Advanced Stage Research Articles

LINC00365 as a potential biomarker for total nephrectomy in advanced-stage renal cell carcinoma patients

BackgroundRenal cell carcinoma (RCC) is one of the most frequent urological cancers globally that has a good prognosis in the early tumor stages. However, there is a poor prognosis in metastatic RCC patients. Therefore, it is needed to evaluate the molecular biology of RCC progression to introduce the efficient diagnostic and therapeutic markers in these patients. Long non-coding RNAs (lncRNAs) have key roles in regulation of molecular mechanisms during RCC progression. In the present study, we assessed the levels of LINC00365 expressions in RCC patients to suggest that as a tumor marker in these patients. MethodsFifty fresh RCC tumor tissues and their normal margins were collected to assess the levels of LINC00365 expressions and probable correlations with clinicopathological features of RCC patients. ResultsThere was significant LINC00365 up regulation in females compared with males (p=0.050). Among the RCC patients with total nephrectomy, there was a significant LINC00365 up regulation in advanced stage compared with primary stage tumors (p=0.035). RCC patients older than 60 years old who were undergone the total nephrectomy had also significant LINC00365 up regulation compared with RCC patients younger than 60 years old (p=0.039). Conclusionsgiven the significant increase in LINC00365 expression in advanced stage RCC tumors and patients over 60 years old who had total nephrectomy; it could serve as a useful diagnostic marker in screening programs for old high-risk individuals. It was also noticed that female RCC patients had elevated levels of LINC00365 expressions in their tumor samples, suggesting its potential use as a gender-specific diagnostic marker for high-risk females. Nevertheless, evaluating the levels of LINC00365 in serum samples of RCC patients is necessary to suggest that as a reliable diagnostic marker in clinical settings.

Sphingosine 1-phosphate receptor subtype 1 (S1P1) activity in the course of Alzheimer's disease

Some specific lipid molecules in the brain act as signaling molecules, neurotransmitters, or neuromodulators, by binding to specific G protein-coupled receptors (GPCR) for neurolipids. One such receptor, sphingosine 1-phosphate receptor subtype 1 (S1P1), is coupled to Gi/o proteins and is involved in cell proliferation, growth, and neuroprotection. S1P1 constitutes an interesting target for neurodegenerative diseases like multiple sclerosis and Alzheimer's disease (AD), in which changes in the sphingolipid metabolism have been observed. This study analyzes S1P1 receptor-mediated activity in healthy brains and during AD progression using postmortem samples from controls and patients at different Braak's stages. Additionally, the distribution of S1P1 receptor activity in human brains is compared to that in commonly used rodent models, rats and mice, through functional autoradiography, measuring [35S]GTPγS binding stimulated by the S1P1 receptor selective agonist CYM-5442 to obtain the distribution of functional activity of S1P1 receptors.S1P1 receptor-mediated activity, along with that of the cannabinoid CB1 receptor, is one of the highest recorded for any GPCR in many gray matter areas of the brain, reaching maximum values in the cerebellar cortex, specific areas of the hippocampus and the basal forebrain. S1P1 signaling is crucial in areas that regulate learning, memory, motor control, and nociception, such as the basal forebrain and basal ganglia. In AD, S1P1 receptor activity is increased in the inner layers of the frontal cortex and underlying cortical white matter at early stages, but decreases in the hippocampus in advanced stages, indicating ongoing brain impairment. Importantly, we identified significant correlations between S1P1 receptor activity and Braak stages, suggesting that S1P1 receptor dysfunction is associated to disease progression, particularly in memory-related regions. The S1P signaling via S1P1 receptor is a promising neurological target due to its role in key neurophysiological functions and its potential to modify the progression of neurodegenerative diseases. Finally, rats are suggested as a preferred experimental model for studying S1P1 receptor-mediated responses in the human brain.

Characterization of small RNAs in the spleen of MASH in a non-human primate model

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced stage, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as a global health issue. This study examines the role of small RNAs in the spleen of MASH using a non-human primate model. We performed high-throughput small RNA sequencing on spleen tissues from MASH-primates, revealing significant alterations in the expression of small non-coding RNAs, especially miRNAs. Notably, miR-96, miR-182, miR-183, and miR-122 showed differential expression in MASH spleens. Predictive and validation studies have identified potential target genes, such as PTX3 and NFIX, that were significantly dysregulated in spleens of MASH. These findings characterized small RNAs in spleen of MASH and offer a novel insight for further research for MASH.

Homologous recombination deficiency score is an independent prognostic factor in esophageal squamous cell carcinoma.

Homologous recombination deficiency (HRD) represents an impairment in the homologous recombination repair (HRR) pathway, crucial for repairing DNA double-strand breaks and contributing to genomic instability in cancer. The HRD score may be a more reliable biomarker than HRR-related gene mutations for identifying patients sensitive to poly(ADP-ribose) polymerase inhibitors. Despite its relevance in various cancers, the HRD score remains underexplored in esophageal squamous cell carcinoma (ESCC). We retrospectively analyzed HRD scores in 96 ESCC patients, examining correlations with clinical characteristics and survival outcomes, and validated our findings using the TCGA dataset. Genomic sequencing utilized a custom superHRD next-generation sequencing panel, and HRD scores were calculated from 54,000 single-nucleotide polymorphisms using Kruskal-Wallis rank-sum tests and two cut-off points for analysis. Higher HRD scores correlated with advanced tumor stages, recurrence, and mutations in TP53 and ABCB1, while APC mutations were linked to lower HRD scores. Patients with high HRD scores had significantly shorter disease-free survival (p = 0.013) and a trend toward shorter overall survival (OS) (p = 0.005), particularly those not receiving adjuvant therapy. Conversely, HRD-high patients undergoing adjuvant therapy showed a trend toward longer OS (p = 0.015). Multivariate analysis identified HRD as an independent prognostic factor (hazard ratio = 2.814 for recurrence, p = 0.015). Validation with the TCGA dataset supported these findings. This study highlights the associations between HRD scores, clinical characteristics, and genomic mutations in ESCC, suggesting HRD as a potential prognostic biomarker. HRD assessment may aid in patient stratification and personalized treatment strategies, warranting further investigation to validate the therapeutic implications of HRD scores in ESCC.

Dynamic Anthropometrics in Pancreatic Cancer: Associations Between Body Composition Changes During Neoadjuvant Therapy and Survival Outcomes After Resection.

Assessment of individual tumor biology and response to systemic therapy in pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. The significance of anthropometric (body composition) changes during chemotherapy as a surrogate for tumor biology in the setting of localized PDAC is unknown. A retrospective, single-institution analysis of patients with PDAC who received neoadjuvant therapy (NAT) and pancreatectomy from 2017 to 2021 was performed. Radiologic anthropometric analysis used artificial intelligence-driven software to segment and compute total and sub-compartment muscle area, adipose tissue area, and attenuation values at the level of the L3 vertebra. Kaplan-Meier survival estimates, log-rank tests, and multivariable Cox regression models were used in survival analyses. The inclusion criteria were met by 138 patients. Although decreases in muscle and adipose tissue areas during NAT were predominant, a subset of patients experienced an increase in these compartments. Increases in muscle greater than 5% (hazard ratio [HR], 0.352; 95% confidence interval [CI] 0.135-0.918; p=0.033) and increases in adipose tissue greater than 15% (HR, 0.375; 95% CI 0.144-0.978; p=0.045), were significantly associated with improved survival, whereas loss of visceral fat greater than 15% was detrimental (HR 1.853; CI 1.099-3.124; p=0.021). No significant associations with single time-point anthropometrics were observed. Gains in total muscle and adipose mass were associated with improved pathologic response to systemic therapy and less advanced pathologic tumor stage. Dynamic anthropometric analysis during NAT for PDAC is a stronger prognostic indicator than measurements taken at a single point in time. Repeated anthropometric analysis during preoperative chemotherapy may serve as a biomarker for individual tumor biology and response to therapy.

New insights on the link between Epstein‑Barr virus infection and cognitive decline in neurodegenerative diseases (Review).

Cognitive decline is a frequent complaint in healthy controls and neurological patients, regardless of the underlying pathology. Whilst cognitive impairment can be easily diagnosed in the more advanced stages of neurodegenerative diseases, early detection can be challenging. This is mainly the consequence of the incomplete understanding of the underlying pathophysiological mechanisms. In addition, currently available neurological treatments do not specifically target cognitive decline, since other motor and non-motor symptoms, such as bradykinesia, tremor, autonomic disturbances and depression, are of greater relevance from a therapeutic perspective. In this context, prospective studies must address a number of issues, including the risk factors associated with cognitive deficits in neurodegenerative diseases. The present review aims to offer a novel perspective on the association between Epstein-Barr virus infection and cognitive decline found in patients with neurodegenerative disorders. Specifically, relevant epidemiological studies and clinical trials explaining this connection were reviewed, focusing on the most frequent neurodegenerative disorders. They are namely Alzheimer's disease, Parkinson's disease and multiple sclerosis. Despite their limitations, possible underlying pathophysiological mechanisms that explain the impact of Epstein-Barr virus infection on cognitive decline are expected to offer novel study directions on this clinically relevant topic.

Outcomes in patients with out-of-hospital cardiac arrest according to prehospital advanced airway management timing: a retrospective observational study.

In patients with out-of-hospital cardiac arrest (OHCA), guidelines recommend advanced airway (AA) management at the advanced cardiovascular life support stage; however, the ideal timing remains controversial. Therefore, we evaluated the prognosis according to the timing of AA in patients with OHCA. We conducted a retrospective observational study of patients with OHCA at six major hospitals in Daegu Metropolitan City, South Korea, from August 2019 to June 2022. We compared groups with early and late AA and evaluated prognosis, including recovery of spontaneous circulation (ROSC), survival to discharge, and neurological evaluation, according to AA timing. Of 2,087 patients with OHCA, 945 underwent early AA management and 1,142 underwent late AA management. The timing of AA management did not influence ROSC in the emergency department (5-6 minutes: adjusted odds ratio [aOR], 0.97; p=0.914; 7-9 minutes: aOR, 1.37; p=0.223; ≥10 minutes: aOR, 1.32; p=0.345). The timing of AA management also did not influence survival to discharge (5-6 minutes: aOR, 0.79; p=0.680; 7-9 minutes: aOR, 1.04; p=0.944; ≥10 minutes: aOR, 1.86; p=0.320) or good neurological outcomes (5-6 minutes: aOR, 1.72; p=0.512; 7-9 minutes: aOR, 0.48; p=0.471; ≥10 minutes: aOR, 0.96; p=0.892). AA timing in patients with OHCA was not associated with ROSC, survival to hospital discharge, or neurological outcomes.

Pulmonary metastases revealing a mixed germ cell tumor with a predominant yolk sac tumor component: A case report

Yolk sac tumor of the testis is rare in adults. Its diagnosis is histological, reproducing an extra-embryonic structure (endodermal sinus tissue). It can be present alone or associated with another component, thus forming a mixed germ cell tumor. Treatment involves orchiectomy and chemotherapy in extratesticular stages. Lymph node dissection is indicated if residual masses persist. These tumors are characterized by a poor prognosis at an advanced metastatic stage. However, we report the clinical case of a 69-year-old man who presented with pulmonary metastases from a mixed germ cell tumor of the testis with a predominant Yolk Sac Tumor component, treated by orchiectomy, chemotherapy, and lymph node dissection.

Emerging Technologies and Applications of AI Chips: Integrating Deep Learning Algorithms with Advanced Hardware Architectures

Due to the ongoing promotion of the latest technological revolution and industrial upgrading, as well as the widespread use of artificial intelligence and deep learning, the intelligent Internet of Things terminal has reached a more advanced stage of development. The combination of training data, model algorithms, and processing power is the basis for advancing artificial intelligence. The semiconductor business plays a crucial role in shaping the future of AI algorithms and the computing power industry. This study explores the progression of artificial intelligence, and essential technologies, and examines the categorization and structure of AI chips. The process of deep learning was then analyzed, demonstrating the application of AI in real life. Next, this study showcases distinct AI chip-related models, specifically designed for the automated implementation of Convolutional Neural Networks (CNNs) on Field-Programmable Gate Arrays (FPGAs). The study then proceeds to examine the unique procedure and the significance of the resulting data. The future of AI was examined in the domains of space exploration, healthcare, and autonomous driving, along with future forecasts.

Demographics and clinical outcomes of flow-gradient patterns of aortic stenosis: an analysis of the CURRENT AS Registry-2

Abstract Background Low-gradient (LG) severe aortic stenosis (AS) has not been fully characterized compared with high-gradient (HG) AS. Methods Among 3369 patients with severe AS enrolled in the CURRENT AS Registry-2, the current study population consisted of 3363 patients with data on left ventricular ejection fraction (LVEF) after excluding patients with LG AS without indexed stroke volume data. Patients were divided into 4 groups (LG AS with reduced LVEF: N=285, paradoxical low-flow low-gradient [LFLG] AS: N=220, normal-flow low-gradient [NFLG] AS: N=872, and HG AS: N=1986). Results Compared to HG AS, LG AS with reduced LVEF more often had cardiovascular comorbidities, advanced cardiac damage stages, and frailty with less extensive aortic valve (AV) calcification by computed tomography (CT), and paradoxical LFLG AS more often had atrial fibrillation, concomitant valvular disease, advanced cardiac damage stages, and frailty with less extensive AV calcification, while NFLG AS were less often symptomatic, and had comparable cardiac damage stages, and frailty with less extensive AV calcification. Patients with the 3 types of LG AS less often underwent surgical or transcatheter aortic valve replacement than those with HG AS (cumulative 3-year incidence: LG AS with reduced LVEF: 64.5%, paradoxical LFLG AS: 59.1%, NFLG AS: 54.2%, and HG AS: 87.3%, P<0.001). Cumulative 3-year incidence of death or heart failure hospitalization was much higher in patients with LG AS with reduced LVEF and paradoxical LFLG AS than in those with HG AS (cumulative 3-year incidence: LG AS with reduced LVEF: 65.9%, paradoxical LFLG: 51.1%, NFLG: 35.5%, and HG: 30.5%, P<0.001). After adjusting confounders, LG AS with reduced LVEF and paradoxical LFLG AS compared with HG AS were independently associated with higher risk for death or heart failure hospitalization (HR: 1.82, 95%CI: 1.49-2.23, P<0.001; HR 1.43, 95%CI: 1.13-1.82, P=0.003, respectively), but not NFLG AS (HR 1.03, 95%CI: 0.88-1.21, P=0.68). Conclusions Aortic stenosis might be less severe in LG AS than in HG AS when assessed by the CT calcium score of the aortic valve, and each of the 3 hemodynamic types of LG AS had distinct clinical, and echocardiographic characteristics as well as clinical outcomes that were different from HG AS.Different patterns of severe AS

Frailty and associated outcomes in patients with transthyretin cardiac amyloidosis

Abstract Introduction Despite older age at diagnosis, the prevalence and clinical impact of frailty, an age-related geriatric syndrome, in patients with transthyretin cardiac amyloidosis (ATTR-CA) is poorly described. Purpose To determine: (1) the prevalence of frailty in ATTR amyloidosis patients; (2) the clinical frailty phenotype in ATTR amyloidosis (3) the independent and incremental prognostic value of frailty. Methods All consecutive patients diagnosed with ATTR-CA who underwent frailty assessment at two high-volume tertiary care centres from September 2019 to April 2023 were included in the study. Functional assessment was performed with the Rockwood Clinical Frailty Scale (CFS), an established frailty screening tool that stratifies patients on a nine-point scale ranging from 1 (very well) to 9 (terminally ill) providing a useful measure of physiological reserve. Frailty was defined as CFS >4. Functional status was further categorized as follows: 'non-frail' (CFS 1-3), ‘mild’ frailty (CFS 4-5), and 'moderate-to-severe' frailty (CFS 6-9). Logistic regression analysis was used to identify factors associated with CFS 6-9. Cox regression analysis was used to determine the independent and incremental prognostic value of frailty. Results The study comprised 880 patients with ATTR-CA (719 [81.7%] with wt-ATTR-CA, 85 [9.7%] with p.(V142I) hATTR-CA and 76 [8.6%] with a non-p.(V142I) hATTR-CA. Overall, 43.0% (N=378) were considered ‘non-frail’ (CFS 1-3). Prevalence of ‘mild’ frailty (CFS 4-5) was 41.4% (N=364), while prevalence of 'moderate-to-severe' frailty (CFS 6-9) was 15.7% (N=138). Frail patients were older, more symptomatic and with advanced disease stage as assessed with the National Amyloidosis Centre (NAC) staging system. At logistic regression analysis, age, female gender, non-p.(V142I) variants and NAC stage were associated with 'moderate-to-severe' frailty. Over a median 22 months, 16.8% died, with mortality rising with higher CFS levels. At Cox multivariable analysis, CFS was strongly associated with mortality (CFS 4-5 vs 1-3: Hazard Ratio [HR] 2.821, 95% C.I. 1.724-4.613; CFS 6-9 vs 1-3: HR 6.179, 95% C.I. 3.694-10.335, overall p-value<0.001), along with NAC stage and age. The addition of CFS to the NAC staging system significantly improved the goodness-of-fit of the model (X2: 73.26, p<0.00001), and significantly improved the discriminatory ability of the NAC alone (Figure, Harrell’s C statistics: 0.78, 95% C.I. [0.72-0.83] vs 0.69, 95% C.I. [0.64-0.75], p<0.0001). CONCLUSION Frailty is highly prevalent in patients with ATTR-CA, with up to 57% of patients living with some degree of frailty. Older age, female gender, non-p.(V142I) hATTR-CA variants and advanced disease stage were independently associated with moderate to severe frailty. Frailty was independently associated with all-cause mortality after adjusting for known predictors and increased the global predictivity of the NAC Score.Survival by Frailty Status and NAC

The association between the mental health disorders, substance abuse, and tobacco use with head & neck cancer stage at diagnosis.

Mental health disorders, substance abuse, and tobacco use are prevalent in the US population. However, the association between these conditions and head and neck cancer (HNC) stage is poorly understood. This research aims to uncover the relationship between pre-existing mental health disorders, substance abuse, and tobacco use and HNC stage at diagnosis in patients receiving care in an integrated, public safety-net healthcare system. This study was a secondary data analysis of linked hospital tumor registries and electronic health record (EHR) data. The study's primary independent variables were the comorbidities of mental health disorders, substance abuse, and tobacco use. The dependent variable was HNC stage at diagnosis, operationalized as early stage (i.e., stages I, II, and III) and advanced stage (stage IV, IVA, IVB, or IVC). The analysis included multivariable logistic regression adjusted for covariates of demographic variables, tumor anato RESULTS: The study population consisted of 357 patients with median age of 59years, and was primarily male (77%), diverse (Black or African American 41%; Hispanic 22%), and from neighborhoods with low income (median average annual household income $39,785). Patients with a history of mental health disorders with or without tobacco use had significantly lower odds of advanced stage HNC at diagnosis (adjusted OR = 0.35, 95% Confidence Interval [CI]: 0.17-0.72.) while patients with a history of substance abuse with or without tobacco use had significantly higher odds of advanced stage HNC at diagnosis (adjusted OR 1.41, 95% CI: 1.01-1.98) than patients with no history of mental health disorders, substance abuse, or tobacco use. The relationship between HNC stage at diagnosis and the comorbidities of mental health disorders, substance abuse, or tobacco differs depending on the type and co-occurrence of these comorbidities. These findings demonstrate the need for innovative care delivery models and education initiatives tailored to meet the needs of patients with mental health disorders, substance abuse, and tobacco use that facilitate early detection of HNC.

WOMEN’S CAREER DEVELOPMENT IN STEM AND THE ROLE OF SELF-CONCEPTS: A LITERATURE REVIEW

The purpose of this article is to carry out a systematic, integrative literature review to identify how self-concepts impact women’s career development in predominantly male professions (STEM – Science, Technology, Engineering and Mathematics), considering the stages of career choice, permanence, and advancement. The review examined 282 studies. It investigated the main characteristics of the selected studies based on the categories of analysis. Most research on women’s career development and self-concepts focuses on the stage of career choice and few studies address the permanence and advancement stages. Specific contributions to STEM contexts are even scarcer in all stages. The most discussed self-concepts are self-efficacy and self-esteem, with little to no research considering the locus of control and self-confidence. By identifying the most relevant theoretical contributions in the field, the review is useful for researchers and career advisors who seek to understand the impact of self-concepts on women’s career development in predominantly male professions and to better support their practices. Recommendations for further research are provided.

COADREADx: A comprehensive algorithmic dissection of colorectal cancer unravels salient biomarkers and actionable insights into its discrete progression

Background Colorectal cancer is a common condition with an uncommon burden of disease, heterogeneity in manifestation, and no definitive treatment in the advanced stages. Renewed efforts to unravel the genetic drivers of colorectal cancer progression are paramount. Early-stage detection contributes to the success of cancer therapy and increases the likelihood of a favorable prognosis. Here, we have executed a comprehensive computational workflow aimed at uncovering the discrete stagewise genomic drivers of colorectal cancer progression. Methods Using the TCGA COADREAD expression data and clinical metadata, we constructed stage-specific linear models as well as contrast models to identify stage-salient differentially expressed genes. Stage-salient differentially expressed genes with a significant monotone trend of expression across the stages were identified as progression-significant biomarkers. The stage-salient genes were benchmarked using normals-augmented dataset, and cross-referenced with existing knowledge. The candidate biomarkers were used to construct the feature space for learning an optimal model for the digital screening of early-stage colorectal cancers. The candidate biomarkers were also examined for constructing a prognostic model based on survival analysis. Results Among the biomarkers identified are: CRLF1, CALB2, STAC2, UCHL1, KCNG1 (stage-I salient), KLHL34, LPHN3, GREM2, ADCY5, PLAC2, DMRT3 (stage-II salient), PIGR, HABP2, SLC26A9 (stage-III salient), GABRD, DKK1, DLX3, CST6, HOTAIR (stage-IV salient), and CDH3, KRT80, AADACL2, OTOP2, FAM135B, HSP90AB1 (top linear model genes). In particular the study yielded 31 genes that are progression-significant such as ESM1, DKK1, SPDYC, IGFBP1, BIRC7, NKD1, CXCL13, VGLL1, PLAC1, SPERT, UPK2, and interestingly three members of the LY6G6 family. Significant monotonic linear model genes included HIGD1A, ACADS, PEX26, and SPIB. A feature space of just seven biomarkers, namely ESM1, DHRS7C, OTOP3, AADACL2, LPHN3, GABRD, and LPAR1, was sufficient to optimize a RandomForest model that achieved > 98% balanced accuracy (and performant recall) of cancer vs. normal on external validation. Design of an optimal multivariate model based on survival analysis yielded a prognostic panel of three stage-IV salient genes, namely HOTAIR, GABRD, and DKK1. Based on the above sparse signatures, we have developed COADREADx, a web-server for potentially assisting colorectal cancer screening and patient risk stratification. COADREADx provides uncertainty measures for its predictions and needs clinical validation. It has been deployed for experimental non-commercial use at: https://apalanialab.shinyapps.io/coadreadx/.

Gender-related differences in the timing of intervention for aortic stenosis: focus on cardiac damage

Abstract Background and aim: There is an increasing awareness of gender-related differences in the management of cardiovascular diseases. Our aim was to assess whether cardiac damage prior to intervention for severe aortic stenosis (AS) differs according to gender. Methods Retrospective analysis of a prospective cohort of patients with AS who underwent surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) in a tertiary care center from 2017 to 2022. Echocardiographic parameters prior to surgery were collected, and patients were classified into categories of a cardiac damage staging system. (1) Several echocardiographic variables according to gender were evaluated. Results 869 patients were included, of which 350 underwent TAVR and 519 were treated with SAVR. Females represented 52.4% (n=272) of TAVR patients and 37.7% (n=132) of SAVR patients. In the echocardiogram performed before the intervention, both in the TAVR and the SAVR cohort, female patients had worse diastolic function (significantly higher values of E/e’), and greater involvement of pulmonary vasculature damage (significantly higher pulmonary artery systolic pressure and worse right ventricular-arterial coupling (Table-Figure 1). When applying an available cardiac damage staging system (1), we documented that women were treated at a statistically significant more advanced stage compared to men (Figure 2). Conclusions There are gender-related differences in the timing of aortic stenosis intervention, both with TAVR and SAVR. Women are operated on at a more advanced stage of cardiac damage, particularly regarding the parameters of diastolic function and right-side damage. These findings should be taken into account to improve intervention timing and outcomes, especially for women.Table-Figure 1Figure 2

Stress memory of heart failure in hematopoietic niche promotes recurrence via adipocytic skewing of mesenchymal stromal cells

Abstract Background Heart failure (HF) is marked by recurrent acute decompensations, which poses significant treatment challenges in advanced stages. Our preceding work demonstrated that hematopoietic stem cells (HSCs) from HF-experienced mice induce cardiac fibrosis and dysfunction when transplanted, as a result of epigenetic alterations favoring myeloid hematopoiesis and impeding the differentiation of monocytes into cardiac mature macrophages. These findings hint at epigenetic modifications in HSCs as potential drivers of HF recurrence, suggesting their manipulation as a novel therapeutic strategy. However, the exact mechanisms by which HF-associated stress leads to these epigenetic changes remain unclear. Given the crucial role of bone marrow mesenchymal stromal cells (MSCs) in maintaining HSC stemness, this study explores the impact of cardiac stress on MSC function and its subsequent effect on HSCs. Purpose This study aims to elucidate the mechanisms behind the phenotypic changes in HSCs and to identify novel therapeutic targets to mitigate HF recurrence by investigating the role of MSCs in the hematopoietic niche under cardiac stress. Methods & Results Initially, we examined MSC phenotypic changes during HF using bulk and single-cell RNA sequencing. Results from transverse aortic constriction (TAC) model mice revealed a shift towards adipocyte differentiation under cardiac stress. Histological analyses confirmed an increase in adipocytes in TAC mice compared to controls, suggesting a stress-induced predisposition of MSCs towards adipocytic lineage commitment. This trend was further supported by ex vivo models using MSCs isolated from TAC mice. Notably, the proportion of adipocyte lineage-specific MSCs correlated with cardiac dysfunction severity. Subsequently, we assessed the impact of HF-conditioned MSCs on HF development by transplanting healthy HSCs with MSCs from control or TAC mice. Mice receiving HF-conditioned MSCs developed HF, evidenced by reduced ejection fraction and cardiac fibrosis. In these mice, a notable increase in HSC proliferation and a relative increase of myeloid cells within the peripheral blood were observed, along with an increase in proinflammatory cardiac macrophages. These findings suggest HF induces a "stress memory" in bone marrow MSCs. To test the potential of inhibiting adipocyte differentiation of MSCs in erasing this stress memory, we administered MSC phenotype-modulating agents to TAC mice, resulting in improved cardiac function and the disappearance of adipocytes from the bone marrow. Conclusions This study sheds light on how cardiac stress affects the bone marrow niche, leading to adipocytic skewing of MSCs and subsequent alterations in HSCs, thereby exacerbating cardiac dysfunction. The potential of targeting bone marrow niche components in HF treatment is highlighted.

Delays in diagnosis and treatment initiation of ATTR cardiac amyloidosis: a real-world data analysis

Abstract Introduction Cardiac amyloidosis (CA) is a serious condition characterized by the accumulation of abnormal protein deposits in the heart muscle, leading to functional impairments and, ultimately, heart failure. Transthyretin amyloid cardiomyopathy (ATTR-CM) is the most common form encountered in CA diagnosis with previously underestimated prevalence. ATTR-CM poses a diagnostic challenge, with a substantial number of cases diagnosed late and at advanced stages. The availability of specific pharmacological treatment using the transthyretin-stabilizer tafamidis further emphasizes the need for timely diagnosis. Here, we aim to assess delays in diagnosis and initiation of therapy in a real-world collective of patients with ATTR-CM. Methods All individuals diagnosed from 01/2018 to 05/2023 with ATTR-CM at our university hospital, Germany, were systematically assessed for eligibility in this study. Specifically, we enrolled patients who were undergoing transthyretin stabilizer therapy. The investigation aimed to determine the duration, in days, from the initial suspicion of heart disease to the definitive diagnosis of ATTR-CM. It was also investigated whether the diagnosis of ATTR-CM was made more quickly over time as awareness increased. Additionally, the study assessed the time elapsed until patients received pharmacological therapy following the confirmed diagnosis. The study was approved by the local ethics committee (23-11500-BO). Results After screening of 194 consecutive patients, 154 were included in the analysis, while 40 patients were excluded due to insufficient records. The results of this study reveal that a median of 300 (113-962) days elapsed from the initial suspicion of amyloidosis to the final confirmation. Initial indications of CA often presented as nonspecific symptoms such as unclear dyspnea (16.2% n=25), abnormal echocardiography (75.3% n=116), or, in rare cases, incidental findings (8.4% n=13). Following the diagnosis, an additional median of 84 (46-163.5) days passed before the first prescription of a transthyretin stabilizer. To assess an improvement of ATTR-CM diagnosis over time, we stratified the data into tertiles by date of first diagnosis. The results showed a gradually decrease in medium time to diagnosis of 466 (181-1035) days in the earliest tertile (2018-2019) to 389 (141-1508) days in the most recent tertile (2022-2023) (p<0.001). Conclusion This study shows a major healthcare deficit and underscores the medical need for improved screening procedures and diagnostic modalities to expedite the timely diagnosis of CA, as early identification of the condition is crucial for enhancing the quality of life for patients and preventing life-threatening complications.

Upper tract urothelial carcinoma: epidemiology, presentation, and high-risk endemic populations.

Upper tract urothelial carcinoma (UTUC) only accounts for 5-10% of all urothelial cancers but these patients present with high stage disease and 2 out of 3 patients have evidence of muscle-invasion at time of diagnosis. Furthermore, 10% of UTUC patients have associated Lynch syndrome and therefore diagnosis of UTUC should prompt timely evaluation and familial counseling. The purpose of this review is to outline the current evidence on the epidemiology, presentation, and high-risk endemic populations of UTUC through review of contemporary publications occurring over the preceding 18 months. Both the American Urological Association (AUA) and European Association of Urology (EAU) have published updated guidelines within the last 18 months for the management of UTUC. Of note, the updated guidelines give special consideration to identifying patients with risk factors for Lynch syndrome and recommend universal histologic testing for those with high probability of having Lynch syndrome cancers as well as referral for genetic counseling and germline testing. UTUC is an overall rare malignancy but tends to present with advanced stage and muscle-invasion. A proper understanding of the epidemiology, presentation, and high-risk endemic populations is necessary to develop preventive and interventional strategies.

Immune therapeutic strategies for the senescent tumor microenvironment.

Senescent cells can either to promote immunosuppressive tumor microenvironment or facilitate immune surveillance. Despite the revolutionary impact of cancer immunotherapy, durable responses in solid tumors, particularly in advanced stages, remain limited. Recent studies have shed light on the influence of senescent status within the tumor microenvironment (TME) on therapy resistance and major efforts are needed to overcome these challenges. This review summarizes recent advancements in targeting cellular senescence, with a particular focus on immunomodulatory approaches on the hallmarks of cellular senescence.

Lung cancer screening: Real screening site data, Vojvodina, Serbia

Abstract Background Lung cancer (LC) is the top cause of cancer-related deaths globally and in Serbia, often diagnosed in advanced stage of disease with when 5-year survival is 10% to 20%. LC screening with low-dose CT (LDCT) can decrease LC mortality and overall mortality. The first pilot LC screening program in Serbia started in the Institute for Pulmonary Diseases of Vojvodina in September 2020. The main objective of this study was to analyze LC patient characteristics according to their screening status. Methods This retrospective study utilized LC hospital registry data from September 2020 to December 2023, including gender, age at diagnosis, settlement area, smoking habits, cancer histological type, TNM classification, disease stage (1-4), and data on participation in LC screening. Group differences were assessed using chi-square and Student’s t-tests, with analyses conducted in SPSS v24.0. Results During observed period from a total of 4649 LC cases 2948 (63.4%) were males, and 73 (1.6%) were included in LC screening. Average age of all LC patients was 66 years, without differences between groups (p = 0.778). Significant differences between groups by gender were find (p = 0.042). Non-screened LC patients were significantly common males compared to females (63.6% vs 36.4%), while among screened difference by gender were lower (52.1% vs 47.9%, respectively). Screened compared to non-screened LC patients have significantly lower percentage of SCLC (9.6% vs 19.1%), and higher percentage of NSCLC (90.4% vs 80.9%), (p = 0.040). According to LC stage, screened compared to non-screened patients were significantly common diagnosed in stage I of disease (45.8% vs 7.8%), and significantly less common in higher LC stages; stage IIIB (11.1% vs 22.5%), and in stage IV (22.2% vs 45.7%), (p < 0.001). Conclusions LC screening with LDCT is proven secondary preventive measure with significant influence on decreasing LC mortality by increasing number of LC patients in early stages of disease. Key messages • Lung cancer screening with low-dose CT significantly increases early-stage diagnoses, improving survival chances. • Population strategies to prevent smoking and screening programs for high-risk groups are needed to reduce lung cancer incidence and mortality rates in Serbia.