Hepatitis E Virus: What More Do We Need to Know?

Hepatitis E virus (HEV) infection is typically a self-limiting, acute illness that spreads through the gastrointestinal tract but replicates in the liver. However, chronic infections are possible in immunocompromised individuals. The HEV virion has two shapes: exosome-like membrane-associated quasi-enveloped virions (eHEV) found in circulating blood or in the supernatant of infected cell cultures and non-enveloped virions ("naked") found in infected hosts' feces and bile to mediate inter-host transmission. Although HEV is mainly spread via enteric routes, it is unclear how it penetrates the gut wall to reach the portal bloodstream. Both virion types are infectious, but they infect cells in different ways. To develop personalized treatment/prevention strategies and reduce HEV impact on public health, it is necessary to decipher the entry mechanism for both virion types using robust cell culture and animal models. The contemporary knowledge of the cell entry mechanism for these two HEV virions as possible therapeutic target candidates is summarized in this narrative review.

Gene Expression Comparison between Alcohol-Exposed versus Not Exposed Pancreatic Ductal Adenocarcinoma Patients Reveals a Peculiar TGFß-Related Phenotype: An Exploratory Analysis.

Background: Over the past few decades, there has been much debate and research into the link between alcohol consumption and the development and progression of pancreatic ductal adenocarcinoma (PDAC). Objectives: To contribute to the ongoing discussion and gain further insights into this topic, our study analysed the gene expression differences in PDAC patients based on their alcohol consumption history. Methods: To this end, we interrogated a large publicly available dataset. We next validated our findings in vitro. Results: Our findings revealed that patients with a history of alcohol consumption showed significant enrichment in the TGFß-pathway: a signaling pathway implicated in cancer development and tumor progression. Specifically, our bioinformatic dissection of gene expression differences in 171 patients with PDAC showed that those who had consumed alcohol had higher levels of TGFß-related genes. Moreover, we validated the role of the TGFß pathway as one of the molecular drivers in producing massive stroma, a hallmark feature of PDAC, in patients with a history of alcohol consumption. This suggests that inhibition of the TGFß pathway could serve as a novel therapeutic target for PDAC patients with a history of alcohol consumption and lead to increased sensitivity to chemotherapy. Our study provides valuable insights into the molecular mechanisms underlying the link between alcohol consumption and PDAC progression. Conclusions: Our findings highlight the potential significance of the TGFß pathway as a therapeutic target. The development of TGFß-inhibitors may pave the way for developing more effective treatment strategies for PDAC patients with a history of alcohol consumption.

Aplastic Anemia as a Roadmap for Bone Marrow Failure: An Overview and a Clinical Workflow.

In recent years, it has become increasingly apparent that bone marrow (BM) failures and myeloid malignancy predisposition syndromes are characterized by a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of children and adults with unexplained hematopoiesis defects. Clinically, hypocellular BM failure still represents a challenge in pathobiology-guided treatment. There are three fundamental topics that emerged from our review of the existing data. An exogenous stressor, an immune defect, and a constitutional genetic defect fuel a vicious cycle of hematopoietic stem cells, immune niches, and stroma compartments. A wide phenotypic spectrum exists for inherited and acquired BM failures and predispositions to myeloid malignancies. In order to effectively manage patients, it is crucial to establish the right diagnosis. New theragnostic windows can be revealed by exploring BM failure pathomechanisms.

Varied functions of immune checkpoints during cancer metastasis.

Immune checkpoints comprise diverse receptors and ligands including costimulatory and inhibitory molecules, which play monumental roles in regulating the immune system. Immune checkpoints retain key potentials in maintaining the immune system homeostasis and hindering the malignancy development and autoimmunity. The expression of inhibitory immune checkpoints delineates an increase in a plethora of metastatic tumors and the inhibition of these immune checkpoints can be followed by promising results. On the other hand, the stimulation of costimulatory immune checkpoints can restrain the metastasis originating from diverse tumors. From the review above, key findings emerged regarding potential functions of inhibitory and costimulatory immune checkpoints targeting the metastatic cascade and point towards novel potential Achilles' heels of cancer that might be exploited therapeutically in the future.

Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression.

Interactions of malignant multiple myeloma (MM) plasma cells (MM-cells) with the microenvironment control MM-cell growth, survival, drug-resistance and dissemination. As in MM microvascular density increases in the bone marrow (BM), we investigated whether BM MM endothelial cells (MMECs) control disease progression via the junctional adhesion molecule A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MMECs in 111 newly diagnosed (NDMM) and 201 relapsed-refractory (RRMM) patients compared to monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. Elevated membrane expression of JAM-A on MMECs predicted poor clinical outcome. Mechanistically, addition of recombinant JAM-A to MMECs increased angiogenesis whereas its inhibition impaired angiogenesis and MM growth in 2D and 3D in vitro cell culture and chorioallantoic membrane-assays. To corroborate these findings, we treated MM bearing mice with JAM-A blocking mAb and demonstrated impaired MM progression corresponding to decreased MM-related vascularity. These findings support JAM-A as an important mediator of MM progression through facilitating MM-associated angiogenesis. Collectively, elevated JAM-A expression on bone marrow endothelial cells is an independent prognostic factor for patient survival in both NDMM and RRMM. Blocking JAM-A restricts angiogenesis in vitro, in embrio and in vivo and represents a suitable druggable molecule to halt neoangiogenesis and MM progression.

Effects of Metformin and Vitamin D on Clinical Outcome in Cholangiocarcinoma Patients.

BACKGROUND AND AIMS: In the last few years, there has been increasing interest in non-cancer medications and their potential anti-cancer activity. Data are not available in cholangiocarcinoma (CCA) patients. The aim of this study is to fill this gap by investigating the potential impact in terms of clinical outcome of the common non-cancer medications. METHODS: All consecutive patients with CCAs were retrospectively identified from 7 Italian medical institutions. We investigated the role of intake of vitamin D, aspirin, metformin, statins, and diuretics. RESULTS: A total of 537 patients with CCAs were identified; 197 patients undergoing surgery were evaluated for disease-free survival (DFS), and 509 patients with an advanced stage were evaluated for overall survival (OS). A longer DFS was found in patients with intake of vitamin D versus never users (HR 0.55, 95% CI 0.32-0.92, p = 0.02). In an advanced stage an association with OS was found in patients with intake of metformin versus never users (HR 0.70, 95% CI 0.52-0.93, p = 0.0162), and in patients who have started taking metformin after chemotherapy versus before chemotherapy and never users (HR 0.44, 95% CI 0.26-0.73, p = 0.0016). CONCLUSIONS: Our results highlighted that vitamin D intake improves DFS in patients undergoing surgery. Metformin intake after starting chemotherapy can improve the clinical outcome in advanced disease. These results could open up new therapeutic strategies in cholangiocarcinoma patients. We are planning to undertake a prospective study to validate these data.

Photodynamic Therapy with Zinc Phthalocyanine Inhibits the Stemness and Development of Colorectal Cancer: Time to Overcome the Challenging Barriers?

Photodynamic therapy (PDT) is a light-based cancer therapy approach that has shown promising results in treating various malignancies. Growing evidence indicates that cancer stem cells (CSCs) are implicated in tumor recurrence, metastasis, and cancer therapy resistance in colorectal cancer (CRC); thus, targeting these cells can ameliorate the prognosis of affected patients. Based on our bioinformatics results, SOX2 overexpression is significantly associated with inferior disease-specific survival and worsened the progression-free interval of CRC patients. Our results demonstrate that zinc phthalocyanine (ZnPc)-PDT with 12 J/cm2 or 24 J/cm2 irradiation can substantially decrease tumor migration via downregulating MMP9 and ROCK1 and inhibit the clonogenicity of SW480 cells via downregulating CD44 and SOX2. Despite inhibiting clonogenicity, ZnPc-PDT with 12 J/cm2 irradiation fails to downregulate CD44 expression in SW480 cells. Our results indicate that ZnPc-PDT with 12 J/cm2 or 24 J/cm2 irradiation can substantially reduce the cell viability of SW480 cells and stimulate autophagy in the tumoral cells. Moreover, our results show that ZnPc-PDT with 12 J/cm2 or 24 J/cm2 irradiation can substantially arrest the cell cycle at the sub-G1 level, stimulate the intrinsic apoptosis pathway via upregulating caspase-3 and caspase-9 and downregulating Bcl-2. Indeed, our bioinformatics results show considerable interactions between the studied CSC-related genes with the studied migration- and apoptosis-related genes. Collectively, the current study highlights the potential role of ZnPc-PDT in inhibiting stemness and CRC development, which can ameliorate the prognosis of CRC patients.

From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy.

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

A Promising Role of TGF-ß Pathway in Response to Regorafenib in Metastatic Colorectal Cancer: A Case Report.

Colorectal cancer (CRC) is one of the most common cancer types around the world. The prognosis of patients with advanced diseases is still poor in spite of currently available therapeutic options. Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved to treat refractory metastatic colorectal cancer (mCRC). We investigated Somatic mutations in several genes involved in immunological response and cancer progression in both long/short responder mCRC patients who underwent third-line therapy with regorafenib to identify predictive biomarkers of response using Ion Torrent PGM sequencing and bioinformatic tools. We found Somatic mutations in TGFBR1, TGFBR2, and TGFBR3 genes in primary tumor and metastases samples of long-responder patients. Furthermore, our bioinformatic results show that they were mainly enriched in immune response, cell junction, and cell adhesion in long responder patients, particularly in primary tumor and metastatic sites. These data suggest that the TGF-b pattern could be the leading actor of a prolonged response to this drug.

Immune Checkpoint Inhibitor-Related Myositis: From Biology to Bedside.

: Immune checkpoint inhibitor (ICI)-related inflammatory diseases, including polymyositis (PM) and dermatomyositis (DM), in patients suffering from neoplastic disorders represent a medical challenge. The treatment of these conditions has taken on new urgency due to the successful and broad development of cancer-directed immunological-based therapeutic strategies. While primary and secondary PM/DM phenotypes have been pathophysiologically characterized, a rational, stepwise approach to the treatment of patients with ICI-related disease is lacking. In the absence of high-quality evidence to guide clinical judgment, the available data must be critically assessed. In this literature review, we examine partially neglected immunological and clinical findings to obtain insights into the biological profiles of ICI-related PM/DM and potential treatment options. We show that differential diagnosis is essential to stratifying patients according to prognosis and therapeutic impact. Finally, we provide a comprehensive assessment of druggable targets and suggest a stepwise patient-oriented approach for the treatment of ICI-related PM/DM.

Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies.

The few therapeutic strategies for advance hepatocellular carcinoma (HCC) on poor knowledge of its biology. For several years, sorafenib, a tyrosine kinase inhibitors (TKI) inhibitor, has been the approved treatment option, to date, for advanced HCC patients. Its activity is the inhibition of the retrovirus-associated DNA sequences protein (RAS)/Rapidly Accelerated Fibrosarcoma protein (RAF)/mitogen-activated and extracellular-signal regulated kinase (MEK)/extracellular-signal regulated kinases (ERK) signaling pathway. However, the efficacy of sorafenib is limited by the development of drug resistance, and the major neuronal isoform of RAF, BRAF and MEK pathways play a critical and central role in HCC escape from TKIs activity. Advanced HCC patients with a BRAF mutation display a multifocal and/or more aggressive behavior with resistance to TKI. Moreover, also long non-coding RNA (lnc-RNA) have been studied in epigenetic studies for BRAF aggressiveness in HCC. So far, lnc-RNA of BRAF could be another mechanism of cancer proliferation and TKI escape in HCC and the inhibition could become a possible strategy treatment for HCC. Moreover, recent preclinical studies and clinical trials evidence that combined treatments, involving alternative pathways, have an important role of therapy for HCC and they could bypass resistance to the following TKIs: MEK, ERKs/ribosomal protein S6 kinase 2 (RSK2), and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). These initial data must be confirmed in clinical studies, which are currently ongoing. Translational research discoveries could create new strategies of targeted therapy combinations, including BRAF pathway, and they could eventually bring light in new treatment of HCC.

Emerging role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.

Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70-80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib had been the standardcare for almost a decade until 2018 when the Food and Drug Administration approved an alternative first-line agent namely lenvatinib. Cabozantinib, regorafenib, and ramucirumab also displayed promising results in second line settings. FOLFOX4, however, results inan alternative first-line treatment for the Chineseclinical oncology guidelines. Moreover,nivolumab and pembrolizumab,two therapeutics against the Programmed death (PD)-ligand 1 (PD-L1)/PD1 axis have been recently approvedfor subsequent-line therapy. However, similar to other solid tumors, the response rate of single agent targeting PD-L1/PD1 axis is low. Therefore, a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors (ICIs), the addition of ICIs after resection or during loco-regional therapy, ICIs in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with a careful assessmentof new ICIs-based combinatory approaches.

Predictive and Prognostic Factors in HCC Patients Treated with Sorafenib.

Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first.

Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications.

UNLABELLED: Obesity is an important risk factor for breast cancer (BC) in postmenopausal women; interlinked molecular mechanisms might be involved in the pathogenesis. Increased levels of estrogens due to aromatization of the adipose tissue, inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and prostaglandin E2, insulin resistance and hyperactivation of insulin-like growth factors pathways, adipokines, and oxidative stress are all abnormally regulated in obese women and contribute to cancerogenesis. These molecular factors interfere with intracellular signaling in the mitogen-activated protein kinase and phosphatydilinositol-3-phosphate/mammalian target of rapamycin (mTOR) pathways, which regulate the progression of the cell cycle, apoptosis, and protein synthesis. In this context, structural defects of typical genes related to both BC and obesity, such as leptin, leptin receptor, serum paraoxonase/arylesterase 1, the fat mass and obesity-associated gene and melanocortin receptor 4, have been associated with a high or low risk of BC development. The early detection of these gene alterations might be useful as risk predictors in obese women, and targeting these pathways involved in the BC pathogenesis in obese women is a potential therapeutic tool. In particular, mTOR pathway deregulation concurs in both obesity and BC, and inhibition of this might disrupt the molecular interlinks in a similar manner to that of metformin, which exerts definite anticancer activity and is currently used as an antidiabetic drug with a weight-reducing property. The identification of both genetic and pharmacological implications on the prevention and management of BC is the ultimate aim of these studies. IMPLICATIONS FOR PRACTICE: Obese women are at risk of breast cancer, but clinicians lack concrete tools for the prevention or early diagnosis of this risk. The present study, starting from the biology and the molecular defects characterizing both obesity and breast cancer, analyzed the potential molecules and genetic defects whose early identification could delineate a risk profile. Three steps are proposed that are potentially achievable in the clinical assessment of obese women, namely the evaluation of altered levels of serum molecules, the identification of genetic polymorphisms, and the study of the transcriptomic profile of premalignant lesions. Finally, the therapeutic implications of this molecular assessment were evaluated.

Navigating Lymphomas through BCR Signaling and Double-Hit Insights: Overview.

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating from B, T, or NK lymphocytes. They represent approximately 4-5% of new cancer cases and are classified according to the revised WHO system based on cell lineage, morphology, immunophenotype, and genetics. Diagnosis requires adequate biopsy material, though integrated approaches are used for leukemic presentations. Molecular profiling is improving classification and identifying prognostic markers. Indolent NHLs, such as follicular lymphoma and marginal zone lymphoma, typically pursue a non-aggressive clinical course with long survival. Aggressive diffuse large B-cell lymphoma (DLBCL) is the most common subtype. Recent studies have elucidated pathogenic mechanisms like MYC translocations and BCR pathway mutations. "Double hit" lymphomas with MYC and BCL2/BCL6 alterations confer a poor prognosis. Treatment approaches are evolving, with chemoimmunotherapy remaining standard for many indolent cases while intensified regimens and targeted agents show promise for refractory or high-risk aggressive disease. Continued elucidation of the genetic and microenvironmental underpinnings of lymphomagenesis is critical for developing personalized therapeutic strategies.

Endocrine-metabolic assessment checklist for cancer patients treated with immunotherapy: A proposal by the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE) and Italian Society of Pharmacology (SIF) multidisciplinary group.

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy.

Corrigendum: Can vitamin D status influence seroconversion to SARS-COV2 vaccines?

[This corrects the article DOI: 10.3389/fimmu.2022.1038316.].

The Complexity of the Tumor Microenvironment in Hepatocellular Carcinoma and Emerging Therapeutic Developments.

This review explores various aspects of the HCC TME, including both cellular and non-cellular components, to elucidate their roles in tumor development and progression. Specifically, it highlights the significance of cancer-associated fibroblasts (CAFs) and their contributions to tumor progression, angiogenesis, immune suppression, and therapeutic resistance. Moreover, this review emphasizes the role of immune cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T-cells (Tregs), in shaping the immunosuppressive microenvironment that promotes tumor growth and immune evasion. Furthermore, we also focused only on the non-cellular components of the HCC TME, including the extracellular matrix (ECM) and the role of hypoxia-induced angiogenesis. Alterations in the composition of ECM and stiffness have been implicated in tumor invasion and metastasis, while hypoxia-driven angiogenesis promotes tumor growth and metastatic spread. The molecular mechanisms underlying these processes, including the activation of hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) signaling, are also discussed. In addition to elucidating the complex TME of HCC, this review focuses on emerging therapeutic strategies that target the TME. It highlights the potential of second-line treatments, such as regorafenib, cabozantinib, and ramucirumab, in improving overall survival for advanced HCC patients who have progressed on or were intolerant to first-line therapy. Furthermore, this review explores the implications of the Barcelona Clinic Liver Cancer (BCLC) staging and classification system in guiding HCC management decisions. The BCLC system, which incorporates tumor stage, liver function, and performance status, provides a framework for treatment stratification and prognosis prediction in HCC patients. The insights gained from this review contribute to the development of novel therapeutic interventions and personalized treatment approaches for HCC patients, ultimately improving clinical outcomes in this challenging disease.

Breaking through Multiple Myeloma: A Paradigm for a Comprehensive Tumor Ecosystem Targeting.

Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic lesions. MM patients typically experience bone pain, kidney damage, fatigue due to anemia, and infections. Historically, MM was an incurable disease with a life expectancy of around three years after diagnosis. However, over the past two decades, the development of novel therapeutics has significantly improved patient outcomes, including response to treatment, remission duration, quality of life, and overall survival. These advancements include thalidomide and its derivatives, lenalidomide and pomalidomide, which exhibit diverse mechanisms of action against the plasma cell clone. Additionally, proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib disrupt protein degradation, proving specifically toxic to cancerous plasma cells. Recent advancements also involve monoclonal antibodies targeting surface antigens, such as elotuzumab (anti-CS1) and daratumumab (anti-CD38), bispecific t-cell engagers such as teclistamab (anti-BCMA/CD3) and Chimeric antigen receptor T (CAR-T)-based strategies, with a growing focus on drugs that exhibit increasingly targeted action against neoplastic plasma cells and relevant effects on the tumor microenvironment.

Polybrominated Diphenyl Ethers (PBDEs) and Human Health: Effects on Metabolism, Diabetes and Cancer.

There is increasing evidence of the role of endocrine disruptors (EDs) derived from commonly employed compounds for manufacturing and processing in altering hormonal signaling and function. Due to their prolonged half-life and persistence, EDs can usually be found not only in industrial products but also in households and in the environment, creating the premises for long-lasting exposure. Polybrominated diphenyl ethers (PBDEs) are common EDs used in industrial products such as flame retardants, and recent studies are increasingly showing that they may interfere with both metabolic and oncogenic pathways. In this article, a multidisciplinary panel of experts of the Italian Association of Medical Diabetologists (AMD), the Italian Society of Diabetology (SID), the Italian Association of Medical Oncology (AIOM), the Italian Society of Endocrinology (SIE) and the Italian Society of Pharmacology (SIF) provides a review on the potential role of PBDEs in human health and disease, exploring both molecular and clinical aspects and focusing on metabolic and oncogenic pathways.