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JCMM Annual Review on Advances in Biotechnology for the Treatment of Haematological Malignancies: A Review of the Latest In-Patient Developments 2024-2025.

Advances in biotechnology are set to revolutionise the treatment of haematological malignancies. Current treatments have limited efficacy due to their high toxicity and poor long-term outcomes, particularly in acute myeloid leukaemia (AML). In 2024-2025, emerging targeted therapies promise improved results with reduced adverse effects. This review is the first of an annual series exploring the latest in-patient developments in several key areas, focusing on mechanisms. We present advances in the use and action of several therapies including epigenetic modulators, protein degraders, apoptotic i

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming.

Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiatio

Замена иммуноглобулина: Понятия управления несколькими миеломами.

Immunoglobulin (Ig) - заместительная терапия (IGRT) - состоит из применения низкодозированных поликлонных иг человека для лечения первичной и вторичной гипогаммаглобулинемии, которая связана с периодическими инфекциями и иммунной дисфункцией. ИГРТ восстанавливает физиологические уровни антител и вызывает иммуномумудуляторный эффект путем укрепления клеток иммунного эффекта, тем самым уменьшая инфекцию. Здесь мы описываем фармакологию различных составов иг с уделением особого внимания их механизму действий как низкодозированный ИГРТ, включая прямой антимикробный эффект и иммунодуляторную функци

Гипоксия в множестве склерозов.

Низкая доступность кислорода (гипоксии) является заметной, но плохо понимаемой особенностью множественного склероза (МС). Неизвестно, вызывает ли гипоксия патологию и симптомы MS или она является следствием других патологических явлений, таких, как воспаление и сосудистая дисфункция. Здесь мы резюмируем имеющуюся литературу о взаимосвязи между гипоксией и как патологическими, так и симптомными характеристиками MS. Острая экологическая гипоксия (т.е. высота) может вызвать или облегчить события, связанные с MS, возможно, путем усиления гипоксии тканей в центральной нервной системе. Соответственн

Using ncRNAs as Tools in Cancer Diagnosis and Treatment-The Way towards Personalized Medicine to Improve Patients' Health.

Although the first discovery of a non-coding RNA (ncRNA) dates back to 1958, only in recent years has the complexity of the transcriptome started to be elucidated. However, its components are still under investigation and their identification is one of the challenges that scientists are presently facing. In addition, their function is still far from being fully understood. The non-coding portion of the genome is indeed the largest, both quantitatively and qualitatively. A large fraction of these ncRNAs have a regulatory role either in coding mRNAs or in other ncRNAs, creating an intracellular

Painful boney metastases.

Boney metastasis may lead to terrible suffering from debilitating pain. The most likely malignancies that spread to bone are prostate, breast, and lung. Painful osseous metastases are typically associated with multiple episodes of breakthrough pain which may occur with activities of daily living, weight bearing, lifting, coughing, and sneezing. Almost half of these breakthrough pain episodes are rapid in onset and short in duration and 44% of episodes are unpredictable. Treatment strategies include: analgesic approaches with "triple opioid therapy", bisphosphonates, chemotherapeutic agents, ho

The multiple roles of interferon regulatory factor family in health and disease.

Interferon Regulatory Factors (IRFs), a family of transcription factors, profoundly influence the immune system, impacting both physiological and pathological processes. This review explores the diverse functions of nine mammalian IRF members, each featuring conserved domains essential for interactions with other transcription factors and cofactors. These interactions allow IRFs to modulate a broad spectrum of physiological processes, encompassing host defense, immune response, and cell development. Conversely, their pivotal role in immune regulation implicates them in the pathophysiology of v

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… In U937 cells treated with PMA, both IRF1 and IRF2 undergo acetylation facilitated by p300 and p300/ CREB-binding protein (CBP)-associated factor (PCAF). 136 The p300-mediated IRF1 acetylation sites include the N-terminal Lys39 and Lys78. 137 In addition, IRF1 can be specifically acetylated by KAT8 at …

Future perspectives in melanoma research: meeting report from the "Melanoma Bridge", Napoli, December 5th-8th 2013.

The fourth "Melanoma Bridge Meeting" took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers.

The epigenetic revolution in hematology: from benchside breakthroughs to clinical transformations.

The field of hematology has experienced a substantial evolution with the acknowledgment of epigenetic processes as essential factors in the development of hematological malignancies. This review article examines the influence of epigenetic alterations, namely DNA methylation and histone modifications, on the onset and advancement of conditions such as acute myeloid leukemia and myelodysplastic syndromes. We discuss how these epigenetic modifications lead to the deregulation of gene expression, eventually promoting leukemogenesis. The emergence of epigenetic therapies, such as DNA methyltransfe

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… Abbreviation: DNMTs: DNA methyltransferases; KMTs: Lysine methyltransferases; NSD: Nuclear SET domain; PRMTs: Protein arginine methyltransferases; CBP: CREB-binding protein; MBD: methyl-CpG-binding domain proteins; ZBTB: Zinc finger and BTB domain; BET: Bromodomain (BRD) and extra-terminal; IDH: Isocitrate …

AIMP1 promotes multiple myeloma malignancy through interacting with ANP32A to mediate histone H3 acetylation.

BackgroundMultiple myeloma (MM) is the second most common hematological malignancy. An overwhelming majority of patients with MM progress to serious osteolytic bone disease. Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) participates in several steps during cancer development and osteoclast differentiation. This study aimed to explore its role in MM.MethodsThe gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis. Enzyme-linked immunosorbent assay, immunohistochemistry, and Western blotti

Absence of Biomarker-Driven Treatment Options in Small Cell Lung Cancer, and Selected Preclinical Candidates for Next Generation Combination Therapies.

Lung cancer is the second most common cancer in the United States, and small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. In SCLC, more than other malignancies, the standard of care is based on clinical demonstration of efficacy, and less on a mechanistic understanding of why certain treatments work better than others. This is in large part due to the virulence of the disease, and lack of clinically or biologically relevant biomarkers beyond routine histopathology. While first line therapies work in the majority of patients with extensive stage disease, development of re

Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue.

In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called 'master modulators' of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogram

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… Evidence for involvement of activator protein-1 and CREB-binding protein/p300. J. Biol. Chem. 2001;276:12440–12448. doi: 10.1074/jbc.M007237200. 32. Badawi A.F., Badr M.Z. …

Chemokines in COPD: From Implication to Therapeutic Use.

: Chronic Obstructive Pulmonary Disease (COPD) represents the 3rd leading cause of death in the world. The underlying pathophysiological mechanisms have been the focus of extensive research in the past. The lung has a complex architecture, where structural cells interact continuously with immune cells that infiltrate into the pulmonary tissue. Both types of cells express chemokines and chemokine receptors, making them sensitive to modifications of concentration gradients. Cigarette smoke exposure and recurrent exacerbations, directly and indirectly, impact the expression of chemokines and chem

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… TNFα and IFNγ synergistically enhance transcriptional activation of CXCL10 in human airway smooth muscle cells via STAT-1, NF-κB, and the transcriptional coactivator CREB-binding protein J. Biol. Chem. 2010 285 29101 29110 10.1074/jbc.M109.099952 20833730 PMC2937941 121. Cole A.M. Ganz T. …

Combination of the PI3K inhibitor Idelalisib with the conventional cytostatics cytarabine and dexamethasone leads to changes in pathway activation that induce anti-proliferative effects in B lymphoblastic leukaemia cell lines.

BackgroundThe introduction of combined conventional cytostatics and pathway-specific inhibitors has opened new treatment options for several cancer types including hematologic neoplasia such as leukaemias. As the detailed understanding of the combination-induced molecular effects is often lacking, the identification of combination-induced molecular mechanisms bears significant value for the further development of interventional approaches.MethodsCombined application of conventional cytostatic agents (cytarabine and dexamethasone) with the PI3K-inhibitor Idelalisib was analysed on cell-biologic

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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… Emerging research suggests that the lysine acetyltransferase (KAT) family can catalyze various acylations, including those by p300/CREB-binding protein (CBP) and Gcn5-related N-acetyltransferase (GNAT). …

Aging modulation of the immune system and immunotherapy efficacy in cancer.

Immunosenescence is characterized by immune decline and chronic inflammation. With advancing age, the incidence of tumors increases significantly. Understanding how immunosenescence influences the initiation and progression of tumors, as well as its implications for tumor immunotherapy, has become a matter of urgent importance. This review begins with an analysis of the phenotypic changes and underlying mechanisms associated with immune system and immune cell aging, and further explores the interplay between immunosenescence and tumorigenesis. Evidence indicates that cytokines, cell interactio

Ранняя реакция на рост Gene 1 Выгоды Аутоиммунная болезнь путем поощрения дифференциации ячеек в качестве регулятора Foxp3.

Foxp3+ Регулирующие T (Treg) клетки, как один из подтипов CD4+T клеток, являются важнейшим сторожем в патогенезе самоантигенных реактивных заболеваний. В этом контексте мы продемонстрировали, что выборочная абляция гена раннего реагирования роста 1 (Egr-1) в CD4+T клеток усугубила экспериментальный аутоиммунный энцефаломиелит (EAE) в мюриновых моделях. Отсутствие Egr-1 в клетках CD4+T, полученное из мышей EAE и наивных клеток CD4+T, препятствовало дифференциации и влиянию Treg. Важно то, что в CD4+T клеток нескольких склерозных пациентов как Egr-1, так и Foxp3 было обнаружено снижение. Дальней

HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy that occurs in HTLV-1 infected patients. Most ATL patients develop osteolytic lesions and hypercalcemia of malignancy, causing severe skeletal related complications and reduced overall survival. The HTLV-1 virus encodes 2 viral oncogenes, Tax and HBZ. Tax, a transcriptional activator, is critical to ATL development, and has been implicated in pathologic osteolysis. HBZ, HTLV-1 basic leucine zipper transcription factor, promotes tumor cell proliferation and disrupts Wnt pathway modulators; however, its role in ATL induced o

Ремонт тканей в центральной нервной системе: эпигенетическое программирование регуляторных Т клеток.

Регулирующие Т клетки хорошо известны своей иммуномодуляционной ролью, но также их регенеративная функция все чаще признается в различных типах тканей, включая скелетные мышцы, легкие и центральную нервную систему (ЦНС). В CNS Tregs, как было показано, поощряют дифференциацию олигодендроцитов в прекурсорных клетках, и их взаимодействие с микроглией поддерживает стимулирующую регенеративную микроокружную среду в мозгу. Подавляющая функция Tregs в значительной степени зависит от эпигенетической сигнатуры, в частности метилации ДНК, определенной сети связанных с Treg генов, включая FOXP3, CTLA4,

Reactive oxygen species (ROS) in cancer: from mechanism to therapeutic implications.

Reactive oxygen species (ROS) act as critical secondary messengers in various intracellular signaling pathways that regulate cellular proliferation, differentiation, and survival under normal physiological conditions. However, dysregulation of redox signaling-driven by genetic mutations, epigenetic alterations, and posttranscriptional or posttranslational modifications-plays a central role in malignant transformation and cancer progression. Cancer cells typically exhibit elevated basal ROS levels due to increased metabolic activity, mitochondrial dysfunction, and oncogene activation. This mode