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A novel mechanism in regulating drug sensitivity, growth, and apoptosis of bortezomib-resistant multiple myeloma cells: the USP4/KLF2/HMGA2 cascade.

BackgroundMultiple myeloma (MM) is a malignant disorder originating from plasma cells. Bortezomib (BTZ) resistance has become a huge obstacle to MM treatment. Herein, we elucidated the action of Kruppel-like factor 2 (KLF2), a crucial transcription factor (TF), on BTZ resistance of MM.MethodsTwo BTZ-resistant cell lines (MM1.S/BTZ and NCI-H929/BTZ) were generated and used. KLF2 mRNA was quantified by quantitative PCR, and protein expression was analyzed by immunoblotting. MTT cell cytotoxicity assay was used to test BTZ sensitivity. Cell growth was detected by MTT and EdU assays. Flow cytometr

Kinase Inhibitors and Ovarian Cancer.

Ovarian cancer is fifth in the rankings of cancer deaths among women, and accounts for more deaths than any other gynecological malignancy. Despite some improvement in overall-(OS) and progression-free survival (PFS) following surgery and first-line chemotherapy, there is a need for development of novel and more effective therapeutic strategies. In this mini review, we provide a summary of the current landscape of the clinical use of tyrosine kinase inhibitors (TKIs) and mechanistic target of rapamycin (mTOR) inhibitors in ovarian cancer. Emerging data from phase I and II trials reveals that a

Precision Medicine in Inflammatory Bowel Disease: A Spotlight on Emerging Molecular Biomarkers.

Inflammatory bowel diseases (IBD) remain challenging in terms of understanding their causes and in terms of diagnosing, treating, and monitoring patients. Modern diagnosis combines biomarkers, imaging, and endoscopic methods. Common biomarkers like CRP and fecal calprotectin, while invaluable tools, have limitations and are not entirely specific to IBD. The limitations of existing markers and the invasiveness of endoscopic procedures highlight the need to discover and implement new markers. With an ideal biomarker, we could predict the risk of disease development, as well as the possibility of

Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans.

Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro-computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patie

CAR-Engineered Cell Therapies Beyond Cancer: Reprogramming Fibrosis and Immune-Mediated Inflammation.

Chimeric antigen receptor (CAR)-engineered cell therapies are being extended from hematological malignancies to autoimmune, inflammatory, and fibrotic diseases, although the maturity of evidence differs markedly among platforms and indications. Early clinical evidence from case reports, small case series, and early-phase trials suggests that CD19- or BCMA-directed CAR-T cells can induce deep B-cell or plasma-cell depletion and sustained remission in selected patients with refractory autoimmune diseases; however, their comparative efficacy, durability, and long-term safety remain incompletely d

Tumor Cell Survival Factors and Angiogenesis in Chronic Lymphocytic Leukemia: How Hot Is the Link?

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic CD5+/CD19+ B lymphocytes in the blood. These cells migrate to and proliferate in the bone marrow and lymphoid tissues. Despite the development of new therapies for CLL, drug resistance and disease relapse still occur; novel treatment approaches are therefore still needed. Inhibition of the angiogenesis involved in the progression of CLL might be a relevant therapeutic strategy. The literature data indicate that vascular endothelial growth factor, angiopoietin-2, and matrix metalloproteinase-9 are pro-angiogen

Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies.

Chemotherapy (CT) is one of the flagship options for the treatment of cancers worldwide. It involves the use of cytotoxic anticancer agents to kill or inhibit the proliferation of cancer cells. However, despite its clinical efficacy, CT triggers side effect toxicities in several organs, which may impact cancer patient's quality of life and treatment outcomes. While the side effect toxicity is consistent with non-ferroptotic mechanisms involving oxidative stress, inflammation, mitochondrial impairment and other aberrant signalling leading to apoptosis and necroptosis, recent studies show that f

Exploiting artificial intelligence in precision oncology: an updated comprehensive review.

Precision oncology considers the genetic makeup of both the tumor and the cancer patient, medical history, clinical metadata, lifestyle and environmental factors. Thus, adoption of precision cancer medicine mandates sophisticated integrative analysis. Being a master in sorting and solving the puzzle pieces, artificial intelligence (AI)-powered frameworks emerged to fill the gap via executing multimodal analysis and generating meaningful outputs. Herein, we systematically discussed the opportunities and challenges of exploiting AI-assisted models in preclinical cancer research and in clinical o

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… HIBRID: a DL-based analysis of H&E stained whole slide images combined with circulating tumor DNA (which detects molecular residual disease) enhanced risk stratification in patients with stage II-IV colorectal cancer [ 126 ]. …

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project.

The Chimeric Antigen Receptor (CAR) T Cell Safety Database Project explored the use of cross-study safety data to identify risk factors associated with severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) after CAR T cell administration. Sponsors voluntarily submitted data for 1,926 subjects from 17 phases 1 and 2 studies (six acute lymphocytic leukemia [ALL], five non-Hodgkin's lymphoma [NHL], and six multiple myeloma [MM] studies). Subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. Subjects who received CAR T c

The Production Processes and Biological Effects of Intravenous Immunoglobulin.

Immunoglobulin is a highly diverse autologous molecule able to influence immunity in different physiological and diseased situations. Its effect may be visible both in terms of development and function of B and T lymphocytes. Polyclonal immunoglobulin may be used as therapy in many diseases in different circumstances such as primary and secondary hypogammaglobulinemia, recurrent infections, polyneuropathies, cancer, after allogeneic transplantation in the presence of infections and/or GVHD. However, recent studies have broadened the possible uses of polyclonal immunoglobulin showing that it ca

Появляющаяся роль BTK Inhibitors в многоразовом склерозе: от иммунобиологии к клиническому переводу.

Множественный склероз (MS), аутоиммунное заболевание, предполагает периферическую иммунную активацию, за которой следует воспаление CNS в разрозненной форме. Несмотря на то, что высокоэффективные методы коррекции заболеваний (HO-DMT) оказались эффективными в борьбе с рецидивами у пациентов с синдромом MS, они не позволяют эффективно ориентироваться на хроническую микрогильевую активацию и удушающие повреждения у пациентов с синдромом MS. Тейросиновые ингибиторы киназы Брютона (BTKis), которые являются перорально активными и способными пересечь мозговой барьер, были признаны эффективными для мо

Complete Blood Count Parameters and Bone Health: Clinical and Experimental Evidence.

Osteoporotic fractures pose a significant burden in aging populations, yet current assessment strategies may overlook systemic factors influencing bone health. Emerging evidence suggests that complete blood count (CBC) parameters, including red blood cell indices, white blood cell (WBC) counts and subtypes, and platelet counts, are associated with skeletal fragility and fracture risk. Anemia has been consistently linked to reduced bone mineral density and increased fracture susceptibility, potentially due to impaired oxygen delivery and osteoblast dysfunction. Elevated red cell distribution wi

The Circular Life of Human CD38: From Basic Science to Clinics and Back.

Monoclonal antibodies (mAbs) were initially considered as a possible "magic bullet" for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since canc

Biopharmaceutical and pharmacokinetic attributes to drive nanoformulations of small molecule tyrosine kinase inhibitors.

Buoyed by the discovery of small-molecule tyrosine kinase inhibitors (smTKIs), significant impact has been made in cancer chemotherapeutics. However, some of these agents still encounter off-target toxicities and suboptimal efficacies due to their inferior biopharmaceutical and/or pharmacokinetic properties. Almost all of these molecules exhibit significant inter- and intra-patient variations in plasma concentration-time profiles. Thus, therapeutic drug monitoring, dose adjustments and precision medicine are being contemplated by clinicians. Complex formulations or nanoformulation-based drug d

Exposome and unhealthy aging: environmental drivers from air pollution to occupational exposures.

The aging population worldwide is facing a significant increase in age-related non-communicable diseases, including cardiovascular and brain pathologies. This comprehensive review paper delves into the impact of the exposome, which encompasses the totality of environmental exposures, on unhealthy aging. It explores how environmental factors contribute to the acceleration of aging processes, increase biological age, and facilitate the development and progression of a wide range of age-associated diseases. The impact of environmental factors on cognitive health and the development of chronic age

Extraglandular Manifestations of Sjögren’s Syndrome (SS): Dermatologic, Arthritic, Endocrine, Pulmonary, Cardiovascular, Gastroenterology, Renal, Urology, and Gynecologic Manifestations

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Pituitary Adenylate Cyclase-Activating Polypeptide: 30 Years in Research Spotlight and 600 Million Years in Service.

Emerging from the depths of evolution, pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors (i.e., PAC1, VPAC1, VPAC2) are present in multicellular organisms from Tunicates to humans and govern a remarkable number of physiological processes. Consequently, the clinical relevance of PACAP systems spans a multifaceted palette that includes more than 40 disorders. We aimed to present the versatility of PACAP1-38 actions with a focus on three aspects: (1) when PACAP1-38 could be a cause of a malfunction, (2) when PACAP1-38 could be the cure for a malfunction, and (3) when PA

PPARs in Irradiation-Induced Gastrointestinal Toxicity.

The use of radiation therapy to treat cancer inevitably involves exposure of normal tissues. Although the benefits of this treatment are well established, many patients experience distressing complications due to injury to normal tissue. These side effects are related to inflammatory processes, and they decrease therapeutic benefit by increasing the overall treatment time. Emerging evidence indicates that PPARs and their ligands are important in the modulation of immune and inflammatory reactions. This paper discusses the effects of abdominal irradiation on PPARs, their role and functions in i

Diagnostic and Therapeutic Challenges in the Management of Intermediate and Frail Elderly Multiple Myeloma Patients.

Multiple myeloma (MM) mostly affects elderly patients, which represent a highly heterogeneous population. Indeed, comorbidities, frailty status and functional reserve may vary considerably among patients with similar chronological age. For this reason, the choice of treatment goals and intensity is particularly challenging in elderly patients, and it requires a multidimensional evaluation of the patients and the disease. In recent years, different tools to detect patient frailty have been developed, and the International Myeloma Working Group frailty score currently represents the gold standar

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