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Bone Disease in Multiple Myeloma: Biologic and Clinical Implications.

Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells localized within the bone marrow. Bone disease with associated osteolytic lesions is a hallmark of MM and develops in the majority of MM patients. Approximately half of patients with bone disease will experience skeletal-related events (SREs), such as spinal cord compression and pathologic fractures, which increase the risk of mortality by 20-40%. At the cellular level, bone disease results from a tumor-cell-driven imbalance between osteoclast bone resorption and osteoblast bone form

Transcriptome Analysis Reveals Altered Inflammatory Pathway in an Inducible Glial Cell Model of Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 (DM1), the most frequent inherited muscular dystrophy in adults, is caused by the CTG repeat expansion in the 3'UTR of the DMPK gene. Mutant DMPK RNA accumulates in nuclear foci altering diverse cellular functions including alternative splicing regulation. DM1 is a multisystemic condition, with debilitating central nervous system alterations. Although a defective neuroglia communication has been described as a contributor of the brain pathology in DM1, the specific cellular and molecular events potentially affected in glia cells have not been totally recognized. Thus,

The Role of Natural Killer Cells in Soft Tissue Sarcoma: Prospects for Immunotherapy.

Soft-tissue sarcomas (STS) represent about 80% of sarcomas, and are a heterogeneous group of rare and malignant tumors. STS arise from mesenchymal tissues and can grow into structures such as adipose tissue, muscles, nervous tissue and blood vessels. Morphological evaluation has been the standard model for the diagnosis of sarcomas, and even in samples with similar characteristics, they present a diversity in cytogenetic and genetic sequence alterations, which further increases the diversity of sarcomas. This variety is one of the main challenges for the classification and understanding of STS

Recent advances in use of fresh frozen plasma, cryoprecipitate, immunoglobulins, and clotting factors for transfusion support in patients with hematologic disease.

Hematologic diseases include a broad range of acquired and congenital disorders, many of which affect plasma proteins that control hemostasis and immune responses. Therapeutic interventions for these disorders include transfusion of plasma, cryoprecipitate, immunoglobulins, or convalescent plasma-containing therapeutic antibodies from patients recovering from infectious diseases, as well as concentrated pro- or anticoagulant factors. This review will focus on recent advances in the uses of plasma and its derivatives for patients with acquired and congenital hematologic disorders.

Abstract

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"Complimenting the Complement": Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of death in the US and worldwide. HCC remains a global health problem and is highly aggressive with unfavorable prognosis. Even with surgical interventions and newer medical treatment regimens, patients with HCC have poor survival rates. These limited therapeutic strategies and mechanistic understandings of HCC immunopathogenesis urgently warrant non-palliative treatment measures. Irrespective of the multitude etiologies, the liver microenvironment in HCC is intricately associated with chronic

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… Under normal physiologic and homeostatic conditions, C3 is primarily produced by hepatocytes and restricted mostly to the extracellular space. …

Breaking into HIV-1's Epigenetic Vault: Cure Strategies to Eliminate the Viral Reservoir.

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that integrates into the host cell's DNA as a provirus. Transcription from the provirus is regulated in large part by cellular proteins and epigenetic factors. These may be repressive or permissive to productive infection. The host factors that regulate this balance are therefore attractive targets for HIV-1 therapeutics. Indeed, proviral chromatin is the focus of two of the current HIV-1 cure strategies. "Shock and Kill" uses latency reversal agents to open the provirus's chromatin, promoting high levels of gene expression that induc

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… During productive and acute infection, capsid proteins assemble at the plasma membrane, and the viral protease (PR) cleaves the Gag-Pol polyprotein to release the mature virion into the extracellular space (reviewed in [ 15 ]). … Indeed, wild-type Tat is produced by HIV-1-infected cells in the CNS and excreted to the extracellular space, which contributes to neuroinflammation and aberrant gene expression in nearby cells, ultimately contributing to the development of HIV-1-associated neurocognitive disorders (HAND) (see references …

Biologics in Kidney Transplantation: Why and How Should We Personalize Their Dosage?

The therapeutic arsenal of immunosuppressive drugs in kidney transplantation has recently expanded with the introduction of biologics, approved or used off-label, that specifically target the immune system. Although therapeutic drug monitoring is well established for calcineurin inhibitors, its utility for biological immunosuppressants remains unclear. The objective of this narrative review was to evaluate whether biologics used to prevent or treat renal allograft rejection could be suitable candidates for therapeutic drug monitoring. This review provides (1) a comprehensive and up-to-date syn

Clostridium butyricum alleviates multiple myeloma by remodeling the bone marrow microenvironment and inhibiting PI3K/AKT pathway through the gut‒bone axis.

Emerging evidence reveals a strong connection between the gut microbiota and cancer. However, the exact role of gut microbiota dysbiosis in multiple myeloma (MM) is poorly understood, and the therapeutic potential of microbiota-targeted interventions represents a promising strategy that demands urgent mechanistic and translational investigation. First, we conducted a comprehensive microbiome-metabolite analysis between MM patients and healthy individuals. The result revealed a marked compositional difference characterized by reduced abundances of butyrate-producing bacteria and diminished buty

Next Generation Therapeutics for the Treatment of Myelofibrosis.

Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leukemia. JAK inhibitors are the only approved therapy for myelofibrosis and have been successful in reducing spleen and symptom burden. However, they do not significantly impact disease progression and many patients are ineligible due to coexisting cytopenias. Patients who are refractory to JAK inhibition also have a dismal survival. Therefore, non-JAK inhibitor-based therapies are being explored in pre-clinical and clini

Immune defects in the risk of infection and response to vaccination in monoclonal gammopathy of undetermined significance and multiple myeloma.

The plasma cell proliferative disorders monoclonal gammopathy of undetermined significance (MGUS) and malignant multiple myeloma (MM) are characterized by an accumulation of transformed clonal plasma cells in the bone marrow and production of monoclonal immunoglobulin. They typically affect an older population, with median age of diagnosis of approximately 70 years. In both disorders, there is an increased risk of infection due to the immunosuppressive effects of disease and conjointly of therapy in MM, and response to vaccination to counter infection is compromised. The underlying factors in

Tumor heterogeneity as a driver of drug resistance and its implications for personalized therapy.

Tumors are highly dynamic diseases characterized by significant heterogeneity. They consist of multiple cellular populations with distinct properties that respond differently to therapeutic pressure. This heterogeneity may arise from spatial variation across tumor regions (spatial heterogeneity) as well as from temporal changes during tumor evolution and treatment (temporal heterogeneity). As a consequence, drug-resistant subclones often emerge under therapy and contribute to treatment failure. Advances in single-cell and spatial multi-omics technologies enable precise quantification of tumor

The roles of Cryptochrome-1: the circadian clock as a control point in cancer therapy.

In this review, we carefully describe the composition and operation of cryptochrome-1 (CRY1). We introduce four related signaling pathways, namely cAMP/PKA/CREB signaling way, HIFα signaling way, NF-κB signaling way, STAT3 signaling way, FOXO signaling pathway and Hedgehog (HH) signaling pathway. We also emphasize the current understanding of the complex roles CRY1 plays in the progression of various solid tumors. We propose that its function represents a novel therapeutic target that could pave the way for new cancer treatments. Additionally, we summarize three emerging therapeutic strategies

Crosstalk between Circadian Rhythm Dysregulation and Tumorigenesis, Tumor Metabolism and Tumor Immune Response.

Circadian rhythm is a self-regulating 24-hour system that synchronizes with the day and night cycle in organisms. The regulation of this system is controlled by clock genes, which function to harmoniously express molecular levels that facilitate the orderly coordination of various cellular processes, such as sleep, metabolism, endocrine function, cell proliferation and immunity. The root cause of tumorigenesis is that the body loses its normal regulation of cell growth at the genetic level. Long-term disruptions in circadian rhythms caused by factors such as shift work, jet lag, and unstable s

Recent Advances in Zinc Oxide Nanoparticles (ZnO NPs) for Cancer Diagnosis, Target Drug Delivery, and Treatment.

Cancer is regarded as one of the most deadly and mirthless diseases and it develops due to the uncontrolled proliferation of cells. To date, varieties of traditional medications and chemotherapies have been utilized to fight tumors. However, their immense drawbacks, such as reduced bioavailability, insufficient supply, and significant adverse effects, make their use limited. Nanotechnology has evolved rapidly in recent years and offers a wide spectrum of applications in the healthcare sectors. Nanoscale materials offer strong potential for curing cancer as they pose low risk and fewer complica

Optimizing the Clinical Impact of CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia: Looking Back While Moving Forward.

Chimeric antigen receptor T-cell (CAR-T) therapy has been successful in creating extraordinary clinical outcomes in the treatment of hematologic malignancies including relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). With several FDA approvals, CAR-T therapy is recognized as an alternative treatment option for particular patients with certain conditions of B-ALL, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, or multiple myeloma. However, CAR-T therapy for B-ALL can be surrounded by challenges such as various adverse events including the life

Therapeutic potential of alpha-tocopherol in reducing oxidative stress and inflammatory damage after experimental traumatic brain injury and pentylenetetrazol-induced seizures.

The effects of alpha-tocopherol on seizure parameters, locomotor-cognitive functions, inflammatory response, oxidative stress response, histopathological changes, immunohistochemical parameters, and miRNA fold changes were investigated in rats with traumatic brain injury (TBI) and pentylenetetrazol (PTZ)-induced seizures. Sprague-Dawley male rats were randomly divided into three groups: Control (n = 8), TBI + PTZ (n = 10), and TBI + PTZ + tocopherol (n = 10). After inducing TBI in animals using the weight-drop method, increased post-injury seizure susceptibility was achieved by administering s

miRNAs and lncRNAs as Novel Therapeutic Targets to Improve Cancer Immunotherapy.

Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure has not yet been achieved for most malignancies and more efforts are urgently needed. Noncoding RNAs (ncRNA), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate several biological processes via selective targeting of crucial molecular signaling pathways. Recent

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… Role of Exosomal ncRNA as Anticancer and Drug Resistance Cargo Exosomes are lipid bilayer vesicles, with a size range of 40–150 nm in diameter, that are released via exocytosis into the extracellular space by a variety of cell types including immune cells and cancer cells. …

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

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