The Omics-Driven Machine Learning Path to Cost-Effective Precision Medicine in Chronic Kidney Disease.

Chronic kidney disease (CKD) poses a significant and growing global health challenge, making early detection and slowing disease progression essential for improving patient outcomes. Traditional diagnostic methods such as glomerular filtration rate and proteinuria are insufficient to capture the complexity of CKD. In contrast, omics technologies have shed light on the molecular mechanisms of CKD, helping to identify biomarkers for disease assessment and management.

Exploring glioma heterogeneity through omics networks: from gene network discovery to causal insights and patient stratification.

Gliomas are primary malignant brain tumors with a typically poor prognosis, exhibiting significant heterogeneity across different cancer types. Each glioma type possesses distinct molecular characteristics determining patient prognosis and therapeutic options. This study aims to explore the molecular complexity of gliomas at the transcriptome level, employing a comprehensive approach grounded in network discovery.

Priority-Elastic net for binary disease outcome prediction based on multi-omics data.

Background: High-dimensional omics data integration has emerged as a prominent avenue within the healthcare industry, presenting substantial potential to improve predictive models. However, the data integration process faces several challenges, including data heterogeneity, priority sequence in which data blocks are prioritized for rendering predictive information contained in multiple blocks, assessing the flow of information from one omics level to the other and multicollinearity.

Methods: We propose the Priority-Elastic net algorithm, a hierarchical regression method extending Priority-Lasso for the binary logistic regression model by incorporating a priority order for blocks of variables while fitting Elastic-net models sequentially for each block.

Inferring Diagnostic and Prognostic Gene Expression Signatures Across WHO Glioma Classifications: A Network-Based Approach.

Tumor heterogeneity is a challenge to designing effective and targeted therapies. Glioma-type identification depends on specific molecular and histological features, which are defined by the official World Health Organization (WHO) classification of the central nervous system (CNS). These guidelines are constantly updated to support the diagnosis process, which affects all the successive clinical decisions.

Mural cell-derived chemokines provide a protective niche to safeguard vascular macrophages and limit chronic inflammation.

Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, we investigated the mechanisms sustaining vascular macrophages.

The ischemic model of chronic muscle spasm and pain.

This article was not intended to be a complete review of the electromyography of pathological muscle states, but it was written to illustrate how the "Coletti Method of EMG ChemoDenervation" (CMECD®) protocol for the treatment of chronic pain resulting from chronic muscle spasm was developed and established. That process led to an unexpected understanding of the underlying pathophysiology of chronic muscle spasm, which represents a paradigm shift in our understanding and ultimately in our treatment of muscle spasm-induced chronic pain. Other investigators had brought to light the presence of spontaneous electrical activity (SEA) in states of muscle spasm.

A Model-Based Framework to Identify Optimal Administration Protocols for Immunotherapies in Castration-Resistance Prostate Cancer.

Prostate cancer (PCa) is one of the most frequent cancer in male population. Androgen deprivation therapy is the first-line strategy for the metastatic stage of the disease, but, inevitably, PCa develops resistance to castration (CRPC), becoming incurable. In recent years, clinical trials are testing the efficacy of anti-CTLA4 on CRPC.

Modeling the effect of immunotherapies on human castration-resistant prostate cancer.

In this paper we analyze the potential effect of immunotherapies on castration-resistant form of human Prostate Cancer (PCa). In particular, we examine the potential effect of the dendritic vaccine sipuleucel-T, the only currently available immunotherapy option for advanced PCa, and of ipilimumab, a drug targeting the Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), exposed on the CTLs membrane, currently under Phase II clinical trial. The model, building on the one by Rutter and Kuang, includes different types of immune cells and interactions and is parameterized on available data.

A QSP model of prostate cancer immunotherapy to identify effective combination therapies.

Immunotherapy, by enhancing the endogenous anti-tumor immune responses, is showing promising results for the treatment of numerous cancers refractory to conventional therapies. However, its effectiveness for advanced castration-resistant prostate cancer remains unsatisfactory and new therapeutic strategies need to be developed. To this end, systems pharmacology modeling provides a quantitative framework to test in silico the efficacy of new treatments and combination therapies.

17β-Estradiol attenuates p38MAPK activity but not PKCα induced by angiotensin II in the brain.

17β-Estradiol (E2) has been shown to modulate the renin-angiotensin system in hydromineral and blood pressure homeostasis mainly by attenuating angiotensin II (ANGII) actions. However, the cellular mechanisms of the interaction between E2 and angiotensin II (ANGII) and its physiological role are largely unknown. The present experiments were performed to better understand the interaction between ANGII and E2 in body fluid control in female ovariectomized (OVX) rats.

CD36-triggered cell invasion and persistent tissue colonization by tumor microvesicles during metastasis.

Tumor microvesicles are a peculiar type of extracellular vesicles that circulate in the blood of patients with metastatic cancer. The itineraries and immune cell interactions of tumor microvesicles during the intravascular and extravascular stages of metastasis are largely unknown. We found that the lipid receptor CD36 is a major mediator of the engulfment of pancreatic tumor microvesicles by myeloid immune cells in vitro and critically samples circulating tumor microvesicles by resident liver macrophages in mice in vivo.

Distinct Pathogenesis of Pancreatic Cancer Microvesicle-Associated Venous Thrombosis Identifies New Antithrombotic Targets In Vivo.

Objective: Cancer patients are at high risk of developing deep venous thrombosis (DVT) and venous thromboembolism, a leading cause of mortality in this population. However, it is largely unclear how malignant tumors drive the prothrombotic cascade culminating in DVT.

Approach And Results: Here, we addressed the pathophysiology of malignant DVT compared with nonmalignant DVT and focused on the role of tumor microvesicles as potential targets to prevent cancer-associated DVT.

The surface chemistry determines the spatio-temporal interaction dynamics of quantum dots in atherosclerotic lesions.

Aim: To optimize the design of nanoparticles for diagnosis or therapy of vascular diseases, it is mandatory to characterize the determinants of nano-bio interactions in vascular lesions.

Materials & Methods: Using ex vivo and in vivo microscopy, we analyzed the interactive behavior of quantum dots with different surface functionalizations in atherosclerotic lesions of ApoE-deficient mice.

Results: We demonstrate that quantum dots with different surface functionalizations exhibit specific interactive behaviors with distinct molecular and cellular components of the injured vessel wall.

Systemic Administration of Antipsychotic Asenapine Pre or Postnatal does not Induce Anxiety-like Behaviors in Mice.

Background And Objective: Asenapine is an atypical antipsychotic approved by US Food and Drug Administration in 2009 and by European Medicines Agency in 2010 for Schizophrenia and Bipolar Disorder treatment. Currently, many studies have been developed in an attempt to clarify and minimize the risks related to the use of psychotropic during pre/postnatal period on patients with a history of mental disorders.

Conclusion: The aim of this study was to test the impact of pre and/or postnatal exposition to asenapine on mice offspring behavior.

Short-Term High-Fat Diet Increases Leptin Activation of CART Neurons and Advances Puberty in Female Mice.

Leptin is a permissive factor for puberty initiation, participating as a metabolic cue in the activation of the kisspeptin (Kiss1)-gonadotropin-releasing hormone neuronal circuitry; however, it has no direct effect on Kiss1 neurons. Leptin acts on hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons, participating in the regulation of energy homeostasis. We investigated the influence of a short-term high-fat diet (HFD) on the effect of leptin on puberty timing.

Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice.

Deep venous thrombosis (DVT) is one of the most common cardiovascular diseases, but its pathophysiology remains incompletely understood. Although sterile inflammation has recently been shown to boost coagulation during DVT, the underlying molecular mechanisms are not fully resolved, which could potentially identify new anti-inflammatory approaches to prophylaxis and therapy of DVT. Using a mouse model of venous thrombosis induced by flow reduction in the vena cava inferior, we identified blood-derived high-mobility group box 1 protein (HMGB1), a prototypical mediator of sterile inflammation, to be a master regulator of the prothrombotic cascade involving platelets and myeloid leukocytes fostering occlusive DVT formation.

Dual-Track Clearance of Circulating Bacteria Balances Rapid Restoration of Blood Sterility with Induction of Adaptive Immunity.

Efficient clearance of bacteremia prevents life-threatening disease. Platelet binding to intravascular bacteria, a process involving platelet glycoprotein GPIb and bacterial opsonization with activated complement C3, influences blood clearance and anti-infective immunity. Using intravital microscopy of the bloodstream of mice infected with Listeria monocytogenes, we show that bacterial clearance is not a uniform process but a "dual-track" mechanism consisting of parallel "fast" and "slow" pathways.

Estradiol and angiotensin II crosstalk in hydromineral balance: Role of the ERK1/2 and JNK signaling pathways.

The angiotensin II (ANGII) receptor AT1 plays an important role in the control of hydromineral balance, mediating the dipsogenic and natriorexigenic effects and neuroendocrine responses of ANGII. While estradiol (E2) is known to modulate several actions of ANGII in the brain, the molecular and cellular mechanisms of the interaction between E2 and ANGII and its physiological role in the control of body fluids remain unclear. We investigated the influence of E2 (40 μg/kg) pretreatment and extracellular-signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) cell signaling on the dipsogenic and natriorexigenic effects, as well as the neuroendocrine responses to angiotensinergic central stimulation in ovariectomized rats (OVX).

Osmoregulation requires brain expression of the renal Na-K-2Cl cotransporter NKCC2.

The Na-K-2Cl cotransporter 2 (NKCC2) was thought to be kidney specific. Here we show expression in the brain hypothalamo-neurohypophyseal system (HNS), wherein upregulation follows osmotic stress. The HNS controls osmotic stability through the synthesis and release of the neuropeptide hormone, arginine vasopressin (AVP).

Gaseous modulators in the control of the hypothalamic neurohypophyseal system.

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are gaseous molecules produced by the brain. Within the hypothalamus, gaseous molecules have been highlighted as autocrine and paracrine factors regulating endocrine function. Therefore, in the present review, we briefly discuss the main findings linking NO, CO, and H2S to the control of body fluid homeostasis at the hypothalamic level, with particular emphasis on the regulation of neurohypophyseal system output.

Quantifying and monitoring overdiagnosis in cancer screening: a systematic review of methods.

Objective: To determine the optimal method for quantifying and monitoring overdiagnosis in cancer screening over time.

Design: Systematic review of primary research studies of any design that quantified overdiagnosis from screening for nine types of cancer. We used explicit criteria to critically appraise individual studies and assess strength of the body of evidence for each study design (double blinded review), and assessed the potential for each study design to accurately quantify and monitor overdiagnosis over time.