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Inherited Platelet Disorders: An Updated Overview.

Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 1011 platelet per day as well as appropriate survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either platelet count or platelet functions, comprise a heterogenous group of about sixty rare diseases caused by molecular anomalies in many culprit genes. Their clinical relevance is highly variable according to the specific disease and even within the same type, ranging from almost negligible to life-threateni

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… FLNA-RT: Thrombocytopenia with filaminopathy (syndromic or only thrombocytopenia); TUBB1-RT; Thrombocytopenia due to variants affecting tubulin b1; ACTN1-RT: Thrombocytopenia due to variants affecting Actinin-1; SLFN14-RT: SLFN14-Related thrombocytopenia; TPM4-RT: Thrombocytopenia due to variants in tropomyosin … Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia. J. Clin. Investig. 2017;127:814–829. doi: 10.1172/JCI86154. 73. Stritt S., Nurden P., Favier R., Favier M., Ferioli S., Gotru S.K., van Eeuwijk J.M., Schulze H., Nurden A.T., Lambert M.P., et al. …

Resveratrol: Molecular Mechanisms, Health Benefits, and Potential Adverse Effects.

Resveratrol (RES), a naturally occurring polyphenolic compound, has garnered significant attention due to its diverse biological activities, which include anti-inflammatory, antioxidant, and antiaging properties. This review synthesizes current evidence concerning the molecular mechanisms, therapeutic efficacy, and safety profile of RES across a variety of pathologies, with an emphasis on the latest research conducted in recent years. Mechanistically, RES is known to modulate critical signaling pathways such as the activation of sirtuin 1. These actions collectively contribute to the attenuati

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… MAPK, mitogen‐activated protein kinase; NLRP3, NOD‐like receptor thermal protein domain associated protein 3; Nrf2, nuclear factor erythroid 2‐related factor 2; PINK1, PTEN‐induced putative kinase 1; ROS, reactive oxygen species; SIRT1, sirtuin 1; sMaf, small Maf; TNF‐α, tumor necrosis factor‐α; TrkB, tropomyosin … Moreover, SIRT1 can regulate various physiological and pathological processes by modulating the activity of multiple targets, including FOXO3a, phospho‐tropomyosin receptor kinase B, and p53, thereby mediating neuroprotection in HD models [ 167 ]. …

Exploring novel therapeutic strategies: Could psychedelic perspectives offer promising solutions for Alzheimer's disease comorbidities?

The increasing prevalence of dementia within an ageing global population, combined with prolonged life expectancy, accentuates Alzheimer's disease (AD) as a multifaceted healthcare challenge. This challenge is further compounded by the limited therapeutic options currently available. Addressing the intricacies of AD management, the mitigation of comorbidities has emerged as a pivotal facet of treatment. Comorbid conditions, such as neurobehavioral symptoms, play a role in shaping the clinical course, management, and outcomes of this pathology; highlighting the importance of comprehensive care

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… 4-isoxazolepropionic acid receptor; BDNF expression, brain-derived neurotrophic factor expression; LSD, lysergic acid diethylamide; psychedelic DOI, psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; TCB-2, 4-Bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide; TrkB receptors, tropomyosin …

Uncertainties about the benefit-risk balance of oncology medicines assessed by the European Medicines Agency.

BackgroundDrug regulators assess and describe uncertainties regarding treatment outcomes and the benefit-risk balance of newly authorised medicines. We aimed to evaluate the type and number of uncertainties described in the benefit-risk assessment for initial marketing authorisations of oncology medicines assessed by the European Medicines Agency (EMA). We also aimed to develop a systematic classification of uncertainties to contribute to improved communication about uncertainties.Materials and methodsWe included all medicines containing a new active substance assessed by the EMA and granted a

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… programmed death-ligand 1; PD-L2, programmed death-ligand 2; PFS, progression-free survival; PI, proteasome inhibitors; PK/PD, pharmacokinetics/pharmacodynamics; PR, partial response; PS, performance status; RMP, risk management plan; RRMM, relapsed and refractory multiple myeloma; SD, stable disease; TRK, tropomyosin …

Molecular-Guided Precision Oncology in Cancer of Unknown Primary: A State-of-the-Art Perspective.

Cancer of unknown primary (CUP) is evolving from a diagnosis of exclusion treated with empirical chemotherapy to a molecularly defined entity amenable to precision-based interventions. This heterogeneous entity, comprising 2-3% of all metastatic malignancies, encompasses diverse cancers with clinically occult primary sites at diagnosis after a thorough workup. Recent landmark trials including CUPISCO and Fudan CUP-001 have demonstrated significant survival improvements with molecularly guided therapies compared to empirical chemotherapy, fundamentally enhancing and complementing traditional or

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… ISH—in situ Hybridization, IHC—Immunohistochemistry, ORR—Overall Response Rate, OS—Overall Survival; CUP: Cancer of Unknown Primary; MSI-H: Microsatellite Instability-High; dMMR: Deficient Mismatch Repair; TMB-H: Tumor Mutational Burden-High; NTRK: Neurotrophic Tyrosine Receptor Kinase (gene); TRK: Tropomyosin …

Ketogenic Diet in Cancer Prevention and Therapy: Molecular Targets and Therapeutic Opportunities.

Although cancer is still one of the most significant global challenges facing public health, the world still lacks complementary approaches that would significantly enhance the efficacy of standard anticancer therapies. One of the essential strategies during cancer treatment is following a healthy diet program. The ketogenic diet (KD) has recently emerged as a metabolic therapy in cancer treatment, targeting cancer cell metabolism rather than a conventional dietary approach. The ketogenic diet (KD), a high-fat and very-low-carbohydrate with adequate amounts of protein, has shown antitumor effe

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… Furthermore, MiR-21 contributes to cancer progression by targeting tumor suppressor mRNAs such as tropomyosin 1 [ 217 ], programmed cell death 4 (PDCD4) [ 218 ], phosphatase, and tensin homolog (PTEN) [ 219 ]. …

A prognostic model for anoikis-related genes in pancreatic cancer.

Anoikis, a distinct form of programmed cell death, is crucial for both organismal development and maintaining tissue equilibrium. Its role extends to the proliferation and progression of cancer cells. This study aimed to establish an anoikis-related prognostic model to predict the prognosis of pancreatic cancer (PC) patients. Gene expression data and patient clinical profiles were sourced from The Cancer Genome Atlas (TCGA-PAAD: Pancreatic Adenocarcinoma) and the International Cancer Genome Consortium (ICGC-PACA: Pancreatic Ductal Adenocarcinoma). Non-cancerous pancreatic tissue gene expressio

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… The tropomyosin receptor kinase (TRK) family has recently become a focal point in research. TRK comprises three transmembrane protein receptors: TrkA, TrkB, and TrkC, which are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. …

Current and Emerging Therapeutic Targets for the Treatment of Cholangiocarcinoma: An Updated Review.

Cholangiocarcinoma is a malignancy of the bile ducts that is often associated with late diagnosis, poor overall survival, and limited treatment options. The standard of care therapy for cholangiocarcinoma has been cytotoxic chemotherapy with modest improvements in overall survival with the addition of immune checkpoint inhibitors. The discovery of actionable mutations has led to the advent of targeted therapies against FGFR and IDH-1, which has expanded the treatment landscape for this patient population. Significant efforts have been made in the pre-clinical space to explore novel immunothera

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… NTRK The family of neurotrophic tropomyosin kinase receptors (NTRK) is a transmembrane tyrosine kinase that is integral to neural development through the activation of growth signaling pathways. NTRK protein fusions have been implicated in multiple solid tumor malignancies [ 46 ]. …

Reciprocal interactions between osteoclasts and nociceptive sensory neurons in bone cancer pain.

Many common cancers such as breast, prostate, and lung cancer metastasize to bones at advanced stages, producing severe pain and functional impairment. At present, the current pharmacotherapies available for bone cancer pain are insufficient to provide safe and efficacious pain relief. In this narrative review, we discuss the mechanisms used by cancer cells within the bone tumor microenvironment (TME) to drive bone cancer pain. In particular, we highlight the reciprocal interactions between tumor cells, bone-resorbing osteoclasts, and pain-sensing sensory neurons (nociceptors), which drive bon

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… a variety of factors that also contribute to peripheral sensitization and pain, including bradykinins, endothelins, and growth factors. 42 , 57 In particular, nerve growth factor (NGF) released from macrophages and cancer cells seems to play a critical role in nerve sprouting, engaging its receptor tropomyosin …

Роль альфа-рецептора, активированного пероксидисом, в нейродегенеративных заболеваниях и других неврологических расстройствах: перспективы клинического применения.

Альфа-рецептор, активированный с помощью пероксисом, является членом сверхсемейства суперрецептора ядерного гормона и функционирует в качестве коэффициента транскрипции, связанного с регулированием клеточного метаболизма. Предыдущие исследования показали, что PPARα играет ключевую роль в возникновении и развитии нейродегенеративных заболеваний. Таким образом, альфа-агонисты, работающие на рецепторах, привлекают все большее внимание в качестве потенциальных средств лечения неврологических расстройств. Цель этого обзора состоит в том, чтобы прояснить прогресс в области исследований, касающихся п

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… Similar to BDNF, NT3 is known to regulate synaptic plasticity through the tropomyosin-related kinase B receptor (Chao, 2003; Patel et al., 2020). In AD, PPARα deficiency has been shown to affect the neuronal activity of cultured hippocampal neurons and synaptic plasticity in mice. …

The Health-Promoting Effects and the Mechanism of Intermittent Fasting.

Intermittent fasting (IF) is an eating pattern in which individuals go extended periods with little or no energy intake after consuming regular food in intervening periods. IF has several health-promoting effects. It can effectively reduce weight, fasting insulin levels, and blood glucose levels. It can also increase the antitumor activity of medicines and cause improvement in the case of neurological diseases, such as memory deficit, to achieve enhanced metabolic function and prolonged longevity. Additionally, IF activates several biological pathways to induce autophagy, encourages cell renew

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… uncoordinated 51-like kinase-1; mTORC1: mammalian target of rapamycin protein complex-1; BDNF: brain-derived neurotrophic factor; CREB: cAMP-response element-binding protein; IGF-1: insulin-like growth factor-1; AMPK: AMP-dependent protein kinase; PS-1: presenilin-1; PSD95: postsynaptic density-95; TrkB: tropomyosin …

Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin-proteasome.

Skeletal muscle adapts its mass as consequence of physical activity, metabolism and hormones. Catabolic conditions or inactivity induce signaling pathways that regulate the process of muscle loss. Muscle atrophy in adult tissue occurs when protein degradation rates exceed protein synthesis. Two major protein degradation pathways, the ubiquitin-proteasome and the autophagy-lysosome systems, are activated during muscle atrophy and variably contribute to the loss of muscle mass. These degradation systems are controlled by a transcription dependent program that modulates the expression of rate-lim

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… Recently, Trim32 has been reported to degrade thin filaments (actin, tropomyosin and troponins), α-actinin and desmin ( Cohen et al., 2012 ). …

Therapeutic Advances in Oncology.

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment

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… Microsatellite instability-high/mismatch-repair deficiency (MSI-H/dMMR) | Keytruda (pembrolizumab) | PD-1 inhibitor antibody | 15 tumor types (2017) Tumor Mutational Burden-High (TMB-H) | Keytruda (pembrolizumab) | PD-1 inhibitor antibody | 10 tumor types (2020) NTRK fusions | Vitrakvi (larotrectinib) | Pan-tropomyosin-related …

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives.

Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-mol

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… Entrectinib (Rozlytrek) | TRKA/B/C/ROS1/ALK | Solid tumors with NTRK fusion (2019) | Roche Currently, there are still some ALK inhibitors under clinical investigation, such as the pan-TKIs entrectinib, 31 belizatinib, 32 and repotrectinib, 33 which target oncogenic rearrangements in ALK, ROS, and tropomyosin … TRK inhibitors The tropomyosin receptor kinase (TRK) family is composed of three members, TRKA, TRKB, and TRKC, which are encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1 , NTRK2 , and NTRK3 , respectively. 225 To activate TRK receptors, neurotrophins (TRK ligands) bind to the …

An updated overview of the search for biomarkers of osteoporosis based on human proteomics.

Osteoporosis is a chronic metabolic disease that increases bone fragility and, leads to severe osteoporotic fractures. In recent years, the use of high-throughput omics to explore physiological and pathological biomarkers related to bone metabolism has gained popularity. In this review, we first briefly review the technical approaches of proteomics. Additionally, we summarize the relevant literature in the last decade to provide a comprehensive overview of advances in human proteomics related to osteoporosis. We describe the specific roles of various proteins related to human bone metabolism,

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… Among them, protein factors such as DEAD box protein 5 (DDX5), 26S protease regulatory subunit 7 (PSMC 2), casein kinase I isoform alpha (CSNK1A1), integrin-linked kinase (ILK), and tropomyosin alpha 4 (TPM4) exhibit altered expression in the bone marrow microenvironment of osteoporosis patients. …

The challenge of pharmacotherapy for musculoskeletal pain: an overview of unmet needs.

Musculoskeletal disorders are characterized by several impairments, including pain, affecting muscles, bones, joints and adjacent connective tissue, resulting in temporary or permanent functional limitations and disability. Musculoskeletal pain is particularly prevalent worldwide and greatly impacts the quality of life, social participation and economic burden. To date, several issues persist about the classification of musculoskeletal pain and its management strategies and resources. The treatment of musculoskeletal pain conditions is complex and often requires a multimodal approach, includin

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… The NGF is an essential growth factor for the development of sensory and sympathetic neurons during embryogenesis, but by binding to an appropriate tropomyosin receptor kinase A receptor (TrkA), it modulates the pain pathway through the enhancement of the neurotrophic and nociceptor functions. 96 Different …

A Mechanistic Understanding of Axon Degeneration in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapeutic agents cause many short and long term toxic side effects to peripheral nervous system (PNS) that drastically alter quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and enduring disorder caused by several anti-neoplastic agents. CIPN typically presents with neuropathic pain, numbness of distal extremities, and/or oversensitivity to thermal or mechanical stimuli. This adverse side effect often requires a reduction in chemotherapy dosage or even discontinuation of treatment. Currently there are no effective treatment options for CIPN. While the under

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… Target-derived neurotrophins bind and activate tropomyosin receptor kinase (Trk) receptors in the innervating axon terminals. Endocytosis of the activated receptors results in signaling endosomes that are retrogradely trafficked along the axons. …

Abstracts of the 5(th) Cachexia Conference, Barcelona, Spain, December 5-8, 2009.

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Спасение гиппокампальной синаптической пластичности и эффективности памяти Финголимода (FTY720) в модели APP/PS1 болезни Альцгеймера сопровождается коррекцией метаболизма финголипидов, полиаминов и фосфолипидного насыщенного состава.

Ранее, наши метаболомические, транскриптомные и геномные исследования характеризовали путь церамида/шфингомилена как терапевтическую цель в болезни Альцгеймера, и мы показали, что FTY720, фингозин-1-фосфахатный рецептор, утвержденный для лечения множественных склерозов, восстанавливает синаптическая пластичность и память в мышах APP/PS1. Для дальнейшего изучения того, как FTY720 спасает патологию, мы провели метаболический анализ мозга, плазмы и печени обученных APP/PS1 и диких мышей. APP/PS1 мыши продемонстрировали локальные нарушения мозга в полиаминах, фосфолипидах и сфинголипидах. Большинс

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… The most explored pathways affected by FTY720 and S1P are cyclic adenosine monophosphate (cAMP) / cAMP response element-binding protein (CREB) 73 – 75 , and brain-derived neurotrophic factor (BDNF) / tropomyosin receptor kinase B axis 74 – 76 , amplified by histone deacetylases 77 – 79 , and with a downstream …

Роль и функции " Ирисина " : перспективы последних изменений и неевродегенеративных заболеваний.

Irisin — пептид, полученный из фибронектина типа III, содержащего домен белка 5 (FNDC5) и производимый главным образом мышечными волокнами в соответствии с регулированием пероксисомных прорациатрированных рецепторов гамма-коативатора 1-альфа (PGC1α) во время упражнения. Ирисин стал объектом обширных исследований в силу его потенциала как метаболического регулятора и его антиоксидантных свойств. В частности, она связана с защитными действиями в мозгу. Несмотря на растущий интерес, остается много вопросов относительно молекулярных механизмов, лежащих в основе их воздействия. В настоящем обзоре р

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… Glutathione peroxidase 4; GSK-3: Glycogen synthase kinase-3; GYS1: Glycogen synthase; MAPK: Mitogen-activated protein kinase; MYD88: Myeloid differentiation primary response 88; NF-κB: Nuclear factor-κB; NQO1: NAD(P)H Quinone Dehydrogenase 1; NRF2: Nuclear factor erythroid 2-related factor 2; NTRK2: Tropomyosin …