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Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1.

The lysosomal storage disorders Niemann-Pick disease Type C1 (NPC1) and Type C2 (NPC2) are rare diseases caused by mutations in the NPC1 or NPC2 gene. Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark. A total of 95% of cases are due to a deficiency of NPC1 and only 5% are caused by NPC2 deficiency. Clinical manifestations include neurological symptoms and systemic

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… This could cause ER stress and ultimately trigger the unfolded protein response [ 83 ]. …

Field-Deployable Treatments For Leishmaniasis: Intrinsic Challenges, Recent Developments and Next Steps.

Leishmaniasis is a neglected tropical disease endemic primarily to low- and middle-income countries, for which there has been inadequate development of affordable, safe, and efficacious therapies. Clinical manifestations of leishmaniasis range from self-healing skin lesions to lethal visceral infection with chances of relapse. Although treatments are available, secondary effects limit their use outside the clinic and negatively impact the quality of life of patients in endemic areas. Other non-medicinal treatments, such as thermotherapies, are limited to use in patients with cutaneous leishman

Evolving Therapeutic Strategies in ANCA-Associated Vasculitis: Current Standards and Emerging Targets for GPA and MPA.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are severe autoimmune disorders characterized by necrotizing small-vessel inflammation, and are classified among anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Standard induction therapy combines glucocorticoids (GCs) with rituximab (RTX) or cyclophosphamide (CYC), with growing emphasis on GC minimization and selective use of avacopan in patients at high risk of GC toxicity. For maintenance therapy, fixed-interval RTX generally outperforms conventional oral agents and biomarker-guided re-dosin

Drug-Drug Interactions of Cannabidiol with Standard-of-Care Chemotherapeutics.

Cannabidiol (CBD) is an easily accessible and affordable Marijuana (Cannabis sativa L.) plant derivative with an extensive history of medical use spanning thousands of years. Interest in the therapeutic potential of CBD has increased in recent years, including its anti-tumour properties in various cancer models. In addition to the direct anticancer effects of CBD, preclinical research on numerous cannabinoids, including CBD, has highlighted their potential use in: (i) attenuating chemotherapy-induced adverse effects and (ii) enhancing the efficacy of some anticancer drugs. Therefore, CBD is ga

Circulating Tumour Cells (CTCs) in NSCLC: From Prognosis to Therapy Design.

Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells (CTCs), the efficacy of standard treatment methods is insufficient and results in treatment failure and reduced patient survival. CTCs are seen not only as an isolated phenomenon but also a key inherent part of the formation of metastasis and a key factor in cancer death.

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… Moreover, the cytotoxic effect of curcumin or its analogues can be detected via the accumulation of curcuminoids in the ER and the upregulation of the ER stress-related unfolded protein response, which leads to inhibition of protein synthesis and cell cycle arrest [ 357 , 358 ]. …

Monoclonal Gammopathies and the Bone Marrow Microenvironment: From Bench to Bedside and Then Back Again.

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called "smoldering" MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TM

mTOR Cross-Talk in Cancer and Potential for Combination Therapy.

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understandi

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… Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat. Rev. Cancer. 2008;8:851–864. doi: 10.1038/nrc2501. 65. Guertin D.A., Sabatini D.M. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9–22. doi: 10.1016/j.ccr.2007.05.008. 66. …

Checking NEKs: Overcoming a Bottleneck in Human Diseases.

In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as th

Hypoxia within the glioblastoma tumor microenvironment: a master saboteur of novel treatments.

Glioblastoma (GBM) tumors are the most aggressive primary brain tumors in adults that, despite maximum treatment, carry a dismal prognosis. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness and maintenance of glioma stem cells and creates an overall immunosuppressive landscape. This article reviews how hypoxic conditions overlap with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, represent promising avenues f

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… Strategies to improve immunotherapies Various approaches have been suggested to address hypoxia in cancer, including inhibition of HIF signaling, the use of hypoxia-activated prodrugs (HAPs), targeting downstream pathways like the unfolded protein response (UPR) and mTOR, as well as metabolic interventions …

Tumor Biology Hides Novel Therapeutic Approaches to Diffuse Large B-Cell Lymphoma: A Narrative Review.

Diffuse large B-cell lymphoma (DLBCL) is a malignancy of immense biological and clinical heterogeneity. Based on the transcriptomic or genomic approach, several different classification schemes have evolved over the years to subdivide DLBCL into clinically (prognostically) relevant subsets, but each leaves unclassified samples. Herein, we outline the DLBCL tumor biology behind the actual and potential drug targets and address the challenges and drawbacks coupled with their (potential) use. Therapeutic modalities are discussed, including small-molecule inhibitors, naked antibodies, antibody-dru

Обнаружение корневых причинных генов с вспышками с высокой пропускной способностью.

Уровни корневой причинно-следственной экспрессии - или коренные причинные гены для короткого периода - соответствуют первоначальным изменениям генной экспрессии, которые порождают симптомы пациента как эффект ниже по течению. Выявление коренных причинно-следственных генов имеет решающее значение для разработки методов лечения, которые изменяют болезнь в момент ее возникновения, однако никакие существующие алгоритмы не пытаются определить коренные причинно-следственные гены на основе данных. Данные РНК-последовательность (RNA-seq) создают такие проблемы, как погрешность измерения, высокомерност

SUBJECT INDEX Volume 125 (JANUARY–JUNE, 2004)

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Molecular and cellular mechanisms of skeletal muscle atrophy: an update.

Skeletal muscle atrophy is defined as a decrease in muscle mass and it occurs when protein degradation exceeds protein synthesis. Potential triggers of muscle wasting are long-term immobilization, malnutrition, severe burns, aging as well as various serious and often chronic diseases, such as chronic heart failure, obstructive lung disease, renal failure, AIDS, sepsis, immune disorders, cancer, and dystrophies. Interestingly, a cooperation between several pathophysiological factors, including inappropriately adapted anabolic (e.g., growth hormone, insulin-like growth factor 1) and catabolic pr

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… Because of an abnormal sarcoplasmic reticulum, Atg7 null muscles also reveal activation of ER chaperones, such as BiP and phosphorylation of eIF2a [ 174 , 175 ], suggesting induction of an unfolded protein response. …

Regulation of immunogenic cell death and potential applications in cancer therapy.

Immunogenic cell death (ICD), a type of regulatory cell death, plays an important role in activating the adaptive immune response. Activation of the tumor-specific immune response is accompanied by the cell surface exposure of calreticulin and heat-shock proteins, the secretion of adenosine triphosphate, and the release of high mobility group box-1. In this review, we summarize and classify the latest types of ICD inducers and their molecular mechanisms, and discuss the effects and potential applications of inducing ICD by chemotherapy drugs, targeted drugs, and oncolytic viruses in clinical r

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… Zika virus infection has been proven to induce ER stress by triggering the unfolded protein response, and cause oxidative stress and redox imbalance. ER stress is precisely the key molecular mechanism of ICD. …

Anti-Inflammatory Drugs as Anticancer Agents.

Inflammation is strictly associated with cancer and plays a key role in tumor development and progression. Several epidemiological studies have demonstrated that inflammation can predispose to tumors, therefore targeting inflammation and the molecules involved in the inflammatory process could represent a good strategy for cancer prevention and therapy. In the past, several clinical studies have demonstrated that many anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAIDs), are able to interfere with the tumor microenvironment by reducing cell migration and increasin

Current Therapeutic Options for the Main Monogenic Autoinflammatory Diseases and PFAPA Syndrome: Evidence-Based Approach and Proposal of a Practical Guide.

Monogenic autoinflammatory diseases are rare conditions caused by genetic abnormalities affecting the innate immunity. Previous therapeutic strategies had been mainly based on results from retrospective studies and physicians' experience. However, during the last years, the significant improvement in their genetic and pathogenic knowledge has been accompanied by a remarkable progress in their management. The relatively recent identification of the inflammasome as the crucial pathogenic mechanism causing an aberrant production of interleukin 1β (IL-1β) in the most frequent monogenic autoinflamm

Chimeric antigen receptor modified T-cells for cancer treatment.

T cells engineered with the chimeric antigen receptor (CAR) are rapidly emerging as an important immunotherapy for hematologic malignancies. The anti-cluster of differentiation (CD)19 CAR-T cell therapy has been remarkably successful against refractory/relapsed acute lymphoblastic leukemia (ALL), and a complete remission rate as high as 90% was observed, in both children and adults. Although the achievement of clinical efficacy using CAR-T cell therapy for solid tumors has encountered several obstacles that were associated with the multiple mechanisms contributing to an immunosuppressive micro

Precision-Engineered CD3 T-Cell Engagers for Solid Tumours: Conditional Activation, Microenvironment Modulation, and Clinical Translation.

BackgroundT-cell-engaging bispecific antibodies (TCEs) have transformed haematological malignancy treatment (blinatumomab > 40% complete remission), yet solid tumour efficacy remains limited (MethodsReview of 55 phase I-III trials of CD3-based TCEs in solid tumours, including tarlatamab (DLL3-targeted, small-cell lung cancer) and xaluritamig (STEAP1-targeted, prostate cancer). Analysis of next-generation engineering strategies and resistance mechanisms via genomic and immunohistochemical data.ResultResponse rates now approach ~40% in selected settings, marking an inflection point. In extensive

Demographic, epidemiological, and health transitions: are they relevant to population health patterns in Africa?

BackgroundStudies of trends in population changes and epidemiological profiles in the developing world have overwhelmingly relied upon the concepts of demographic, epidemiological, and health transitions, even though their usefulness in describing and understanding population and health trends in developing countries has been repeatedly called into question. The issue is particularly relevant for the study of population health patterns in Africa and sub-Saharan Africa, as the history and experience there differs substantially from that of Western Europe and North America, for which these conce

An Appraisal of the Oleocanthal-Rich Extra Virgin Olive Oil (EVOO) and Its Potential Anticancer and Neuroprotective Properties.

Dietary consumption of olive oil represents a key pillar of the Mediterranean diet, which has been shown to exert beneficial effects on human health, such as the prevention of chronic non-communicable diseases like cancers and neurodegenerative diseases, among others. These health benefits are partly mediated by the high-quality extra virgin olive oil (EVOO), which is produced mostly in Mediterranean countries and is directly made from olives, the fruit of the olive tree (Olea europaea L.). Preclinical evidence supports the existence of antioxidant and anti-inflammatory properties exerted by t