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Notch signaling deregulation in multiple myeloma: A rational molecular target.

Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple

Bleeding Propensity in Waldenström Macroglobulinemia: Potential Causes and Evaluation.

Waldenström macroglobulinemia (WM) is a rare, incurable, low-grade, B cell lymphoma. Symptomatic disease commonly results from marrow or organ infiltration and hyperviscosity secondary to immunoglobulin M paraprotein, manifesting as anemia, bleeding and neurological symptoms among others. The causes of the bleeding phenotype in WM are complex and involve several intersecting mechanisms. Evidence of defects in platelet function is lacking in the literature, but factors impacting platelet function and coagulation pathways such as acquired von Willebrand factor syndrome, hyperviscosity, abnormal

Роль ядерных рецепторов в развитии множественного склероза: обзор.

Множественный склероз (MS) является следствием раннего возбудительного демиэлирования и прогрессивных нейродегенеративных повреждений в центральной нервной системе (КНС). Несмотря на неясный патогенез MS, происходят два основных процесса: ремонт олигодендроцита и липидный метаболизм. Было отмечено, что ядерные рецепторы играют роль линейных датчиков, регуляторов транскрипционных факторов и модуляторов генного выражения. Один из членов этой семьи, ретиноид X-рецептор (RXR), который образует гетеродимерный комплекс с рецептором печени X (LXR), был замешан в патофизиологии MS. Кроме того, было вы

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… Moreover, it heterodimerizes RXR with a permissive partner to determine the unfolded protein response (UPR) and ER stress (Aranda and Pascual 2001 ). RXR prompts PPARγ to manage oxidative stress responses and suppresses autophagy to improve NRF2 expression in epileptic conditions in vivo. … protein response (UPR) and ER stress, which are key factors in cellular response to protein misfolding and inflammation RXR/NURR1, UPR genes, protein-folding chaperones CNS Cells, Microglia Enhances proper protein folding, reduces ER stress-induced inflammation Alzheimer’s, Parkinson’s, MS Could support …

Stochasticity of anticancer mechanisms underlying clinical effectiveness of vorinostat.

The Food and Drug Administration (FDA) has approved vorinostat, also called Zolinza®, for its effectiveness in fighting cancer. This drug is a suberoyl-anilide hydroxamic acid belonging to the class of histone deacetylase inhibitors (HDACis). Its HDAC inhibitory potential allows it to accumulate acetylated histones. This, in turn, can restore normal gene expression in cancer cells and activate multiple signaling pathways. Experiments have proven that vorinostat induces histone acetylation and cytotoxicity in many cancer cell lines, increases the level of p21 cell cycle proteins, and enhances p

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… UPR: unfolded protein response. PERK: protein kinase r-like endoplasmic reticulum kinase. RCC: renal cell cancers. Ku-86: a specific DNA repair enzyme that is part of a protein complex known as the Ku heterodimer. CAR: chimeric antigen receptor. … Indeed, Kahali et al. [ 51 ] showed that GRP78 is vorinostat biological target and that activation of the unfolded protein response (UPR) via phosphorylation of protein-like endoplasmic reticulum kinase (PERK) contributes to its anticancer potential. …

Apoptosis and (in) Pain-Potential Clinical Implications.

The deregulation of apoptosis is involved in the development of several pathologies, and recent evidence suggests that apoptosis may be involved in chronic pain, namely in neuropathic pain. Neuropathic pain is a chronic pain state caused by primary damage or dysfunction of the nervous system; however, the details of the molecular mechanisms have not yet been fully elucidated. Recently, it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect signals released by injured tissues and respond to these damage signals. TRP channels are similar to the

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… Such ER stress initiates an evolutionarily conserved signaling cascade called the unfolded protein response (UPR), which is a self-protective signaling pathway. The accumulation of unfolded proteins in the ER can activate the UPR to restore ER function. …

Application of Nanoparticles for Magnetic Hyperthermia for Cancer Treatment-The Current State of Knowledge.

Hyperthermia (HT) is an anti-cancer therapy commonly used with radio and chemotherapies based on applying heat (39-45 °C) to inhibit tumor growth. However, controlling heat towards tumors and not normal tissues is challenging. Therefore, nanoparticles (NPs) are used in HT to apply heat only to tumor tissues to induce DNA damage and the expression of heat shock proteins, which eventually result in apoptosis. The aim of this review article is to summarize recent advancements in HT with the use of magnetic NPs to locally increase temperature and promote cell death. In addition, the recent develop

Dendritic cell biology and its role in tumor immunotherapy.

As crucial antigen presenting cells, dendritic cells (DCs) play a vital role in tumor immunotherapy. Taking into account the many recent advances in DC biology, we discuss how DCs (1) recognize pathogenic antigens with pattern recognition receptors through specific phagocytosis and through non-specific micropinocytosis, (2) process antigens into small peptides with proper sizes and sequences, and (3) present MHC-peptides to CD4+ and CD8+ T cells to initiate immune responses against invading microbes and aberrant host cells. During anti-tumor immune responses, DC-derived exosomes were discovere

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… Meanwhile, the accumulation of unfolded proteins in the ER can also cause ER stress, which in turn enhances unfolded protein response (UPR), resulting in the reduced DC expression of MHC-I molecules and an impaired anti-tumor T cell response. …

Cellular and molecular mechanisms of muscle atrophy.

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of co

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… Ablation of Atg7, the unique E1 enzyme of the autophagic machinery, causes disorganized sarcomeres and activation of the unfolded protein response, which in turn triggers myofiber degeneration; this phenotype is associated with complete inhibition of autophagosome formation, leading to abnormal mitochondria …

Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials?

IntroductionMedullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in recent years. Proteasome inhibitors (PrIn) have shown the ability to improve patient outcomes, including survival and quality of life, in several malignancies, due to their ability to impair cell proliferation and cause apoptosis through the inhibition of the proteasome activity. Consequently, these drugs could represent a useful tool, alone or in combination with other treatments, in MTC patients.Aim of the studyThis r

Изменения лакта и лактилации в неврологических расстройствах.

Значительное внимание стало уделяться изучению изменений в лактилации различных целевых органов как в области здравоохранения, так и в области болезней. Многие жизненно важные процессы и начало болезней связаны не только с избытком белков, но и в первую очередь регулируются различными посттрансляционными изменениями белков. Лактат, который раньше считался лишь побочным продуктом анаэробного метаболизма, превратился в важнейшую энергетическую субстрату и сигнализирующую молекулу, связанную как с физиологическими, так и патологическими процессами в нервной системе. Кроме того, в недавних исследо

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… L-lactate promotes the unfolded protein response, activates NRF2, and protects cells from oxidative stress (Tauffenberger et al., 2019). … In 2019, Tauffenberger et al. utilized neuroblastoma cells (SH-SY5Y) as an in vitro model and found that L-lactate promotes the unfolded protein response and activates nuclear factor erythroid 2-related factor 2. …

Green Tea Catechins for Prostate Cancer Prevention: Present Achievements and Future Challenges.

Green tea catechins (GTCs) are a family of chemically related compounds usually classified as antioxidant molecules. Epidemiological evidences, supported by interventional studies, highlighted a more than promising role for GTCs in human prostate cancer (PCa) chemoprevention. In the last decades, many efforts have been made to gain new insights into the mechanism of action of GTCs. Now it is clear that GTCs' anticancer action can no longer be simplistically limited to their direct antioxidant/pro-oxidant properties. Recent contributions to the advancement of knowledge in this field have shown

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… For the maintenance of protein homeostasis (proteostasis), eukaryotic cells have developed a complex protein quality control system, which comprises molecular chaperons, the ER-associated degradation (ERAD) mechanism, the unfolded protein response (UPR), and the two most important systems of protein …

Prognostic Value of PSMB5 and Correlations with LC3II and Reactive Oxygen Species Levels in the Bone Marrow Mononuclear Cells of Bortezomib-Resistant Multiple Myeloma Patients.

Proteasome inhibitors (PIs) constitute the most common type of induction treatment for multiple myeloma. Interactions between the proteasome, autophagy, and reactive oxygen species (ROS) have been shown in the past, thus emphasizing the need for a better understanding of the underlying pathophysiology. For this study, bone marrow mononuclear cells from 110 myeloma patients were collected at different disease stages. PSMB5 and LC3I/II protein levels were determined using Western blot, proteasome proteolytic activity (PPA) with spectrofluorometry, and ROS with flow cytometry. PSMB5 accumulation

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… As a result, the accumulation of an excessive intracellular proteinic load, which would otherwise trigger the unfolded protein response (UPR) and induce endoplasmic reticulum (ER) stress and apoptotic cell death [ 38 ]. … Proteasome Inhibitors Induce a Terminal Unfolded Protein Response in Multiple Myeloma Cells Blood 2006 107 4907 4916 10.1182/blood-2005-08-3531 16507771 PMC1895817 39. Perel G. Bliss J. Thomas C.M. …

Real world data on light chain cardiac amyloidosis: Still a delayed diagnosis.

Cardiac amyloidosis (CA) represents a myocardial disorder developed by fibril deposition of a heterogeneous group of misfolding proteins. Despite being rare, a high clinical index of suspicion and novel advanced diagnostic methods seem to facilitate its early recognition. Currently nine types of cardiac amyloidosis have been described with AL and ATTR being the most common. Light chain amyloidosis (AL) is a life-threatening disease, resulting from clonal plasma cells that produce amyloidogenic light chain fragments causing organ damage including the heart. Morbidity and mortality of these pati

Calcium Signalling in Breast Cancer Associated Bone Pain.

Calcium (Ca2+) is involved as a signalling mediator in a broad variety of physiological processes. Some of the fastest responses in human body like neuronal action potential firing, to the slowest gene transcriptional regulation processes are controlled by pathways involving calcium signalling. Under pathological conditions these mechanisms are also involved in tumoral cells reprogramming, resulting in the altered expression of genes associated with cell proliferation, metastatisation and homing to the secondary metastatic site. On the other hand, calcium exerts a central function in nocicepti

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… SERCA inhibition leads to the reduction of endoplasmic reticulum Ca 2+ level which in turn results in a sustained unfolded protein response [ 55 ] while in MDA-MB-231 cells it induces cell death by excessive autophagy activation [ 56 ]. 3.3. … Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response. J. Biol. Chem. 2017;292:19656–19673. doi: 10.1074/jbc.M117.796920. 56. …

Oncology Nursing During a Pandemic: Critical Reflections in the Context of COVID-19.

ObjectivesTo provide a critical reflection of COVID-19 in the context of oncology nursing and provide recommendations for caring for people affected by cancer during this pandemic.Data sourcesElectronic databases, including CINAHL, MEDLINE, PsychINFO, Scopus, professional web sites, and grey literature were searched using Google Scholar.ConclusionNurses are key stakeholders in developing and implementing policies regarding standards of care during the COVID-19 pandemic. This pandemic poses several challenges for oncology services. Oncology nurses are providing a pivotal role in the care and ma

Exploring the role of histone deacetylase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future perspectives.

Histone deacetylase inhibitors (HDACis) are a significant category of pharmaceuticals that have developed in the past two decades to treat multiple myeloma. Four drugs in this category have received approval from the U.S. Food and Drug Administration (FDA) for use: Panobinonstat (though canceled by the FDA in 2022), Vorinostat, Belinostat and Romidepsin. The efficacy of this group of drugs is attributed to the disruption of many processes involved in tumor growth through the inhibition of histone deacetylase, and this mode of action leads to significant anti-multiple myeloma (MM) activity. In

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… Novel tropolones induce the unfolded protein response pathway and apoptosis in multiple myeloma cells. Oncotarget. 2017;8(44):76085–76098. doi: 10.18632/oncotarget.18543. 82. Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P, Tassone P, Atadja P, Chauhan D, Munshi NC, et al. …

Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer.

Prostate cancer (PCa) is the second-most common cancer in men worldwide and treatment options for patients with advanced or aggressive prostate cancer or recurrent disease continue to be of limited success and are rarely curative. Despite immune checkpoint blockade (ICB) efficacy in some melanoma, lung, kidney and breast cancers, immunotherapy efforts have been remarkably unsuccessful in PCa. One hypothesis behind this lack of efficacy is the generation of a distinctly immunosuppressive prostate tumor microenvironment (TME) by regulatory T cells, MDSCs, and type 2 macrophages which have been i

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… The TME is a hostile environment with conditions of hypoxia, nutrient starvation, low pH and abundance of free radicals that induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in its cellular constituents. … protein response VEGF | Vascular endothelial growth factor Zol | Zoledronic acid β-AR | β-adrenergic receptors cAMP | Cyclic adenosine monophosphate eNOS | Endothelial nitric oxide synthase iNOS | Inducible nitric oxide synthase mCRPC | Metastatic castration-resistant prostate cancer mpMRI | Multiparametric …

Pancreatitis: TIGAR-O Version 2 Risk/Etiology Checklist With Topic Reviews, Updates, and Use Primers.

The Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis and Obstructive (TIGAR-O) Pancreatitis Risk/Etiology Checklist (TIGAR-O_V1) is a broad classification system that lists the major risk factors and etiologies of recurrent acute pancreatitis, chronic pancreatitis, and overlapping pancreatic disorders with or without genetic, immunologic, metabolic, nutritional, neurologic, metaplastic, or other features. New discoveries and progressive concepts since the 2001 TIGAR-O list relevant to understanding and managing complex pancreatic disorders require an up

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… This category focuses on genetic variants that increase susceptibility to pancreatic injury, through the trypsin-dependent pathway ( 102 ), a protein misfolding pathway linked to the endoplasmic reticulum with a significant unfolded protein response ( 103 ), or other acinar or duct cell injury or stress … JBS is linked to mutations in the ubiquitin-ligase E3 (UBR1) gene, which is a key part of the unfolded protein response pathway for serine proteases ( 120 , 121 ). …

Диабетическая иммунотерапия Адаптация с BCG: Metabolic and Immune Reprogramming.

В настоящем обзоре клеточные и молекулярные механизмы, лежащие в основе мультидозы Bacille Calmette-Guérin (BCG), характеризуются как лечебная иммунная терапия для улучшения глицемии аутоиммунного диабета. Данные BCG чаще всего представляют собой данные клинических испытаний человека за последние годы. 15 годы в паре с механистическими представлениями. БЦЖ как вакцина имеет отличный послужной список в плане безопасности, который за сто лет был достигнут в области профилактики туберкулеза во всем мире, и за 36 Годы, были утверждены УЛХ при более высоких дозах для лечения рака мочевого пузыря. Н

Efficacy of bortezomib as first-line treatment for patients with multiple myeloma.

Recent years have seen a dramatic change in the approach towards diagnosing and treating Multiple Myeloma. Newer and more target specific approach to treatment has prolonged the survival for patients with multiple myeloma. The proteasome inhibitors make an important class of anti-myeloma drugs that disrupts the proteolytic machinery of the tumor cells preferentially, enhancing their susceptibility to apoptosis. Bortezomib, in particular has shown significant clinical efficacy in myeloma treatment. It is the most commonly used proteasome inhibitor and has been tested to be effective in prolongi

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… Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107(12):4907–16. doi: 10.1182/blood-2005-08-3531. 116. Dong H, Chen L, Chen X, et al. … Dysregulation of unfolded protein response partially underlies proapoptotic activity of bortezomib in multiple myeloma cells. Leuk Lymphoma. 2009;50(6):974–84. doi: 10.1080/10428190902895780. 117. Hideshima T, Bradner JE, Wong J, et al. …