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Selinexor plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: a multicenter, open-label, phase 1 study.

AbstractThe phase 1 portion of SENTRY/XPORT-MF-034 (NCT04562389) evaluated the exportin 1 inhibitor selinexor (40 mg/60 mg once weekly) plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis (n = 24). Primary end points were maximum tolerated selinexor dose, recommended clinical trial dose, and safety. No dose-limiting toxicities were reported. Common adverse events were nausea, fatigue, anemia, thrombocytopenia, constipation, vomiting, and headache. Nausea was transient, mainly grade 1, and managed by prophylactic antiemetics. Four deaths occurred, all unrelated to study treatmen

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… KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin [corrected] in prostate cancer models. BMC Cancer. 2015;15:941. doi: 10.1186/s12885-015-1936-z. 24. Garg M, Kanojia D, Mayakonda A, et al. …

New Insights and Future Perspectives of APRIL in IgA Nephropathy.

IgA nephropathy (IgAN) is characterized by immune-mediated glomerulonephritis, with the accumulation of galactose-deficient IgA1 (Gd-IgA1) in the glomeruli and increased levels of circulating Gd-IgA1 and Gd-IgA1-containing immune complexes. An incomplete understanding of the underlying mechanisms and differences in clinical and pathological features between individuals and ethnicities has contributed to the lack of established treatments for IgAN. A tumor necrosis factor (TNF) family member, a proliferation-inducing ligand (APRIL), is a crucial cytokine essential for the generation and surviva

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… A proliferation-inducing ligand mediates follicular lymphoma B-cell proliferation and cyclin D1 expression through phosphatidylinositol 3-kinase–regulated mammalian target of rapamycin activation Blood 2009 113 5206 5216 10.1182/blood-2008-09-179762 19321861 PMC2686190 47. Chu V.T. Enghard P. …

Epigenetic Modifiers as Novel Therapeutic Targets and a Systematic Review of Clinical Studies Investigating Epigenetic Inhibitors in Head and Neck Cancer.

The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of active investigation. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. This review summarizes the current knowledge on the function of important epigenetic modifiers in head and neck cancer, their clinical implications and di

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… Up-regulation of enhancer of zeste homolog 2 is associated positively with cyclin D1 overexpression and poor clinical outcome in head and neck squamous cell carcinoma. Cancer. 2012;118:2858–2871. doi: 10.1002/cncr.26575. 42. …

Implications of Angiogenesis Involvement in Arthritis.

Angiogenesis, the growth of new blood vessels, is essential in the pathogenesis of joint inflammatory disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA), facilitating the invasion of inflammatory cells and increase in local pain receptors that contribute to structural damage and pain. The angiogenic process is perpetuated by various mediators such as growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as proinflammatory cytokines, various chemokines, matrix components, cell adhesion molecules, proteases, and others.

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… GZMB gene silencing decreased inflammatory cytokine levels and also Bcl-2, cyclin D1, VEGF and basic fibroblast growth factor (bFGF) expression, while simultaneously increasing mRNA and protein levels of caspase 3. …

Novel intriguing strategies attenuating to sarcopenia.

Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and, often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Resistance training combined with amino acid-containing supplements is often utilized to pre

The crosstalk network of non-coding RNAs: Emerging opportunities for the clinical application of osteoporosis.

Current methods for testing bone density lack the capability to detect patients with early bone loss, and existing osteoporosis therapies have limitations in their efficacy and safety. Therefore, the development of more precise and convenient diagnostic technologies and novel treatments is of paramount importance. Extracellular vesicle (EV)-mediated non-coding RNA (ncRNA) interaction networks enable both the detection of early bone loss and targeted therapy for enhanced treatment outcomes. In this review, we highlight the utility of EVs for carrying various ncRNAs (e.g., miRNAs, lncRNAs, and c

Inflammation, Fibrosis and Cancer: Mechanisms, Therapeutic Options and Challenges.

Uncontrolled inflammation is a salient factor in multiple chronic inflammatory diseases and cancers. In this review, we provided an in-depth analysis of the relationships and distinctions between uncontrolled inflammation, fibrosis and cancers, while emphasizing the challenges and opportunities of developing novel therapies for the treatment and/or management of these diseases. We described how drug delivery systems, combination therapy and the integration of tissue-targeted and/or pathways selective strategies could overcome the challenges of current agents for managing and/or treating chroni

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… Specifically, the STAT3-mediated upregulation of anti-apoptotic proteins Bcl-2 families and Mcl-1 resists cell death, while its upregulation of cyclin D1 and c-Myc causes increased cell proliferation. … D1 promoter inhibitor inS3-54A18 [ 173 ]; MMP-2 promoter inhibitor salidroside [ 174 ]; and pyrimethamine-based STAT3 DNA domain binding (DBD) inhibitor 11d ( Figure 10 ) [ 175 ]. …

Waldenström macroglobulinemia: clinical and immunological aspects, natural history, cell of origin, and emerging mouse models.

Waldenström macroglobulinemia (WM) is a rare and currently incurable neoplasm of IgM-expressing B-lymphocytes that is characterized by the occurrence of a monoclonal IgM (mIgM) paraprotein in blood serum and the infiltration of the hematopoietic bone marrow with malignant lymphoplasmacytic cells. The symptoms of patients with WM can be attributed to the extent and tissue sites of tumor cell infiltration and the magnitude and immunological specificity of the paraprotein. WM presents fascinating clues on neoplastic B-cell development, including the recent discovery of a specific gain-of-function

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… MCL can be distinguished from WM based on clinicohistopathologic findings [ 27 ] and, in terms of cancer cytogenetics, the almost invariable occurrence of the hallmark t(11;14)(q13;q32) translocation that recombines IGH (Ig heavy-chain locus) on chromosome 14 and CCND1 (cyclin D1) on chromosome 11 [ … Chromosomal translocations involving IGH , particularly the cyclin D1-activating t(11;14)(q13;q32) exchange mentioned previously, occur in IgM-MM but not WM [ 30 , 31 ]. …

Association Between Interleukin-6 and Head and Neck Squamous Cell Carcinoma: A Systematic Review.

Interleukin-6 (IL-6) is a proinflammatory cytokine which plays an important role in several regulatory mechanisms of cancer. Moreover, experimental and clinical studies have reported that IL-6 targeted therapies might provide significant benefits for cancer treatment. The purpose of this systematic review is to evaluate IL-6 activity in patients with head and neck squamous cell carcinoma (HNSCC). A systematic review of the association between serum, saliva and tumor IL-6 and HNSCC was developed on PubMed/Medline in the publication range from January 1995 to January 2019. Our literature analysi

Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine.

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could

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… Data from retrospective studies indicated that the Cyclin D1 ( CCND1 ) gene, on locus 11q13, was mostly targeted in pPCL, while 14q32 rearrangements targeting 4p16.3 (Fibroblast growth factor receptor 3— FGFR3 and Multiple Myeloma SET domain— MMSET ) or 16q23 ( MAF ) occurred more frequently in sPCL …

Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application.

JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK-STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors o

MicroRNAs and long non-coding RNAs in pancreatic cancer: From epigenetics to potential clinical applications.

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two relevant classes of non-coding RNAs (ncRNAs) that play a pivotal role in a number of molecular processes through different epigenetic regulatory mechanisms of gene expression. As a matter of fact, the altered expression of these types of RNAs leads to the development and progression of a varied range of multifactorial human diseases. Several recent reports elucidated that miRNA and lncRNAs have been implicated in pancreatic cancer (PC). For instance, dysregulation of such ncRNAs has been found to be associated with chemoresistance,

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… Indeed, FGD5‑AS1-mediated downregulation of miR-577 alters the expression levels of β‑catenin, LRP6, cyclin D1, AXIN2, and c‑Myc, thus affecting the Wnt/β-catenin signaling pathway and contributing to the progression of PC. …

Advanced Diagnostic Techniques

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The prince and the pauper. A tale of anticancer targeted agents.

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consiste

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… AMPK activation leads to cell cycle arrest via p53-p21 axis up-regulation, although Cyclin D1 down-regulation may also occur independently of AMPK activation [ 269 ] and protein synthesis-regulation inhibition of the TSC2-mTOR (mammalian target of rapamycin) pathway. …

Omega-3 Fatty Acids and Cancer Cell Cytotoxicity: Implications for Multi-Targeted Cancer Therapy.

Cancer is a major disease worldwide. Despite progress in cancer therapy, conventional cytotoxic therapies lead to unsatisfactory long-term survival, mainly related to development of drug resistance by tumor cells and toxicity towards normal cells. n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can exert anti-neoplastic activity by inducing apoptotic cell death in human cancer cells either alone or in combination with conventional therapies. Indeed, n-3 PUFAs potentially increase the sensitivity of tumor cells to conventional therapies, poss

Another Weapon against Cancer and Metastasis: Physical-Activity-Dependent Effects on Adiposity and Adipokines.

Physically active behavior has been associated with a reduced risk of developing certain types of cancer and improved psychological conditions for patients by reducing anxiety and depression, in turn improving the quality of life of cancer patients. On the other hand, the correlations between inactivity, sedentary behavior, and overweight and obesity with the risk of development and progression of various cancers are well studied, mainly in middle-aged and elderly subjects. In this article, we have revised the evidence on the effects of physical activity on the expression and release of the ad

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… Apelin stimulates MCF-7 BC cell proliferation via the dose-dependent induction of cyclin D1 and amplified in breast cancer 1 (AIB1) and invasion potential by upregulating MMP1 expression [ 72 ], a mechanism also described in A549 lung adenocarcinoma cells [ 73 ]. … Effects of Apelin-13 on Rat Bone Marrow-Derived Mesenchymal Stem Cell Proliferation Through the AKT/GSK3β/Cyclin D1 Pathway. Int. J. Pept. Res. Therap. 2014;20:421–425. doi: 10.1007/s10989-014-9404-1. 76. Li L., Li L., Zhang Z., Jiang Z. …

Heterogeneity in precision oncology.

Precision oncology is a rapidly evolving concept that holds great promise in cancer treatment. However, a cancer complexity attributed to genomic and acquired tumour heterogeneity limits treatment effectiveness and increases toxicity. These limitations refer to both systemic therapies and radiotherapy, which are two mainstays of non-invasive cancer treatment. By understanding cancer heterogeneity and utilising advanced tools to personalise treatment strategies, precision oncology has the potential to revolutionise cancer care. In this article, we review the current status of precision oncology

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… Patients assigned to one of these treatments based on the molecular tumour profile, assessed using biomarkers, such as EGFR, KRAS, VEGF and cyclin D1 FISH, IHC, Sanger sequencing Phase 2, adaptive, randomised, open-label clinical trial 8-week DCR 255 The 8-week 46% DCR for the entire study population … Patients assigned to one of these treatments based on the molecular tumour profile, assessed using biomarkers, such as EGFR, KRAS, VEGF and cyclin D1 | FISH, IHC, Sanger sequencing | Phase 2, adaptive, randomised, open-label clinical trial | 8-week DCR | 255 | The 8-week 46% DCR for the entire study …

Biopharmaceuticals for Cancer Treatment: An Update.

Cancer is one of the most debilitating diseases, causing profound physical and psychological impacts on patients. The global number of cancer patients has been steadily rising over the last few decades. The development of effective cancer therapies remains the primary focus in life science research, requiring a precise understanding of specific pathways and the regulation of tumor markers. The approved cancer therapies demonstrate effectiveness by acting on specific regulatory enzymes, components required for cell division, hormones, and cell-specific receptors, etc. While small-molecule drugs

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

The development of techniques and immunotherapies are widely applied in cancer treatment such as checkpoint inhibitors, adoptive cell therapy, and cancer vaccines apart from radiation therapy, surgery, and chemotherapy give enduring anti-tumor effects. Minority people utilize single-agent immunotherapy, and most people adopt multiple-agent immunotherapy. The difficulties are resolved by including the biomarkers to choose the non-responders’ and responders’ potentials. The possibility of the potential complications and side effects are examined to improve cancer therapy effects. The Head and Ne

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… The STAT3 dimer binds gamma-activated sites in the promoters of a wide variety of target genes in the nucleus of various cancer cells, including head and neck cancer cells and multiple myeloma ( 41 ), influencing the transcription of genes important for cellular proliferation (MYC and cyclin D1), survival …

Selinexor: Targeting a novel pathway in multiple myeloma.

Selinexor is an orally bioavailable selective inhibitor of nuclear export compound that inhibits exportin-1 (XPO1), a novel therapeutic target that is overexpressed in multiple myeloma (MM) and is responsible for the transport of ∼220 nuclear proteins to the cytoplasm, including tumour suppressor proteins. Inhibition of this process has demonstrated substantial antimyeloma activity in preclinical studies, both alone and in combination with established MM therapeutics. Based on a clinical trial programme encompassing multiple combination regimens, selinexor-based therapy has been approved for t

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… Further, cargoes of XPO1 also include the oncoprotein mRNAs cellular myelocytomatosis (c‐MYC), cyclin D1 and murine double minute 2 (MDM2), and their transport to the cytoplasm thus promotes the synthesis of these oncoproteins, which are known to be upregulated in MM [ 29 ]. …