAT1 in Human Solid Tumors; An Update.

The expression of the nuclear paraspeckle assembly transcript 1 (NEAT1), as a well-known long non-coding RNA (lncRNA), is often upregulated in varied types of cancers and associated with poor survival outcomes in patients suffering from tumors. NEAT1 promotes the tumors growth by influencing the various genes' expression profile that regulate various aspects of tumor cell behavior, in particular tumor growth, metastasis and drug resistance. This suggests that NEAT1 are capable of serving as a new diagnostic biomarker and target for therapeutic intervention. Through interrelation with enhancer of zeste homolog 2 (EZH2), NEAT1 acts as a scaffold RNA molecule, and thus regulating the expression EZH2-associated genes. Additionally, by perform as miRNA sponge, it constrains suppressing the interactions between miRNAs-mediated degradation of target mRNAs. In light of this, NEAT1 inhibition by small interfering RNA (siRNA) hampers tumorgenesis. We summarize recent findings about the expression, biological functions, and regulatory process of NEAT1 in human tumors. It specifically emphasizes the clinical significance of NEAT1 as a novel diagnostic biomarker and a promising therapeutic mark for many types of cancers.

Improving malignant fungating wound management among oncology nurses: a best practice implementation project.

Appropriate malignant fungating wound (MFW) care is challenging for oncology nurses, leading to increased stress, compromised care quality, and poor patient outcomes. This study aimed to address best practice barriers and develop evidence-based guidelines for MFW care. This project was guided by the JBI Evidence Implementation Framework, which follows a seven-phase process. Both nurses' skills and patient charts were audited to determine compliance with best practices for comprehensive MFW assessment, wound photo records, use of validated wound assessment tools, appropriate wound care, and patient pain and satisfaction. Bandura's social learning theory was used to guide the development of an online education program and an objective structured clinical examination for skill improvement to prompt behavior change in nurses. A follow-up audit was conducted to measure improvements in knowledge, skills, and self-efficacy among nurses to validate the effectiveness of the intervention. The project resulted in improvements in all four evidence-based practice criteria: (1) comprehensive MFW assessments increased from 27% to 98%; (2) the inclusion of wound photos in medical records increased from 50% to 100%; (3) use of a validated wound assessment tool increased from 0% to 100%; and (4) appropriate interventions to manage wounds and maintain patients' quality of life increased from 50% to 90%. The project integrated a flexible education program, multidisciplinary collaboration, and leadership support to empower nurses to effectively manage MFWs. In addition, Bandura's social learning theory was used to influence nurses' behavior and bring about sustainable changes to organizational culture and practices. http://links.lww.com/IJEBH/A205.

H2A.Z chaperones converge on E2F target genes for melanoma cell proliferation.

High levels of H2A.Z promote melanoma cell proliferation and correlate with poor prognosis. However, the role of the two distinct H2A.Z histone chaperone complexes SRCAP and P400-TIP60 in melanoma remains unclear. Here, we show that individual subunit depletion of SRCAP, P400, and VPS72 (YL1) results in not only the loss of H2A.Z deposition into chromatin but also a reduction of H4 acetylation in melanoma cells. This loss of H4 acetylation is particularly found at the promoters of cell cycle genes directly bound by H2A.Z and its chaperones, suggesting a coordinated regulation between H2A.Z deposition and H4 acetylation to promote their expression. Knockdown of each of the three subunits downregulates E2F1 and its targets, resulting in a cell cycle arrest akin to H2A.Z depletion. However, unlike H2A.Z deficiency, loss of the shared H2A.Z chaperone subunit YL1 induces apoptosis. Furthermore, YL1 is overexpressed in melanoma tissues, and its upregulation is associated with poor patient outcome. Together, these findings provide a rationale for future targeting of H2A.Z chaperones as an epigenetic strategy for melanoma treatment.

Clinical manifestations, prognostic factors, and outcomes of adenovirus pneumonia after allogeneic hematopoietic stem cell transplantation

BackgroundSevere pneumonia is one of the most important causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adenovirus (ADV) is a significant cause of severe viral pneumonia after allo-HSCT, and we aimed to identify the clinical manifestations, prognostic factors, and outcomes of ADV pneumonia after allo-HSCT.MethodsTwenty-nine patients who underwent allo-HSCT at the Peking University Institute of Hematology and who experienced ADV pneumonia after allo-HSCT were enrolled in this study. The Kaplan–Meier method was used to estimate the probability of overall survival (OS). Potential prognostic factors for 100-day OS after ADV pneumonia were evaluated through univariate and multivariate Cox regression analyses.ResultsThe incidence rate of ADV pneumonia after allo-HSCT was approximately 0.71%. The median time from allo-HSCT to the occurrence of ADV pneumonia was 99 days (range 17–609 days). The most common clinical manifestations were fever (86.2%), cough (34.5%) and dyspnea (31.0%). The 100-day probabilities of ADV-related mortality and OS were 40.4% (95% CI 21.1%-59.7%) and 40.5% (95% CI 25.2%-64.9%), respectively. Patients with low-level ADV DNAemia had lower ADV-related mortality and better OS than did those with high-level (≥ 106 copies/ml in plasma) ADV DNAemia. According to the multivariate analysis, high-level ADV DNAemia was the only risk factor for intensive care unit admission, invasive mechanical ventilation, ADV-related mortality, and OS after ADV pneumonia.ConclusionsWe first reported the prognostic factors and confirmed the poor outcomes of patients with ADV pneumonia after allo-HSCT. Patients with high-level ADV DNAemia should receive immediate and intensive therapy.

Superoxide Dismutase Mimetic Avasopasem Manganese Enhances Radiation Therapy Effectiveness in Soft Tissue Sarcomas and Accelerates Wound Healing

Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.

Advances in MET tyrosine kinase inhibitors in gastric cancer.

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally. Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics, the management of gastric cancer calls for better-defined, biomarker-guided, molecular-based treatment strategies. MET is a receptor tyrosine kinase mediating important physiologic processes, such as embryogenesis, tissue regeneration, and wound healing. However, mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types, including gastric cancer, and is associated with poor patient outcomes. As such, MET-targeting therapies are being actively developed and promising progress has been demonstrated, especially with MET tyrosine kinase inhibitors. This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib, tepotinib, capmatinib, and crizotinib. Building on current knowledge, this review further discusses existing challenges in MET alterations testing, possible resistance mechanisms to MET inhibitors, and future directions of MET-targeting therapies.

Traditional Plant-Derived Compounds Inhibit Cell Migration and Induce Novel Cytoskeletal Effects in Glioblastoma Cells

Glioblastomas (GBMs) are aggressive and invasive cancers of the brain, associated with high rates of tumour recurrence and poor patient outcomes despite initial treatment. Targeting cell migration is therefore of interest in highly invasive cancers such as GBMs, to prevent tumour dissemination and regrowth. One current aim of GBM research focuses on assessing the anti-migratory properties of novel or repurposed inhibitors, including plant-based drugs which display anti-cancer properties. We investigated the potential anti-migratory activity of plant-based products with known cytotoxic effects in cancers, using a range of two-dimensional (2D) and three-dimensional (3D) migration and invasion assays as well as immunofluorescence microscopy to determine the specific anti-migratory and phenotypic effects of three plant-derived compounds, Turmeric, Indigo and Magnolia bark, on established glioma cell lines. Migrastatic activity was observed in all three drugs, with Turmeric exerting the most inhibitory effect on GBM cell migration into scratches and from the spheroid edge at all the timepoints investigated (p &lt; 0.001). We also observed novel cytoskeletal phenotypes affecting actin and the focal adhesion dynamics. As our in vitro results determined that Turmeric, Indigo and Magnolia are promising migrastatic drugs, we suggest additional experimentation at the whole organism level to further validate these novel findings.

White Matter Hyperintensity is Associated with Malignant Cerebral Edema in Ischemic Stroke Treated with Thrombectomy

BackgroundWhite matter hyperintensity (WMH) burden may lead to poor clinical outcomes after endovascular thrombectomy (EVT). But the relationship between WMH burden and cerebral edema (CED) is unclear.PurposeTo examine the association between WMH burden and CED and functional outcome in patients treated with EVT.Study TypeRetrospective.Subject344 patients with acute anterior circulation large‐vessel occlusion stroke who received EVT at two comprehensive stroke centers. Mean age was 62.6 ± 11.6 years and 100 patients (29.1%) were female.Field Strength/Sequence3T, including diffusion‐weighted imaging and fluid‐attenuated inversion recovery (FLAIR) images.AssessmentThe severity of WMH was evaluated using the Fazekas scale on a FLAIR sequence before EVT. The severity of CED was assessed using CED score (three for malignant cerebral edema [MCE]) and net water uptake (NWU)/time on post‐EVT cranial CT. The impact of WMH burden on MCE, NWU/time, and 3‐month poor outcome (modified Rankin scale &gt;2) after EVT were assessed.Statistical TestsPearson's chi‐squared test, Fisher exact test, 2‐tailed t test, Mann–Whitney U test, multivariable logistic regression, multivariate regression analysis, Sobel test. A P value &lt;0.05 was considered statistically significant.ResultsWMH burden was not significantly associated with MCE and parenchymal hemorrhage (PH) in the whole population (P = 0.072; P = 0.714). WMH burden was significantly associated with an increased risk of MCE (OR, 1.550; 95% CI, 1.128–2.129), higher NWU/time (Coefficient, 0.132; 95% CI, 0.012–0.240), and increased risk of 3‐month poor outcome (OR, 1.434; 95% CI, 1.110–1.853) in the subset of patients without PH. Moreover, the connection between WMH burden and poor outcome was partly mediated by CED in patients without PH (regression coefficient changed by 29.8%).Data ConclusionWMH burden is associated with CED, especially MCE, and poor outcome in acute ischemic stroke patients treated with EVT. The association between WMH burden and poor outcome may partly be attributed to postoperative CED.Level of Evidence3.Technical EfficacyStage 5.

Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand 1

BackgroundIncreased levels of plasminogen activator inhibitor-1 (PAI-1) in tumors have been found to correlate with poor clinical outcomes in patients with cancer. Although abundant data support the involvement of PAI-1 in cancer progression, whether PAI-1 contributes to tumor immune surveillance remains unclear. The purposes of this study are to determine whether PAI-1 regulates the expression of immune checkpoint molecules to suppresses the immune response to cancer and demonstrate the potential of PAI-1 inhibition for cancer therapy.MethodsThe effects of PAI-1 on the expression of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) were investigated in several human and murine tumor cell lines. In addition, we generated tumor-bearing mice and evaluated the effects of a PAI-1 inhibitor on tumor progression or on the tumor infiltration of cells involved in tumor immunity either alone or in combination with immune checkpoint inhibitors.ResultsPAI-1 induces PD-L1 expression through the JAK/STAT signaling pathway in several types of tumor cells and surrounding cells. Blockade of PAI-1 impedes PD-L1 induction in tumor cells, significantly reducing the abundance of immunosuppressive cells at the tumor site and increasing cytotoxic T-cell infiltration, ultimately leading to tumor regression. The anti-tumor effect elicited by the PAI-1 inhibitor is abolished in immunodeficient mice, suggesting that PAI-1 blockade induces tumor regression by stimulating the immune system. Moreover, combining a PAI-1 inhibitor with an immune checkpoint inhibitor significantly increases tumor regression.ConclusionsPAI-1 protects tumors from immune surveillance by increasing PD-L1 expression; hence, therapeutic PAI-1 blockade may prove valuable in treating malignant tumors.

CDKN2A/B homozygous deletion sensitizes IDH-mutant glioma to CDK4/6 inhibition.

Treatment paradigms for Isocitrate dehydrogenase (IDH) mutant gliomas are rapidly evolving. While typically indolent and responsive to initial treatment, these tumors invariably recur at higher grade and require salvage treatment. Homozygous deletion of the tumor suppressor gene CDKN2A/B frequently emerges at recurrence in these tumors, driving poor patient outcome. We investigated the effect of CDK-Rb pathway blockade on IDH-mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi). Cell viability, proliferation assays and flow cytometry were used to examine the pharmacologic effect of two distinct CDKis, palbociclib and abemaciclib, in multiple patient-derived IDH-mutant glioma lines. Isogenic models were used to directly investigate the influence of CDKN2A/B status on CDKi sensitivity. Orthotopic xenograft tumor models were used to examine efficacy and tolerability of CDKi in vivo. CDKi treatment leads to decreased cell viability and proliferative capacity in patient-derived IDH-mutant glioma lines, coupled with enrichment of cells in G1 phase. CDKN2A inactivation sensitizes IDH-mutant glioma to CDKi in both endogenous and isogenic models with engineered CDKN2A deletion. CDK4/6 inhibitor administration improves survival in orthotopically implanted IDH-mutant glioma models. IDH-mutant gliomas with deletion of CDKN2A/B are sensitized to CDK4/6 inhibitors. These results support investigation of the use of these agents in a clinical setting.

Aberrant ecotropic viral integration site-1 (EVI-1) and myocyte enhancer factor 2C gene (MEF2C) in adult acute myeloid leukemia are associated with adverse t (9:22) & 11q23 rearrangements.

Acute myeloid leukemia (AML) shows multiple chromosomal translocations & point mutations which can be used to refine risk-adapted therapy in AML patients. Ecotropic viral integration site-1 (EVI-1) & myocyte enhancer factor 2C gene (MEF2C) are key regulatory transcription factors in hematopoiesis and leukemogenesis & both drive immune escape. This prospective study involved 80 adult de novo AML patients recruited from Oncology Center, Mansoura University, between March 2019 and July 2021. The MEF2C and EVI1 expression were measured using a Taqman probe-based qPCR assay. The results revealed that EVI1 and MEF2C expression were significantly elevated in AML patients as compared to control subjects (p = 0.001. 0.007 respectively). Aberrant expressions of EVI1 and MEF2C showed a significant negative correlation with hemoglobin levels (p = 0.034, 0.025 respectively), & bone marrow blasts (p = 0.007, 0.002 respectively). 11q23 translocation was significantly associated with EVI1 and MEF2C (p = 0.004 and 0.02 respectively). Also, t (9;22) was significantly associated with EVI1 and MEF2C (p = 0.01 and 0.03 respectively), higher expression of EVI1 and MEF2C were significantly associated with inferior outcome after induction therapy (p = 0.001 and 0.018 respectively) and shorter overall survival (p = 0.001, 0.014 respectively). In conclusion, EVI1 & MEF2C were significantly expressed in AML cases. EVI1 & MEF2C overexpression were significantly associated with 11q23 rearrangements and t (9;22) and were indicators for poor outcome in adult AML patients; These results could be a step towards personalized therapy in those patients.

Risk factors and management of gastrointestinal bleeding in patients with or without antiplatelet and anticoagulation therapy: a multicenter real-world prospective study

BackgroundAntiplatelet and anticoagulation drugs complicate acute gastrointestinal bleeding (GIB) patients. Limited data about the risk factors and patient management has been presented. This study explored the association between previous antiplatelet or anticoagulant drug usage and clinical outcomes in GIB patients to improve awareness further and optimize treatment.MethodsWe conducted a multicenter, non-interventional, real-world prospective study in 106 hospitals in 23 provinces in China. GIB patients confirmed in the emergency department were included and were grouped according to previous drug histories. Univariate analysis, multivariate logistic regression, and multivariate stratification models were performed separately to investigate the associations.ResultsA total of 2299 patients (57.23 ± 17.21 years old, 68.3% male) were included, of whom 20.1% and 2.9% received antiplatelet and anticoagulation therapy, respectively. The all-cause 28-day mortality rates in patients without antiplatelet or anticoagulants, patients undergoing antiplatelet treatment, and patients with anticoagulation therapy were 2.8%, 4.6%, and 10.5%, respectively. After adjusting for confounding factors, both antiplatelet [odd ratio (OR), 2.92; 95% confidence interval (CI), 1.48–5.76; p = 0.002] and anticoagulation therapy (OR, 8.87; 95% CI, 3.02–26.02; p < 0.001) were associated with higher 28-day mortality. In the subgroup analysis, blood transfusion, especially red blood cell transfusion, in patients undergoing antiplatelet and anticoagulation therapy was associated with a decreased death risk.ConclusionWe confirmed an association between concurrent antiplatelet or anticoagulation therapy in GIB patients and elevated 28-day mortality. Blood transfusions could improve poor outcomes in such patients.

Biomarkers to improve functional outcome prediction after ischemic stroke: Results from the SICFAIL, STRAWINSKI, and PREDICT studies.

Acute ischemic stroke (AIS) outcome prognostication remains challenging despite available prognostic models. We investigated whether a biomarker panel improves the predictive performance of established prognostic scores. We investigated the improvement in discrimination, calibration, and overall performance by adding five biomarkers (procalcitonin, copeptin, cortisol, mid-regional pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)) to the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) and age/NIHSS scores using data from two prospective cohort studies (SICFAIL, PREDICT) and one clinical trial (STRAWINSKI). Poor outcome was defined as mRS > 2 at 12 (SICFAIL, derivation dataset) or 3 months (PREDICT/STRAWINSKI, pooled external validation dataset). Among 412 SICFAIL participants (median age 70 years, quartiles 59-78; 63% male; median NIHSS score 3, quartiles 1-5), 29% had a poor outcome. Area under the curve of the ASTRAL and age/NIHSS were 0.76 (95% CI 0.71-0.81) and 0.77 (95% CI 0.73-0.82), respectively. Copeptin (0.79, 95% CI 0.74-0.84), NT-proBNP (0.80, 95% CI 0.76-0.84), and MR-proANP (0.79, 95% CI 0.75-0.84) significantly improved ASTRAL score's discrimination, calibration, and overall performance. Copeptin improved age/NIHSS model's discrimination, copeptin, MR-proANP, and NT-proBNP improved its calibration and overall performance. In the validation dataset (450 patients, median age 73 years, quartiles 66-81; 54% men; median NIHSS score 8, quartiles 3-14), copeptin was independently associated with various definitions of poor outcome and also mortality. Copeptin did not increase model's discrimination but it did improve calibration and overall model performance. Copeptin, NT-proBNP, and MR-proANP improved modest but consistently the predictive performance of established prognostic scores in patients with mild AIS. Copeptin was most consistently associated with poor outcome in patients with moderate to severe AIS, although its added prognostic value was less obvious.

A high-fat diet promotes cancer progression by inducing gut microbiota–mediated leucine production and PMN-MDSC differentiation

A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.