The Interplay between Tumour Microenvironment Components in Malignant Melanoma.

Malignant melanoma has shown an increasing incidence during the last two decades, exhibiting a large spectrum of locations and clinicopathological characteristics. Although current histopathological, biochemical, immunohistochemical, and molecular methods provide a deep insight into its biological behaviour and outcome, melanoma is still an unpredictable disease, with poor outcome. This review of the literature is aimed at updating the knowledge regarding melanoma's clinicopathological and molecular hallmarks, including its heterogeneity and plasticity, involving cancer stem cells population. A special focus is given on the interplay between different cellular components and their secretion products in melanoma, considering its contribution to tumour progression, invasion, metastasis, recurrences, and resistance to classical therapy. Furthermore, the influences of the specific tumour microenvironment or "inflammasome", its association with adipose tissue products, including the release of "extracellular vesicles", and distinct microbiota are currently studied, considering their influences on diagnosis and prognosis. An insight into melanoma's particular features may reveal new molecular pathways which may be exploited in order to develop innovative therapeutic approaches or tailored therapy.

Low Preoperative Prolactin Levels Predict Non-Organ Confined Prostate Cancer in Clinically Localized Disease.

INTRODUCTION: To evaluate the association between preoperative serum prolactin (PRL) levels and risk of non-organ confined prostate cancer (PCa) in clinically localized disease. MATERIALS AND METHODS: From December 2007 to December 2011, 124 patients with clinically localized PCa were retrospectively evaluated. Non-organ confined disease in the surgical specimen was defined according to extra-capsular extension, seminal vesicle invasion, positive surgical margins, and lymph node invasion. The association between clinical factors and serum levels of pituitary-testis hormones with the risk of non-organ confined disease was evaluated. RESULTS: Perioperative factors associated with non-organ confined disease include prostatic-specific antigen (OR 1.144; p = 0.025), proportion of biopsy positive cores (BPC, OR 36.702; p = 0.007), bioptical Gleason Score > 6 (OR 2.785; p = 0.034), and PRL (OR 0.756, p < 0.0001). The association was strong for BPC (area under the curve [AUC] 0.704; p < 0.0001) and PRL (AUC 0.299; p < 0.0001). When we dichotomized according to median value, PRL ≤7.7 µg/L was an independent predictor of extraprostatic disease (OR 6.571; p < 0.0001) with fair discrimination power (AUC 0.704; p < 0.0001). CONCLUSION: Low preoperative PRL levels predict the risk of non-organ confined PCa in clinically localized disease.

[Personalized cancer medicine : Biomarkers for molecular therapy stratification in pancreatic carcinoma]. / Personalisierte Krebsmedizin : Biomarker zur molekularen Therapiestratifizierung im Pankreaskarzinom.

Ductal adenocarcinoma of the pancreas has a very poor prognosis and a rising incidence. Even after curative intent resection, which is possible in a minority of patients, most patients relapse, whereas the majority is diagnosed with inoperable or metastatic disease. That's why palliative systemic chemotherapy is the current therapeutic mainstay. Biomarker-based tumor characterization could identify potential therapy targets and enable a personalized cancer medicine. Although potentially targetable alterations occur at very low frequencies, the possible impact on patient outcome can be significant. This article summarizes some of the contributions to these aspects and gives an outlook on their clinical meaning.

Tumor pyruvate kinase M2: A promising molecular target of gastrointestinal cancer.

Gastrointestinal (GI) cancer is one of the most common causes of cancer-related deaths worldwide. Tumor markers are valuable in detecting post-surgical recurrence or in monitoring response to chemotherapy. Pyruvate kinase isoform M2 (PKM2), a glycolytic enzyme catalyzing conversion of phosphoenolpyruvate (PEP) to pyruvate, confers a growth advantage to the tumor cells and enables them to adapt to the tumor microenvironment. In this review, we have summarized current research on the expression and regulation of PKM2 in tumor cells, and its potential role in GI carcinogenesis and progression. Furthermore, we have also discussed the potential of PKM2 as a diagnostic and screening marker, and a therapeutic target in GI cancer.

Potential Protective Function of Adiponectin in Diabetic Retinopathy.

Adiponectin, one of the most ubiquitous adipokines found in the blood, plays a major role in glucolipid metabolism and energy metabolism and regulation. In recent years, a growing body of research indicates that adiponectin also plays a significant role in diabetic retinopathy. In the present review, we specifically address the protective effects of adiponectin on the development and progression of diabetic retinopathy through improvement in insulin resistance, alleviation of oxidative stress, limiting of inflammation, and prevention of vascular remodeling, with the aim to explore new potential approaches and targets for the prevention and treatment of diabetic retinopathy.

Bioinformatics Prediction and Experimental Validation of the Role of Macrophage Polarization and Ferroptosis in Gestational Diabetes Mellitus.

Purpose: Gestational diabetes mellitus (GDM) is a common metabolic disorder during pregnancy that is associated with placental inflammation and adverse pregnancy outcomes. However, the mechanisms of inflammation in GDM are still unclear. Methods: Bulk transcriptome, single-cell transcriptome, clinical information, and samples were collected from GSE154414, GSE70493, GSE173193 and a retrospective cohort. Bioinformatics prediction was used to explore the mechanisms of placental inflammation, and multiplex immunofluorescence was used to validate the results. Results: First, we found that GDM is characterized by low-grade inflammation and is linked to several adverse pregnancy outcomes, as supported by our collected clinical data. Additionally, we identified ten hub genes (FCGR3B, CXCR1, MMP9, ITGAX, CCL5, GZMB, S100A8, LCN2, TGFB1, and LTF) as potential therapy targets and confirmed the binding of corresponding predictive therapeutic agents by molecular docking. Transcriptome sequencing analysis has shown that macrophages are primarily responsible for the emergence of placental inflammation, and that M1 macrophage polarization increased while M2 macrophage polarization decreased in GDM when compared to the control sample. Multiplex immunofluorescence staining of CD68, CD80, and ACSL4 was performed and suggested that ferroptosis of macrophages may contribute to placental inflammation in GDM. Conclusion: In conclusion, our findings provide a better understanding of the mechanisms of inflammation in GDM and suggest potential therapeutic targets for this condition.

Novelties in the pharmacological approaches for chronic heart failure: new drugs and cardiovascular targets.

Despite recent advances in chronic heart failure (HF) management, the prognosis of HF patients is poor. This highlights the need for researching new drugs targeting, beyond neurohumoral and hemodynamic modulation approach, such as cardiomyocyte metabolism, myocardial interstitium, intracellular regulation and NO-sGC pathway. In this review we report main novelties on new possible pharmacological targets for HF therapy, mainly on new drugs acting on cardiac metabolism, GCs-cGMP pathway, mitochondrial function and intracellular calcium dysregulation.

Therapeutic potential of gene therapy for gastrointestinal diseases: Advancements and future perspectives.

Advancements in understanding the pathogenesis mechanisms underlying gastrointestinal diseases, encompassing inflammatory bowel disease, gastrointestinal cancer, and gastroesophageal reflux disease, have led to the identification of numerous novel therapeutic targets. These discoveries have opened up exciting possibilities for developing gene therapy strategies to treat gastrointestinal diseases. These strategies include gene replacement, gene enhancement, gene overexpression, gene function blocking, and transgenic somatic cell transplantation. In this review, we introduce the important gene therapy targets and targeted delivery systems within the field of gastroenterology. Furthermore, we provide a comprehensive overview of recent progress in gene therapy related to gastrointestinal disorders and shed light on the application of innovative gene-editing technologies in treating these conditions. These developments are fueling a revolution in the management of gastrointestinal diseases. Ultimately, we discuss the current challenges (particularly regarding safety, oral efficacy, and cost) and explore potential future directions for implementing gene therapy in the clinical settings for gastrointestinal diseases.

The regulatory role and mechanism of exosomes in hepatic fibrosis.

Globally, the prevalence and fatality rates of liver disorders are on the rise. Among chronic liver conditions, hepatic fibrosis stands out as a central pathological process. Despite this, approved treatments for hepatic fibrosis are currently lacking. Exosomes, small extracellular vesicles secreted by various cell types, play a significant role in intercellular communication and have emerged as essential mediators in liver fibrosis. In this regard, this review compiles the mechanisms through which exosomes regulate hepatic fibrosis, encompassing diverse targets and signaling pathways. Furthermore, it delves into the regulatory impact of exosomes modulated by natural plant-derived, endogenous, and synthetic compounds as potential therapeutic strategies for addressing hepatic fibrosis.

Speech-language pathologists' treatment goals for preschool language disorders: An ICF analysis.

Purpose: The World Health Organization's International Classification of Functioning, Disability and Health (ICF) provides a comprehensive framework to conceptualise clinical services. This study explored how speech-language pathologists (SLPs) conceptualised therapy goals for preschoolers with language difficulties and disorders within the ICF framework.Method: An online survey was distributed to SLPs practising in a publicly funded Preschool Speech and Language program in Ontario, Canada. SLPs rated their familiarity with the ICF framework, and then reported all therapy goals for one child with language difficulty/disorder on their caseload. For each reported goal, SLPs indicated the ICF component(s) they felt the goal addressed. Researchers then independently categorised SLPs' reported goals into the ICF components.Result: Ninety-three SLPs completed the survey, and 81% reported they were at least "somewhat" familiar with the ICF framework. On average, SLPs reported three therapy goals per child, and felt the Activities and Participation components were most frequently targeted (73% and 72% of all reported goals, respectively). Researchers categorised SLPs' reported goals differently, and identified 57% of goals addressing the Activities component, and 21% the Participation component.Conclusion: There is a need to better understand how SLPs and researchers conceptualise the ICF framework, particularly the Participation component.

Current understanding of autoantibody against angiotensin II type 1 receptor in preeclampsia.

Preeclampsia (PE) remains a leading cause of fetal and maternal mortality. Angiotensin II type 1 receptor autoantibody (AT1-AA) is implicated in the dysregulation of the renin-angiotensin-aldosterone system. A strong relationship between AT1-AA and the occurrence and severity of PE has been confirmed in previous literature. Recent evidences suggested that AT1-AA was responsible for blood pressure elevation, reactive oxygen species synthesis, and inflammatory factors release and engaged in multiple signaling cascades. The inhibition of AT1-AA might be a potential therapeutic target in future days. Here we reviewed the current understanding of AT1-AA, aiming to provide clarity surrounding the role of AT1-AA in PE.

Super enhancers: Pathogenic roles and potential therapeutic targets for acute myeloid leukemia (AML).

Acute myeloid leukemia (AML) is a malignant hematological tumor with disordered oncogenes/tumor suppressor genes and limited treatments. The potent anti-cancer effects of bromodomain and extra-terminal domain (BET) inhibitors, targeting the key component of super enhancers, in early clinical trials on AML patients, implies the critical role of super enhancers in AML. Here, we review the concept and characteristic of super enhancer, and then summarize the current researches about super enhancers in AML pathogenesis, diagnosis and classification, followed by illustrate the potential super enhancer-related targets and drugs, and propose the future directions of super enhancers in AML. This information provides integrated insight into the roles of super enhancers in this disease.

The regulatory role and mechanism of autophagy in energy metabolism-related hepatic fibrosis.

Hepatic fibrosis is a key pathological process of chronic liver diseases, caused by alcohol, toxic and aberrant energy metabolism. It progresses to cirrhosis or even hepatic carcinoma without effective treatment. Studies have shown that autophagy has important regulatory effects on hepatic stellate cells (HSCs) energy metabolism, and then affect the activation state of HSCs. Autophagy maintains hepatic energy homeostasis, and the dysregulation of autophagy can lead to the activation of HSCs and the occurrence and development of hepatic fibrosis. It is necessary to explore the mechanism of autophagy in energy metabolism-related hepatic fibrosis. Herein, the current study summarizes the regulating mechanisms of autophagy through different targets and signal pathways in energy metabolism-related hepatic fibrosis, and discusses the regulatory effect of autophagy by natural plant-derived, endogenous and synthetic compounds for the treatment of hepatic fibrosis. A better comprehension of autophagy in hepatic stellate cells energy metabolism-related hepatic fibrosis may provide effective intervention of hepatic fibrosis, explore the potential clinical strategies and promote the drug treatment of hepatic fibrosis.

Identification of Liver and Plasma microRNAs in Chronic Hepatitis B Virus infection.

Background and Aims: With current standard of care a functional cure for Chronic Hepatitis B (CHB) is only achieved in 1-3% of patients and therefore novel therapies are needed. Disease activity during CHB can be determined by a broad range of virological biomarkers, however these biomarkers are also targets for novel treatment strategies. The aim of this study was to identify novel miRNAs that are differentially expressed in plasma and liver in CHB, and determine whether these miRNAs may serve as biomarkers of disease stage or treatment outcome. Methods: miRNA Next-Generation-Sequencing of plasma and liver samples from CHB patient and controls was performed to identify differentially expressed miRNAs. The identified candidate miRNAs were validated by qPCR in additional plasma and liver samples from two CHB cohorts. Results: Several miRNAs in plasma and liver were found to be differentially expressed between CHB patients and controls. Of the identified miRNAs expression levels of miR-122-5p in plasma were associated with plasma HBsAg, and plasma and liver HBV-DNA levels. Expression levels of miR-223-3p, miR-144-5p and miR-133a-3p in liver were associated with plasma alanine aminotransferase levels. No correlation was observed between miRNA expression levels at baseline and treatment outcome. Conclusions: Limited overlap between plasma and liver miRNAs was found, indicating that plasma miRNAs could be useful as biomarkers for treatment outcome or viral activity during treatment. Whereas liver miRNAs are more likely to be regulated by HBV and could be potential therapeutic targets to control viral activity in liver.

Diverse Roles and Therapeutic Potentials of Circular RNAs in Urological Cancers.

Circular RNAs (circRNAs) are a novel class of noncoding RNAs, which are mainly formed as a loop structure at the exons caused by noncanonical splicing; they are much more stable than linear transcripts; recent reports have suggested that the dysregulation of circRNAs is associated with the occurrence and development of diseases, especially various human malignancies. Emerging evidence demonstrated that a large number of circRNAs play a vital role in a series of biological processes such as tumor cell proliferation, migration, drug resistance, and immune escape. Additionally, circRNAs were also reported to be potential prognostic and diagnostic biomarkers in cancers. In this work, we systematically summarize the biogenesis and characteristics of circRNAs, paying special attention to potential mechanisms and clinical applications of circRNAs in urological cancers, which may help develop potential therapy targets for urological cancers in the future.

New Targets in Heart Failure Drug Therapy.

Despite recent advances in chronic heart failure management (either pharmacological or non-pharmacological), the prognosis of heart failure (HF) patients remains poor. This poor prognosis emphasizes the need for developing novel pathways for testing new HF drugs, beyond neurohumoral and hemodynamic modulation approaches. The development of new drugs for HF therapy must thus necessarily focus on novel approaches such as the direct effect on cardiomyocytes, coronary microcirculation, and myocardial interstitium. This review summarizes principal evidence on new possible pharmacological targets for the treatment of HF patients, mainly focusing on microcirculation, cardiomyocyte, and anti-inflammatory therapy.

Glycosaminoglycans: Carriers and Targets for Tailored Anti-Cancer Therapy.

The tumor microenvironment (TME) is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded by the components of the extracellular matrix (ECM). Glycosaminoglycans (GAGs), natural biomacromolecules, essential ECM, and cell membrane components are extensively altered in cancer tissues. During disease progression, the GAG fine structure changes in a manner associated with disease evolution. Thus, changes in the GAG sulfation pattern are immediately correlated to malignant transformation. Their molecular weight, distribution, composition, and fine modifications, including sulfation, exhibit distinct alterations during cancer development. GAGs and GAG-based molecules, due to their unique properties, are suggested as promising effectors for anticancer therapy. Considering their participation in tumorigenesis, their utilization in drug development has been the focus of both industry and academic research efforts. These efforts have been developing in two main directions; (i) utilizing GAGs as targets of therapeutic strategies and (ii) employing GAGs specificity and excellent physicochemical properties for targeted delivery of cancer therapeutics. This review will comprehensively discuss recent developments and the broad potential of GAG utilization for cancer therapy.

IL33 and Mast Cells-The Key Regulators of Immune Responses in Gastrointestinal Cancers?

The Interleukin (IL-)1 family IL33 is best known for eliciting type 2 immune responses by stimulating mast cells (MCs), regulatory T-cells (Tregs), innate lymphoid cells (ILCs) and other immune cells. MCs and IL33 provide critical control of immunological and epithelial homeostasis in the gastrointestinal (GI) tract. Meanwhile, the role of MCs in solid malignancies appears tissue-specific with both pro and anti-tumorigenic activities. Likewise, IL33 signaling significantly shapes immune responses in the tumor microenvironment, but these effects remain often dichotomous when assessed in experimental models of cancer. Thus, the balance between tumor suppressing and tumor promoting activities of IL33 are highly context dependent, and most likely dictated by the mixture of cell types responding to IL33. Adding to this complexity is the promiscuous nature by which MCs respond to cytokines other than IL33 and release chemotactic factors that recruit immune cells into the tumor microenvironment. In this review, we integrate the outcomes of recent studies on the role of MCs and IL33 in cancer with our own observations in the GI tract. We propose a working model where the most abundant IL33 responsive immune cell type is likely to dictate an overall tumor-supporting or tumor suppressing outcome in vivo. We discuss how these opposing responses affect the therapeutic potential of targeting MC and IL33, and highlight the caveats and challenges facing our ability to effectively harness MCs and IL33 biology for anti-cancer immunotherapy.

Computational analysis of data from a genome-wide screening identifies new PARP1 functional interactors as potential therapeutic targets.

Knowledge of interaction network between different proteins can be a useful tool in cancer therapy. To develop new therapeutic treatments, understanding how these proteins contribute to dysregulated cellular pathways is an important task. PARP1 inhibitors are drugs used in cancer therapy, in particular where DNA repair is defective. It is crucial to find new candidate interactors of PARP1 as new therapeutic targets in order to increase efficacy of PARP1 inhibitors and expand their clinical utility. By a yeast-based genome wide screening, we previously discovered 90 candidate deletion genes that suppress growth-inhibition phenotype conferred by PARP1 in yeast. Here, we performed an integrated and computational analysis to deeply study these genes. First, we identified which pathways these genes are involved in and putative relations with PARP1 through g:Profiler. Then, we studied mutation pattern and their relation to cancer by interrogating COSMIC and DisGeNET database; finally, we evaluated expression and alteration in several cancers with cBioPortal, and the interaction network with GeneMANIA. We identified 12 genes belonging to PARP1-related pathways. We decided to further validate RIT1, INCENP and PSTA1 in MCF7 breast cancer cells. We found that RIT1 and INCENP affected PARylation and PARP1 protein level more significantly in PARP1 inhibited cells. Furthermore, downregulation of RIT1, INCENP and PSAT1 affected olaparib sensitivity of MCF7 cells. Our study identified candidate genes that could have an effect on PARP inhibition therapy. Moreover, we also confirm that yeast-based screenings could be very helpful to identify novel potential therapy factors.

Inflammation and Metabolism in Cancer Cell-Mitochondria Key Player.

Cancer metabolism is an essential aspect of tumorigenesis, as cancer cells have increased energy requirements in comparison to normal cells. Thus, an enhanced metabolism is needed in order to accommodate tumor cells' accelerated biological functions, including increased proliferation, vigorous migration during metastasis, and adaptation to different tissues from the primary invasion site. In this context, the assessment of tumor cell metabolic pathways generates crucial data pertaining to the mechanisms through which tumor cells survive and grow in a milieu of host defense mechanisms. Indeed, various studies have demonstrated that the metabolic signature of tumors is heterogeneous. Furthermore, these metabolic changes induce the exacerbated production of several molecules, which result in alterations that aid an inflammatory milieu. The therapeutic armentarium for oncology should thus include metabolic and inflammation regulators. Our expanding knowledge of the metabolic behavior of tumor cells, whether from solid tumors or hematologic malignancies, may provide the basis for the development of tailor-made cancer therapies.