Prognostic Marker Research Articles

Association between red blood cell distribution width and 30-day mortality in critically ill septic patients: a propensity score-matched study

BackgroundSepsis is the leading cause of death worldwide, and a number of biomarkers have been developed for early mortality risk stratification. Red blood cell distribution width (RDW) is a routinely available hematological data and has been found to be associated with mortality in a number of diseases; therefore, we aim to address the association between RDW and mortality in critically ill patients with sepsis.MethodsWe analyzed data of critically ill adult patients with sepsis on the TriNetX platform, excluding those with hematologic malignancies, thalassemia, and iron deficiency anemia. Propensity score-matching (PSM) (1:1) was used to mitigate confounding effects, and hazard ratio (HR) with 95% confidence (CI) was calculated to determine the association between RDW and 30-day mortality. We further conducted sensitivity analyses through using distinct cut-points of RDW and severities of sepsis.ResultsA total of 256,387 critically ill septic patients were included in the analysis, and 40.0% of them had RDW equal to or higher than 16%. After PSM, we found that high RDW was associated with an increased 30-day mortality rate (HR: 1.887, 95% CI 1.847–1.928). The associations were consistent using distinct cut-points of RDW, with the strength of association using cut-points of 12%, 14%, 16%, 18% and 20% were 2.098, 2.204, 1.887, 1.809 and 1.932, respectively. Furthermore, we found consistent associations among critically ill septic patients with distinct severities, with the association among those with shock, receiving mechanical ventilation, bacteremia and requirement of hemodialysis being 1.731, 1.735, 2.380 and 1.979, respectively.ConclusionWe found that RDW was associated with 30-day mortality in critically ill septic patients, underscoring the potential as a prognostic marker in sepsis. More studies are needed to explore the underlying mechanisms.

The utility of ultrafast MRI and conventional DCE-MRI for predicting histologic aggressiveness in patients with breast cancer.

Prediction of histologic prognostic markers is important for determining management strategy and predicting prognosis. To identify important features of ultrafast and conventional dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) that can predict histopathologic prognostic markers in patients with breast cancer. Preoperative MRI scans of 158 consecutive women (mean age = 54.0 years; age range = 29-86 years) with 163 breast cancers between February 2021 and August 2022 were retrospectively reviewed. Inter-observer agreements for ultrafast MRI parameters were analyzed by two radiologists. The qualitative and quantitative MRI parameters were correlated with histopathologic prognostic markers including molecular subtypes and histologic invasiveness. Inter-observer agreements for ultrafast MRI parameters were excellent (intraclass correlation coefficients of area under the kinetic curve [AUC], maximum slope [MS], maximum enhancement [ME], and slope = 0.987, 0.844, 0.822, and 0.760, respectively). Triple-negative breast cancers (TNBC) were significantly associated with rim enhancement (odds ratio [OR] = 9.4, P = 0.003) and peritumoral edema (OR = 17.9, P = 0.002), compared to luminal cancers. Invasive cancers were associated with lesion type-mass, increased delayed washout, angiovolume, ME, slope, MS, and AUC, compared to in situ cancers. In regression analysis, the combination of MS (>46.2%/s) (OR = 5.7, P = 0.046) and delayed washout (>17.5%) (OR = 17.6, P = 0.01), and that of AUC (>27,410.3) (OR = 9.6, P = 0.04), delayed washout (>17.5%) (OR = 8.9, P = 0.009), and lesion-type mass (OR = 4.6, P = 0.04) were predictive of histologic invasiveness. Conventional DCE-MRI with ultrafast imaging can provide useful information for predicting histologic underestimation and aggressive molecular subtype. MS and AUC on ultrafast MRI can be potential imaging markers for predicting histologic upgrade from DCIS to invasive cancer with high reliability.

LncRNA-WAL Promotes Triple-Negative Breast Cancer Aggression by Inducing β-Catenin Nuclear Translocation

Abstract Because of its insensitivity to existing radiotherapy, namely, chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/β-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated Wnt/β-catenin pathway of TNBC tissues, lnc-WAL (Wnt/β-catenin-associated lncRNA; WAL) was selected as the top upregulated lncRNA in Wnt/β-catenin pathway activation compared with the inactivation group. RNA immunoprecipitation sequencing was used to compare the β-catenin and IgG groups, in which lnc-WAL could interact with β-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted epithelial–mesenchymal transition, the proliferation, migration, and invasion of breast cancer stem cells and TNBC cells. Mechanistically, lnc-WAL inhibited β-catenin protein degradation via AXIN-mediated phosphorylation at serine 45. Subsequently, β-catenin accumulated in the nucleus and activated the target genes. Importantly, Wnt/β-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/AXIN/β-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC. Implications: The positive feedback between lnc-WAL and the Wnt/β-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for patients with TNBC.

Cardiac Hypertrophy in Pregnant Rats, Descendants of Fructose-Fed Mothers, an Effect That Worsens with Fructose Supplementation

The role of fructose consumption in the development of obesity, MetS, and CVD epidemic has been widely documented. Notably, among other effects, fructose consumption has been demonstrated to induce cardiac hypertrophy. Moreover, fructose intake during pregnancy can cause hypertrophy of the maternal heart. Our previous research has demonstrated that maternal fructose intake has detrimental effects on fetuses, which persist into adulthood and are exacerbated upon re-exposure to fructose. Additionally, we found that maternal fructose consumption produces changes in female progeny that alter their own pregnancy. Despite these findings, fructose intake during pregnancy is not currently discouraged. Given that cardiac hypertrophy is a prognostic marker for heart disease and heart failure, this study aimed to determine whether metabolic changes occurring during pregnancy in the female progeny of fructose-fed mothers could provoke a hypertrophic heart. To test this hypothesis, pregnant rats from fructose-fed mothers, with (FF) and without (FC) fructose supplementation, were studied and compared to pregnant control rats (CC). Maternal hearts were analyzed. Although both FF and FC mothers exhibited heart hypertrophy compared to CC rats, cardiac DNA content was more diminished in the hearts of FF dams than in those of FC rats, suggesting a lower number of heart cells. Accordingly, changes associated with cardiac hypertrophy, such as HIF1α activation and hyperosmolality, were observed in both the FC and FF dams. However, FF dams also exhibited higher oxidative stress, lower autophagy, and decreased glutamine protection against hypertrophy than CC dams. In conclusion, maternal fructose intake induces changes in female progeny that alter their own pregnancy, leading to cardiac hypertrophy, which is further exacerbated by subsequent fructose intake.

Extrachromosomal circular DNAs in prostate adenocarcinoma: global characterizations and a novel prediction model

BackgroundThe role of focal amplifications and extrachromosomal circular DNA (eccDNA) is still uncertain in prostate adenocarcinoma (PRAD). Here, we first mapped the global characterizations of eccDNA and then investigate the characterization of eccDNA-amplified key differentially expressed encoded genes (eKDEGs) in the progression, immune response and immunotherapy of PRAD.MethodsCircular_seq was used in conjunction with the TCGA-PRAD transcriptome dataset to sequence, annotate, and filter for eccDNA-amplified differentially expressed coding genes (eDEGs) in PRAD and para-cancerous normal prostate tissues. Afterwards, risk models were created and eKDEGs linked to the PRAD prognosis were identified using Cox and Lasso regression analysis. The immune microenvironment of the risk model was quantified using a variety of immunological algorithms, which also identified its characteristics with regard to immunotherapy, immune response, and immune infiltration.ResultsIn this research, there was no significant difference in the size, type, and chromosomal distribution of eccDNA in PRAD and para-cancerous normal prostate tissues. However, 4,290 differentially expressed eccDNAs were identified and 1,981 coding genes were amplified. Following that, 499 eDEGs were tested in conjunction with the transcriptome dataset from TCGA-PRAD. By using Cox and Lasso regression techniques, ZNF330 and PITPNM3 were identified as eKDEGs of PRAD, and a new PRAD risk model was conducted based on this. Survival analysis showed that the high-risk group of this model was associated with poor prognosis and validated in external data. Immune infiltration analysis showed that the model risks affected immune cell infiltration in PRAD, not only mediating changes in immune cell function, but also correlating with immunophenotyping. Furthermore, the high-risk group was negatively associated with anti-CTLA-4/anti-PD-1 response and mutational burden. In addition, Tumor Immune Dysfunction and Exclusion analyses showed that high-risk group was more prone to immune escape. Drug sensitivity analyses identified 10 drugs, which were instructive for PRAD treatment.ConclusionZNF330 and PITPNM are the eKDEGs for PRAD, which can be used as potential new prognostic markers. The two-factor combined risk model can effectively assess the survival and prognosis of PRAD patients, but also can predict the different responses of immunotherapy to PRAD patients, which may provide new ideas for PRAD immunotherapy.

A retrospective analysis suggests PTEN expression is associated with favorable clinicopathological features of breast cancer

The phosphatase and tensin homolog (PTEN) gene acts as a tumor suppressor by regulating the PI3K/AKT pathway, crucial for cell growth and survival. Mutations or loss of PTEN are common in breast cancer, leading to uncontrolled cell growth. Understanding PTEN’s role is vital for targeted therapies. 276 formalin-fixed paraffin-embedded (FFPE) breast cancer tissue blocks from 2012 to 2016 were analyzed for PTEN expression. Immunohistochemistry was performed to identify and assess tumor related clinicopathological characteristics as well as patient demographics. These were statistically matched with PTEN expression. Only 27.5% of the breast cancer tumors were PTEN-positive. PTEN expression correlated significantly with smaller tumor size, lower tumor grade, positive estrogen and progesterone receptor status, and favorable/unfavorable Ki67 status (p < 0.001). No significant association was found with vascular invasion, histologic type, age, HER2 status, staging, or lymph node involvement (p > 0.05). The study confirms PTEN's association with favorable clinicopathological features in breast cancer, supporting its role as a prognostic marker. These findings underscore the importance of PTEN in breast cancer biology and its potential as a therapeutic target. Furthermore these findings confirm the prevalence of advanced stage and aggressive breast cancer tumors in Ghana.

Identification of telomere-related lncRNAs and immunological analysis in ovarian cancer

BackgroundOvarian cancer (OC) is a global malignancy characterized by metastatic invasiveness and recurrence. Long non-coding RNAs (lncRNAs) and Telomeres are closely connected with several cancers, but their potential as practical prognostic markers in OC is less well-defined.MethodsRelevant mRNA and clinical data for OC were sourced from The Cancer Genome Atlas (TCGA) database. The telomere-related lncRNAs (TRLs) prognostic model was established by univariate/LASSO/multivariate regression analyses. The effectiveness of the TRLs model was evaluated and measured via the nomogram. Additionally, immune infiltration, tumor mutational load (TMB), and drug sensitivity were evaluated. We validated the expression levels of prognostic genes. Subsequently, PTPRD-AS1 knockdown was utilized to perform the CCK8 assay, colony formation assay, transwell assay, and wound healing assay of CAOV3 cells.ResultsA six-TRLs prognostic model (PTPRD-AS1, SPAG5-AS1, CHRM3-AS2, AC074286.1, FAM27E3, and AC018647.3) was established, which can effectively predict patient survival rates and was successfully validated using external datasets. According to the nomogram, the model could effectively predict prognosis. Furthermore, we detected the levels of regulatory T cells and M2 macrophages were comparatively higher in the high-risk TRLs group, but the levels of activated CD8 T cells and monocytes were the opposite. Finally, the low-risk group was more sensitive to anti-cancer drugs. The mRNA levels of PTPRD-AS1, SPAG5-AS1, FAM27E3, and AC018647.3 were significantly over-expressed in OC cell lines (SKOV3, A2780, CAOV3) in comparison to normal IOSE-80 cells. AC074286.1 were over-expressed in A2780 and CAOV3 cells and CHRM3-AS2 only in A2780 cells. PTPRD-AS1 knockdown decreased the proliferation, cloning, and migration of CAOV3 cells.ConclusionOur study identified potential biomarkers for the six-TRLs model related to the prognosis of OC.

T lymphocyte proportion in Alzheimer's disease prognosis.

Bai et al investigate the predictive value of T lymphocyte proportion in Alzheimer's disease (AD) prognosis. Through a retrospective study involving 62 AD patients, they found that a decrease in T lymphocyte proportion correlated with a poorer prognosis, as indicated by higher modified Rankin scale scores. While the study highlights the potential of T lymphocyte proportion as a prognostic marker, it suggests the need for larger, multicenter studies to enhance generalizability and validity. Additionally, future research could use cognitive exams when evaluating prognosis and delve into immune mechanisms underlying AD progression. Despite limitations inherent in retrospective designs, Bai et al's work contributes to understanding the immune system's role in AD prognosis, paving the way for further exploration in this under-researched area.

Trem2-expressing multinucleated giant macrophages are a biomarker of good prognosis in head and neck squamous cell carcinoma.

Patients with head and neck squamous cell carcinomas (HNSCC) often have poor outcomes due to suboptimal risk-management and treatment strategies; yet integrating novel prognostic biomarkers into clinical practice is challenging. Here, we report the presence of multinucleated giant cells (MGC) - a type of macrophages - in tumors from patients with HNSCC, which are associated with a favorable prognosis in treatment-naive and preoperative-chemotherapy-treated patients. Importantly, MGC density increased in tumors following preoperative therapy, suggesting a role of these cells in the anti-tumoral response. To enable clinical translation of MGC density as a prognostic marker, we developed a deep-learning model to automate its quantification on routinely stained pathological whole slide images. Finally, we used spatial transcriptomic and proteomic approaches to describe the MGC-related tumor microenvironment and observed an increase in central memory CD4 T cells. We defined an MGC-specific signature resembling to TREM2-expressing mononuclear tumor associated macrophages, which co-localized in keratin tumor niches.

Investigating the Role of Differentially Expressed Genes and Sex-Specific Genes in Lung Adenocarcinoma: A Transcriptomic Analysis

Lung cancer is a life-threatening disease that affects hundreds of thousands of patients every year. While conventional medicine offers effective treatments for lung cancer, the use of targeted therapy can offer patients a more favorable treatment by being as effective and by minimizing the side effects the patient experiences. The purpose of this research is to identify any differentially expressed or sex-specific genes in lung adenocarcinoma (LUAD) that can act as potential targets for treatment. Using transcriptomic profiles of LUAD tissues from The Cancer Genome Atlas, these profiles are analyzed using the TCGABiolinks library on R. The differentially expressed genes are then used to generate gene ontology, create protein association networks, and identify survival plots of genes using Metascape, STRING, and the Human Protein Atlas respectively. Similar procedures were used for the sex-specific analysis. The gene ontology analysis showed that the TFAP2 family of transcription factors and the PID HNF3B pathway likely promote tumorigenesis in LUAD. Moreover, AGER and SFTPC, genes involved in lung development, were underexpressed in all LUAD samples. Patients with a higher expression of these genes had a higher survival rate than others and can act as potential prognostic markers. In sex-specific genes, it was found that members of the MAGE-A family, a testis antigen family, were highly up-regulated in both males and females. The dysregulation of these genes in females might have a specific role in LUAD progression. These findings can be investigated further to develop better therapies to treat the disease.

Neutrophil-to-lymphocyte ratio at the end of treatment with CDK4/6 inhibitors is an independent prognostic factor for ER-positive HER2-negative advanced breast cancer.

The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR), at the end of treatment (EOT) with CDK4/6 inhibitors abemaciclib and palbociclib in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer. We included 67 patients treated with fulvestrant plus abemaciclib or palbociclib. Overall survival (OS) since the EOT with CDK/4/6 inhibitors was compared in relation to the levels of ALC and NLR. The cut-off values of ALC and NLR were set at 1000/μL and 3, respectively. Patients with a high ALC at EOT showed significantly longer OS than those with a low ALC (p = 0.0358). Moreover, patients with a low NLR at EOT showed significantly longer OS than those with a high NLR at EOT (p = 0.0044). Looking at the changes of ALC and NLR between baseline and the EOT, patients with a high ALC both at baseline and at the EOT showed significantly longer OS than others (p = 0.0201). Similarly, patients with a low NLR both at baseline and at the EOT showed significantly longer OS after EOT than others (p = 0.0136). Multivariable analysis revealed that the NLR at EOT (low vs. high) and changes in NLR (low at baseline to low at EOT vs. others) were significant and independent prognostic factors for OS after EOT (p = 0.0337, p = 0.0039, respectively). NLR at EOT with CDK4/6 inhibitors is a significant and independent prognostic marker for patients with ER-positive HER2-negative advanced breast cancer.

Clinico-pathological association of BCL2 in invasive breast carcinoma: A study from tertiary care health centre in Northern India.

B-cell lymphoma 2 (Bcl-2) is an antiapoptotic protein and an important clinical breast cancer prognostic marker. The aim of this study was to evaluate the relationship between the BCL2 expression and clinico-pathological parameters in breast cancer. Present study is observational cross-sectional study of 100 biopsy proven cases of breast cancer, and cases with resection specimens were included. IHC analyses for ER, PR, Her2neu, Ki67 and Bcl2 were performed in each case. Bcl2 expression was seen in 52% cases. BCL2-positive expression was associated with lower histological grade (0.026), low Ki-67 level (<14%, P < 0.001), hormone receptor positivity (P < 0.001) and luminal breast cancer (P < 0.001) but no association with tumour size, lymphovascular invasion, perineural invasion and TNM stage. Expression of Bcl-2, an antiapoptotic protein, is associated with low-grade, slowly proliferating, luminal A-type BC. IHC analysis of Bcl-2 is simple, inexpensive, readily available test to stratify early-stage hormone-positive patients who can be included in clinical trials for Bcl-2 inhibitors.

Single-cell profiling uncovers proliferative cells as key determinants of survival outcomes in lower-grade glioma patients

Lower-grade gliomas (LGGs), despite their generally indolent clinical course, are characterized by invasive growth patterns and genetic heterogeneity, which can lead to malignant transformation, underscoring the need for improved prognostic markers and therapeutic strategies. This study utilized single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq to identify a novel cell type, referred to as "Prol," characterized by increased proliferation and linked to a poor prognosis in patients with LGG, particularly under the context of immunotherapy interventions. A signature, termed the Prol signature, was constructed based on marker genes specific to the Prol cell type, utilizing an artificial intelligence (AI) network that integrates traditional regression, machine learning, and deep learning algorithms. This signature demonstrated enhanced predictive accuracy for LGG prognosis compared to existing models and showed pan-cancer prognostic potential. The mRNA expression of the key gene PTTG1 from the Prol signature was further validated through quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our findings not only provide novel insights into the molecular and cellular mechanisms of LGG but also offer a promising avenue for the development of targeted biomarkers and therapeutic interventions.

Fructose 1,6-bisphosphate aldolase: A promising prognostic marker for oral cancer and its role in radiotherapy response

Oral cancer remains a significant global health concern and its early detection plays a crucial role in improving patient outcomes. Identifying reliable prognostic markers is essential to guide treatment decisions and enhance survival rates. Fructose 1,6-bisphosphate aldolase (FBA), a glycolytic enzyme, has emerged as a promising candidate for prognostic assessment of oral cancer. This review highlights the role of FBA in tumorigenesis, its potential utility in predicting disease progression and patient survival, and its influence on response to radiotherapy. Recent studies have suggested that dysregulated metabolic pathways involving FBA may contribute to radiation resistance in oral cancer, emphasizing the need for further exploration of FBA-targeted therapeutic strategies. Understanding the role of FBA in oral cancer pathogenesis could pave the way for the development of personalized treatment strategies, including combined radiotherapy.

The HALP score as a prognostic factor in metastatic biliary cancer.

Biliary tract cancers are serious diseases and new biomarkers may be useful for the optimal management and prediction of these cases. This study aimed to evaluate the prognostic significance of the hemoglobin, albumin, lymphocyte, and platelet (HALP) score, a novel composite marker, in patients with metastatic biliary tract cancer. Patients with biliary tract cancers were analyzed retrospectively. Laboratory values, patient and disease characteristics, and survival rates were evaluated. The diagnostic impact of the HALP score was assessed with regression analyses. The study included 106 individuals with metastatic biliary tract cancer. Based on the median HALP score, ≥ 2.22 was considered a high score and < 2.22 was considered low. The overall average survival time was found to be 11.4months. Patients with low HALP scores had median overall survival of 9.5months, while those with high HALP scores had median overall survival of 15.9months. In multivariate analysis, Eastern Cooperative Oncology Group performance status, CA19-9 level, and HALP score remained significant predictors of overall survival. The HALP score appears to be a useful prognostic marker in patients with metastatic biliary tract cancer.

Clinical impact of deep learning-derived intravascular ultrasound characteristics in patients with deferred coronary artery

Prognostic markers for long-term outcomes are lacking in patients with deferred (nonculprit) coronary artery lesions. This study aimed to identify the morphological criteria for predicting adverse outcomes and validate their clinical impact.Using deep learning models, we extracted geometrical parameters and maximal attenuation (or calcium) burden index (ABI-max or CBI-max) from the intravascular ultrasound (IVUS) images of nonculprit vessels in 1115 patients. The endpoints included cardiac death, myocardial infarction, and target vessel revascularization of nonculprit vessel.Cardiac death occurred in 27 (2.4 %) patients at 3 years and 39 (3.5 %) patients at 5 years. At 5 years, the cardiac death-free survival rate was significantly lower with ABP-max ≥11.37 % vs. < 11.37 % (90.0 % vs. 98.7 %), CBI-max ≥13.40 % vs. < 13.40 % (92.8 % vs. 98.4 %), and percent atheroma volume ≥ 51.35 % vs. < 51.35 % (94.0 % vs. 97.7) (all log-rank p < 0.001). The independent predictors of 5-year cardiovascular mortality were age (hazard ratio [HR] 1.21), female sex (HR 0.33), history of heart failure (HR 6.06), chronic kidney disease (HR 18.28), ABI-max (HR 1.04), and CBI-max (HR 1.05). The independent determinants of 5-year target vessel revascularization of nonculprit vessel were fractional flow reserve (HR 0.95 per 0.01 increase), minimal lumen area (HR 0.63), and plaque burden (HR 1.15).In patients with nonculprit coronary artery lesions, a large burden of attenuated or calcified plaques predicted cardiac mortality, while IVUS geometry was associated with repeat revascularization. Thus, deep learning–based IVUS analysis of the whole target vessel may help clinicians identify high-risk lesions.

Epigenetic silencing of ZIC4 unveils a potential tumor suppressor role in pediatric choroid plexus carcinoma

Zic family member ZIC4 is a transcription factor that has been shown to be silenced in several cancers. However, understanding the regulation and function of ZIC4 in pediatric choroid plexus tumors (CPTs) remained limited. This study employed data mining and bioinformatics analysis to investigate the DNA methylation status of ZIC4 in CPTs and its correlation with patient survival. Our results unveiled ZIC4 methylation as a segregating factor, dividing CPT cohorts into two clusters, with hyper-methylation linked to adverse prognosis. Hyper-methylation of ZIC4 was confirmed in a choroid plexus carcinoma-derived cell line (CCHE-45) by bisulfite sequencing. Furthermore, our study demonstrated that demethylating agent and a histone methyltransferase inhibitor could reverse ZIC4 silencing. RNA sequencing and proteomic analysis showed that ZIC4 over-expression influenced genes and proteins involved in immune response, antigen processing and presentation, endoplasmic reticulum stress, and metabolism. Functionally, re-expressing ZIC4 negatively impacted cell proliferation and migration. Ultimately, these findings underscore ZIC4 hyper-methylation as a prognostic marker in CPTs and shed light on potential mechanisms underlying its tumor suppressor role in CPC. This insight paves the way for novel therapeutic targets in treating aggressive CPTs.

SOX9 promotes hypoxic pulmonary hypertension through stabilization of DPP4 in pulmonary artery smooth muscle cells

Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling (PVR), primarily due to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This study aimed to investigate the role and molecular mechanism of SOX9 in hypoxic PH in rats. The findings revealed that SOX9 was upregulated in the pulmonary arteries and PASMCs of hypoxia-exposed rats. SOX9 knockdown inhibited hypoxia-induced proliferation and migration of PASMCs, reduced PVR, and subsequently alleviated hypoxia-induced PH in rats, suggesting that SOX9 plays a critical role in PH. Further investigation demonstrated that SOX9 interacted with DPP4, preventing its ubiquitin degradation in hypoxia-exposed PASMCs. DPP4 knockdown inhibited hypoxia-induced PASMC proliferation and migration, and administration of the DPP4 inhibitor sitagliptin (5 mg/kg) significantly reduced PVR and alleviated hypoxia-induced PH in rats, indicating that SOX9 contributes to PH by stabilizing DPP4. The results also showed that hypoxia induced YAP1 expression and dephosphorylation, leading to YAP1 nuclear localization. YAP1 knockdown promoted the degradation of HIF-1α in hypoxia-exposed PASMCs and inhibited hypoxia-induced proliferation and migration of PASMCs. Additionally, HIF-1α, as a transcription factor, promoted SOX9 expression by binding to the SOX9 promoter in hypoxia-exposed PASMCs. In conclusion, hypoxia promotes the proliferation and migration of PASMCs through the regulation of the YAP1/HIF-1α/SOX9/DPP4 signaling pathway, leading to PH in rats. These findings suggest that SOX9 may serve as a potential prognostic marker and therapeutic target for PH.

Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis

With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used. A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75ECD, plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated. Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40pg/mL and >100pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75ECD, and plasma miR-181ab is more limited. Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency. NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).

Dysmetabolism of Peripheral Blood Monocytes in Type 1 Diabetes Mellitus.

The level of ROS (fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate) and lipid content (fluorescent lipophilic dye Nile Red) in the peripheral blood monocyte fraction from patients with type 1 diabetes mellitus and healthy volunteers were assessed by flow cytofluorimetry. The number of CD36+ monocytes was assessed using specific antibodies. In patients with type 1 diabetes mellitus, the levels of ROS and intracellular lipids in monocytes and the number of cells expressing CD36 fatty acid translocase were elevated. These results indicate metabolic changes in the peripheral blood cells of patients with carbohydrate metabolism disorders and can be considered as possible prognostic markers for the development of type 1 diabetes mellitus complications.