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Using Prognosis-Related Gene Expression Signature and Connectivity Map for Personalized Drug Repositioning in Multiple Myeloma.

BACKGROUND Multiple myeloma (MM) is the second most common hematologic cancer with poor prognosis. Novel therapeutic strategies are needed to decrease the high mortality rate. The aim of this study was to identify prospective agents for MM. MATERIAL AND METHODS A microarray dataset was mined, which contains the transcriptome profiles of 588 MM patients. Univariate Cox analysis was performed to analyze the relationships between genes and clinical outcome. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were determined. Protective and risky genes were uploaded to Connec

Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors.

BACKGROUND: Multiple myeloma (MM) is still a fatal plasma cell cancer. Novel compounds are currently clinically tested as a single agent in relapsing patients, but in best cases with partial response of a fraction of patients, emphasising the need to design tools predicting drug efficacy. Histone deacetylase inhibitors (HDACi) are anticancer agents targeting epigenetic regulation of gene expression and are in clinical development in MM. METHODS: To create a score predicting HDACi efficacy, five MM cell lines were treated with trichostatin A (TSA) and gene expression profiles were determined.

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… Glucose-regulated protein 78 has a central role in the unfolded protein response (UPR). Glucose-regulated protein 78 acetylation following HDACi treatment was described to activate UPR and contributes to the antitumour activity of HDACi. … Class I histone deacetylases localize to the endoplasmic reticulum and modulate the unfolded protein response. FASEB J. 2012;26 (6:2437–2445. doi: 10.1096/fj.11-193706. Kaiser M, Zavrski I, Sterz J, Jakob C, Fleissner C, Kloetzel PM, Sezer O, Heider U. …

Targeted Therapies for Multiple Myeloma.

Multiple myeloma continues to be a challenging disorder to treat despite improved therapies and the widespread use of proteasome inhibitors and immunomodulatory drugs. Although patient outcomes have improved, the disease continues to invariably relapse, and in the majority of cases, a cure remains elusive. In the last decade, there has been an explosion of novel drugs targeting cellular proteins essential for malignant plasma cell proliferation and survival. In this review, we focus on novel druggable targets leading to the development of monoclonal antibodies and cellular therapies against su

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… PIs (such as bortezomib) prevent the degradation of misfolded proteins via the proteasome, resulting in their accumulation within a malignant PC and eventual cell death due to the unfolded protein response [ 18 ]. … Proteasome inhibitors prevent the degradation of misfolded proteins via the proteasome, resulting in eventual cell death due to the unfolded protein response. BCL2 inhibitors such as venetoclax induce mitochondrial outer membrane permeabilization, culminating in apoptosis. …

Иммунный транскриптомный профиль у взрослых женских свиней: доминантный статус оказывает большее влияние, чем экологическая обогащение.

ОКРУЖАЮЩАЯ СРЕДА: Оценка благосостояния сельскохозяйственных животных имеет решающее значение, однако по-прежнему отсутствуют практические физиологические средства. В этом исследовании мы проверили, обнаруживает ли периферийный транскриптом моноядерной клетки крови (PBMC) вариации в связи с благосостоянием свиней. Для этого мы сравнивали животных, состояние благосостояния которых было расценено как отличающееся из-за их жизни в более или менее обогащенной среде и из-за их различного доминирующего положения. Совы размещались в обычном помещении (C, n = 36) или обогащенного (E, n = 35) среда с д

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… protein response | DERL3 | ATF6 , CREB3L2 , HSPA5 , NFE2L2 , XBP1 | 0.003 ERAD pathway | BRSK2 | ATF6 , SEL1L , XBP1 | 0.007 ER stress-induced upregulation of transcription | - | ATF6 , HSPA5 , XBP1 | 0.02 Signaling Reg. small GTPase mediated signal transduction | ARHGEF9 , PLEKHG4B , SWAP70 , VAV2 … Furthermore, highly secretory cell types, such as antibody-secreting cells, exhibit increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) pathway. Accordingly, we identified enriched ER-related biological processes exclusively in the dominance comparison. …

Understanding Mesangial Pathobiology in AL-Amyloidosis and Monoclonal Ig Light Chain Deposition Disease.

Patients with plasma cell dyscrasias produce free abnormal monoclonal Ig light chains that circulate in the blood stream. Some of them, termed glomerulopathic light chains, interact with the mesangial cells and trigger, in a manner dependent of their structural and physicochemical properties, a sequence of pathological events that results in either light chain-derived (AL) amyloidosis (AL-Am) or light chain deposition disease (LCDD). The mesangial cells play a key role in the pathogenesis of both diseases. The interaction with the pathogenic light chain elicits specific cellular processes, whi

Mitochondrial Determinants of Anti-Cancer Drug-Induced Cardiotoxicity.

Mitochondria are key organelles for the maintenance of myocardial tissue homeostasis, playing a pivotal role in adenosine triphosphate (ATP) production, calcium signaling, redox homeostasis, and thermogenesis, as well as in the regulation of crucial pathways involved in cell survival. On this basis, it is not surprising that structural and functional impairments of mitochondria can lead to contractile dysfunction, and have been widely implicated in the onset of diverse cardiovascular diseases, including ischemic cardiomyopathy, heart failure, and stroke. Several studies support mitochondrial t

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… When these quality control systems fail to compensate for the excessive generation/accumulation of misfolded proteins, the mitochondrial unfolded protein response (URPmt) is activated. … Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation Nature 2016 534 710 713 10.1038/nature18302 27350246 PMC4939261 68. Tahrir F.G. Langford D. Amini S. Mohseni Ahooyi T. Khalili K. …

Progress on the Application of Bortezomib and Bortezomib-Based Nanoformulations.

Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in r

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… Dysregulation of unfolded protein response partially underlies proapoptotic activity of bortezomib in multiple myeloma cells Leuk. Lymphoma 2009 50 974 984 10.1080/10428190902895780 19391038 113. Huang X. Gu H. Zhang E. Chen Q. Cao W. Yan H. Chen J. Yang L. Lv N. He J. …

Integrative Transcriptomic and Machine-Learning Analysis Reveals Immune-Inflammatory and Stress-Response Alterations in MRONJ.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive and antiangiogenic therapies, yet its molecular mechanisms remain poorly defined. The present study employed an analysis of microarray data (GSE7116) from peripheral blood mononuclear cells of patients with multiple myeloma, myeloma patients with MRONJ, and healthy controls. Differentially expressed genes were identified using the limma package, followed by functional enrichment analysis, weighted gene co-expression network analysis, and LASSO regression and CytoHubba network ranking. The predicti

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… We suggest that impaired stress-handling pathways—combining altered translational control, oxidative stress, and the unfolded protein response—may worsen immune-mediated tissue injury. There is mechanistic support for this idea. … The Role of the Unfolded Protein Response Pathway in Bone Homeostasis and Potential Therapeutic Target in Cancer-Associated Bone Disease Bone Res. 2025 13 76 10.1038/s41413-025-00457-6 40877255 PMC12394429 43. Tamaoka J. Takaoka K. Hattori H. Ueta M. Maeda H. Yamamura M. Yamanegi K. Noguchi K. …

Mass Spectrometry Approaches for Identification and Quantitation of Therapeutic Monoclonal Antibodies in the Clinical Laboratory.

Therapeutic monoclonal antibodies (MAbs) are an important class of drugs used to treat diseases ranging from autoimmune disorders to B cell lymphomas to other rare conditions thought to be untreatable in the past. Many advances have been made in the characterization of immunoglobulins as a result of pharmaceutical companies investing in technologies that allow them to better understand MAbs during the development phase. Mass spectrometry is one of the new advancements utilized extensively by pharma to analyze MAbs and is now beginning to be applied in the clinical laboratory setting. The rise

Role of bone marrow adipocytes in bone metastasis development and progression: a systematic review.

PurposeBone marrow adipocytes (BMAs) are the most plentiful cells in the bone marrow and function as an endocrine organ by producing fatty acids, cytokines, and adipokines. Consequently, BMAs can interact with tumor cells, influencing both tumor growth and the onset and progression of bone metastasis. This review aims to systematically evaluate the role of BMAs in the development and progression of bone metastasis.MethodsA comprehensive search was conducted on PubMed, Web of Science, and Scopus electronic databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analys

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… In another study, RNA sequencing analysis showed that exposure to adipocytes controls endoplasmic reticulum (ER) stress and the unfolded protein response signature in metastatic prostate cancer cells, partially through coordination by BIP/HSPA5, an ER chaperone ( 33 ). … Adipocyte-driven unfolded protein response is a shared transcriptomic signature of metastatic prostate carcinoma cells . …

Carfilzomib in multiple myeloma: unraveling cardiac toxicities - from mechanisms to diagnosis and management.

The survival rates of patients with hematological malignancies such as multiple myeloma have improved with advances in cancer treatment. However, the risk of cardiovascular disease associated with novel therapeutic agents, including proteasome inhibitors (PIs), is becoming increasingly evident. PIs act on proteasome peptidases, leading to cell cycle arrest or apoptosis. Carfilzomib (CFZ), an intravenously administered irreversible PI, exhibits pronounced cardiovascular toxicity that is characterized by heart failure, hypertension, arrhythmia, and ischemic heart disease (IHD). This review focus

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… CFZ = carfilzomib, eNOS = endothelial nitric oxide synthase, ER = endoplasmic reticulum, ROS = reactive oxygen species, UPR = unfolded protein response, CVAEs = cardiovascular adverse events, PP2A = protein phosphatase 2A. … This outcome subsequently triggers ER stress and the unfolded protein response (UPR), initiating a cascade of apoptotic events that culminate in the apoptosis of MM cells ( Merin and Kelly, 2014 ; Tang et al., 2024 ; Moreau et al., 2012 ). …

The role of CD8+ T cells in the immunoregulation of osteoporosis.

INTRODUCTION: Osteoporosis weakens the skeleton by lowering bone mass and damaging bone microarchitecture. A growing body of evidence points to disruptions in osteoimmune homeostasis as a key driver of this disease. In particular, apoptosis of bone cells and immune cells appears to be a critical contributing mechanism. Within the bone marrow, CD8+ T cells display a surprising functional duality: whether they protect bone or promote its loss depends heavily on local signals. Under healthy conditions or after mechanical loading, activated CD8+ T cells help maintain bone mass. They do so mainly b

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… Endoplasmic reticulum stress contributes to bone loss via effects on CD8 + T cells Work from several groups points to endoplasmic reticulum stress (ERS) and the resultant unfolded protein response (UPR) as important drivers of osteoimmune dysregulation in osteoporosis. … protein response; TCM, Central memory T cells; TEM, Effector memory T cells; TRM, Tissue-resident memory cells; MSC, Mesenchymal stromal cells; scRNAseq, Single-cell RNA sequencing. …

Pterostilbene in the Management and Treatment of Multiple Myeloma.

Multiple Myeloma is a malignancy of the plasma cells of the bone marrow. This cancer rapidly becomes refractory to many of the currently available chemotherapeutic regimens used against it, requiring an alternative option or supplementary therapy. Pterostilbene is a naturally occurring compound in a variety of commonly consumed plants that exhibits strong antioxidant properties and, lately, has shown increasing activity as an anti-neoplastic compound. A review of the literature published since 2015 on Google Scholar and PubMed was conducted, with a focus on randomized controlled trials and an

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… A way that these cells manage this increase in stress is through an expansion of their endoplasmic reticulum and an activation of the unfolded protein response pathway [ 18 ]. …

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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… In fact mitochondrial dysfunction induced by autophagy deficiency stimulated Fgf21 expression through activation of Atf4, a transcription factor activated by the Unfolded Protein Response pathway. …

Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familia

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… Changes to the unfolded protein response (UPR) and autophagy pathways reduce clearance of misfolded proteins [ 211 ]. … Elevated markers of the integrated stress response and unfolded protein response have been identified in postmortem samples from patients with nongenetic ALS [ 224 , 232 ]. …

Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application.

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and n

Динамические характеристики связующих остатков модернизируют связующие свойства нуклеиновой кислоты HIV-1 нуклеокапсидские белковые пальцы.

:: HIV-1 нуклеокапсидский белок (NC) — маленький основной протеин, содержащий two цинковые пальцы (ZF), отделенные короткой связкой. Она участвует в нескольких этапах цикла воспроизведения и выступает в качестве белка, сопровождающего нуклеиновую кислоту, в содействии переносу нуклеиновой кислотной нити во время обратной транскрипции. Недавний анализ three- размерные структуры комплексов NC-нуклеиновых кислот создали новое свойство: непараментированные гуанины, на которые распространяется НС, чаще добавляются в стерминальный цинковый палец (ZF2), чем в N-терминальный цинковый палец (ZF1). Несм

Monoclonal antibody and protein therapeutic formulations for subcutaneous delivery: high-concentration, low-volume vs. low-concentration, high-volume.

Biologic drugs are used to treat a variety of cancers and chronic diseases. While most of these treatments are administered intravenously by trained healthcare professionals, a noticeable trend has emerged favoring subcutaneous (SC) administration. SC administration of biologics poses several challenges. Biologic drugs often require higher doses for optimal efficacy, surpassing the low volume capacity of traditional SC delivery methods like autoinjectors. Consequently, high concentrations of active ingredients are needed, creating time-consuming formulation obstacles. Alternatives to tradition

Роль антиоксидантов в множестве миеломы: диагностика, прогнозирование и терапевтическое применение: обзор сюжета.

Множественная миэлома (ММ) — злокачественная клетка B-клеток с моноклональными плазменными клетками, производящими нефункциональные иммуноглобулины. Она по-прежнему неизлечима из-за de novo или приобретенного сопротивления злокачественных клеток стандартным химиотерапиям. Таким образом, понимание механизма терапевтического сопротивления имеет важнейшее значение для разработки более эффективных мер вмешательства и определения новых целей лечения. MM - это разнородная болезнь, характеризующаяся сложными генетическими изменениями, которые имеют решающее значение для прогнозирования стратификации.

Обзор " Метформин " и " нейродегенерация: всеобъемлющий обзор " .

В рамках этого всеобъемлющего обзора изучается терапевтический потенциал метаформина, хорошо зарекомендовавшего себя лекарство от диабета, при лечении нейродегенеративных расстройств. Первоначально использованная в качестве первой линии обработки для типа 2 диабет, недавние исследования начали изучать эффекты метаформина, выходящие за рамки метаболических расстройств, особенно его нейрозащитные способности против таких заболеваний, как болезнь Паркинсона, болезнь Альцгеймера, болезнь Хантингтона и множественный склероз. Ключевые выводы показывают, что нейрозащитный эффект метформина действует

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… Additionally, metformin directly alleviates endoplasmic reticulum (ER) stress in neurons by activating the AMPK pathway and enhancing the unfolded protein response (UPR), which is particularly significant for neurodegenerative conditions where protein misfolding plays a central role [ 106 , 107 , 108 … Under normal circumstances, cellular quality control systems—such as the autophagy–lysosomal pathway, the ubiquitin–proteasome system, molecular chaperones, and the endoplasmic reticulum stress response system, including the unfolded protein response—are essential in preventing protein aggregation and …