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Targeted protein degradation: advances in drug discovery and clinical practice.

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces chal

Radiolabeled Peptides and Antibodies in Medicine.

Radiolabeled peptides are a relatively new, very specific radiotracer group, which is still expanding. This group is very diverse in terms of peptide size. It contains very small structures containing several amino acids and whole antibodies. Moreover, radiolabeled peptides are diverse in terms of the binding aim and therapeutic or diagnostic applications. The majority of this class of radiotracers is utilized in oncology, where the same structure can be used in therapy and diagnostic imaging by varying the radionuclide. In this study, we collected new reports of radiolabeled peptide applicati

Spontaneous genomic alterations in a chimeric model of colorectal cancer enable metastasis and guide effective combinatorial therapy.

Colon cancer is the second most common cause of cancer mortality in the Western world with metastasis commonly present at the time of diagnosis. Screening for propagation and metastatic behavior in a novel chimeric-mouse colon cancer model, driven by mutant p53 and β-Catenin, led to the identification of a unique, invasive adenocarcinoma. Comparison of the genome of this tumor, CB42, with genomes from non-propagating tumors by array CGH and sequencing revealed an amplicon on chromosome five containing CDK6 and CDK14, and a KRAS mutation, respectively. Single agent small molecule inhibition of

Proceedings of Reanimation 2021, the French Intensive Care Society International Congress.

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Clinical developments in the treatment of relapsed or relapsed and refractory multiple myeloma: impact of panobinostat, the first-in-class histone deacetylase inhibitor.

BackgroundPanobinostat is a new agent for the treatment of relapsed and refractory multiple myeloma (rrMM) as part of a combination regimen. This article presents an overview of the mechanism of action, pharmacokinetics, safety, efficacy, patient care strategies, and role of the agent in treating rrMM patients.ResultsPanobinostat belongs to the class of drugs known as histone deacetylase inhibitors, and has high activity against Class I, II, and IV nonhistone deacetylases and histone deacetylases. It represents the first of its class to receive approval for use in MM, and received priority rev

Isatuximab in combination with cemiplimab in patients with relapsed/refractory multiple myeloma: A phase 1/2 study.

BACKGROUND: Given the incurable nature of multiple myeloma (MM), efforts are made to improve the efficacy of anti-CD38 monoclonal antibodies via combinations with other potentially synergistic therapies. This Phase 1/2 trial (NCT03194867) was designed to determine whether cemiplimab (anti-PD-1) enhances the anti-myeloma activity of isatuximab (anti-CD38) in patients with relapsed and refractory multiple myeloma (RRMM), to confirm the feasibility of the combination, determine its efficacy, and further evaluate its safety. METHODS: Patients received isatuximab 10 mg/kg once weekly for 4 weeks f

Mechanisms and effects of metformin on skeletal muscle disorders.

Skeletal muscle disorders are mostly genetic and include several rare diseases. With disease progression, muscle fibrosis and adiposis occur, resulting in limited mobility. The long course of these diseases combined with limited treatment options affect patients both psychologically and economically, hence the development of novel treatments for neuromuscular diseases is crucial to obtain a better quality of life. As a widely used hypoglycemic drug in clinical practice, metformin not only has anti-inflammatory, autophagy-regulating, and mitochondrial biogenesis-regulating effects, but it has a

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… Wang et al. showed that metformin, as a potential specific dual mTORC1/2 inhibitor, downregulates p-mTOR (Se-2448), p-P70 S6K, p-4 EBP1, and p-AKT (Ser 473) expression through AMPK activation-mediated mTORC1/mTORC2 inhibition, induces autophagy, and causes cell cycle arrest in the G0/G1 phase of myeloma … Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the Ampk/Mtorc1 and Mtorc2 pathways. J Exp Clin Cancer Res. (2018) 37:63. doi: 10.1186/s13046-018-0731-5 55. Vijayan V, Verstreken P. Autophagy in the presynaptic compartment in health and disease. …

Monitoring residues of pesticides in food in Brazil: A multiscale analysis of the main contaminants, dietary cancer risk estimative and mechanisms associated.

IntroductionPesticides pose a risk for cancer development and progression. People are continuously exposed to such substances by several routes, including daily intake of contaminated food and water, especially in countries that are highly pesticide consumers and have very permissive legislation about pesticide contamination as Brazil. This work investigated the relationship among pesticides, food contamination, and dietary cancer risk.MethodsAnalyzed two social reports from the Brazilian Government: the Program for Analysis of Residues of Pesticides in Food (PARA) and The National Program for

Bortezomib treatment causes long-term testicular dysfunction in young male mice.

BackgroundWith increased long-term survivors of childhood cancer patients, therapy-associated infertility has become one of the most common late side-effects and significantly affects their life-quality. Therefore, evaluation of anti-cancer agents on male reproduction and infertility prevention are urgently demanding. The proteasome inhibitor bortezomib has been launched in clinical trials for childhood cancers, however, its potential side effects on reproduction have so far been neither investigated experimentally nor reported in treated children. Thus the present study is designed to explore

New Treatment Strategies for IgA Nephropathy: Targeting Plasma Cells as the Main Source of Pathogenic Antibodies.

Immunoglobulin A nephropathy (IgAN) is a rare autoimmune disorder and the leading cause of biopsy-reported glomerulonephritis (GN) worldwide. Disease progression is driven by the formation and deposition of immune complexes composed of galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1 autoantibodies (anti-Gd-IgA1 antibodies) in the glomeruli, where they trigger complement-mediated inflammation that can result in loss of kidney function and end-stage kidney disease (ESKD). With the risk of progression and limited treatment options, there is an unmet need for therapies that address the formation of

Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review.

Upon the induction of DNA damage, the chromatin structure unwinds to allow access to enzymes to catalyse the repair. The regulation of the winding and unwinding of chromatin occurs via epigenetic modifications, which can alter gene expression without changing the DNA sequence. Epigenetic mechanisms such as histone acetylation and DNA methylation are known to be reversible and have been indicated to play different roles in the repair of DNA. More importantly, the inhibition of such mechanisms has been reported to play a role in the repair of double strand breaks, the most detrimental type of DN

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… NHEJ is the only available pathway in the G0 to G1 phases of the cell cycle. In contrast to HR, it does not use a homologous sister chromatin to fix DSBs, making it a potentially error-prone mechanism ( Shrivastav et al., 2008 ; Jekimovs et al., 2014 ). …

Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgen

Targeting the FGFR signaling pathway in cholangiocarcinoma: promise or delusion?

Cholangiocarcinoma (CCA) is a refractory cancer with limited treatment options and poorly understood molecular mechanisms underlying tumor development. The most effective treatment is surgical resection; however, patients are highly prone to recurrence. Moreover, considering that most patients are diagnosed in advanced stages, treatment options are restricted to palliative care, which results in poor prognosis. Due to the limited effect of chemotherapy and radiotherapy, targeted therapy is becoming a hot topic in the field of biliary cancer treatment. The fibroblast growth factor/fibroblast gr

Safety and Feasibility of Fasting-Mimicking Diet and Effects on Nutritional Status and Circulating Metabolic and Inflammatory Factors in Cancer Patients Undergoing Active Treatment.

In preclinical studies, fasting was found to potentiate the effects of several anticancer treatments, and early clinical studies indicated that patients may benefit from regimes of modified fasting. However, concerns remain over possible negative impact on the patients' nutritional status. We assessed the feasibility and safety of a 5-day "Fasting-Mimicking Diet" (FMD) as well as its effects on body composition and circulating growth factors, adipokines and cyto/chemokines in cancer patients. In this single-arm, phase I/II clinical trial, patients with solid or hematologic malignancy, low nutr

Low-dose daratumumab and bortezomib for the treatment of proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a case report.

BACKGROUND: Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is an exceptionally rare glomerular disease, accounting for only 0.17-3.7% of all renal biopsies, and no consensus-based treatment algo-rithm has been established. Although daratumumab, a humanized anti-CD38 monoclonal antibody, has shown promising efficacy in PGNMID, the existing evidence is limited to small case series using standard-dose regimens (16 mg/kg). Critically, data on reduced-dose daratumumab in elderly patients with CyBorD-refractory disease and multiple comorbidities remain scarce. This

Rice bran arabinoxylan compound as a natural product for cancer treatment - an evidence-based assessment of the effects and mechanisms.

ContextRice bran arabinoxylan compound (RBAC) is a natural immunomodulator with anticancer properties.ObjectiveThis study critically evaluates the available evidence on the biological pathways of RBAC and its effects on cancer treatment.MethodsThis secondary analysis of a scoping review includes studies evaluating the mechanisms of RBAC on healthy or malignant cells, animal models, or humans for cancer prevention or treatment. Data from randomized controlled trials on survival and quality of life outcomes were subjectd to meta analysis.ResultsThe evidence synthesis was based on 38 articles. RB

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… Swiss albino mice + SEC | RBAC markedly increased cell-cycle arrest in the sub-G1 phase was detected by 102% ( p < 0.01) in the RBAC group compared to the control. RBAC treatment also increased the AI/PrI ratio by 2-fold ( p < 0.01). … RBAC significantly ( p < 0.01) upregulated p53, Bax, and caspase-3 while downregulated Bcl-2 gene expression. | Badr El-Din et al. ( 2019 ) 8 | Biobran MGN-3 (25 mg/kg BW i.p. 5 ×/week, either for 12 or 22 weeks) | Wistar albino rats + carcinogen (NDEA + CCl 4 ) | Cell-cycle arrest in the sub-G1 phase …

Changing paradigm in the treatment of amyloidosis: From disease-modifying drugs to anti-fibril therapy.

Cardiac amyloidosis is a rare, debilitating, and usually fatal disease increasingly recognized in clinical practice despite patients presenting with non-specific symptoms of cardiomyopathy. The current standard of care (SoC) focuses on preventing further amyloid formation and deposition, either with anti-plasma cell dyscrasia (anti-PCD) therapies in light-chain (AL) amyloidosis or stabilizers of transthyretin (TTR) in transthyretin amyloidosis (ATTR). The SoC is supplemented by therapies to treat the complications arising from organ dysfunction; for example, heart failure, arrhythmia, and prot

Adjuvant Properties of Caffeic Acid in Cancer Treatment.

Caffeic acid (CA) is a polyphenol belonging to the phenylpropanoid family, commonly found in plants and vegetables. It was first identified by Hlasiwetz in 1867 as a breakdown product of caffetannic acid. CA is biosynthesized from the amino acids tyrosine or phenylalanine through specific enzyme-catalyzed reactions. Extensive research since its discovery has revealed various health benefits associated with CA, including its antioxidant, anti-inflammatory, and anticancer properties. These effects are attributed to its ability to modulate several pathways, such as inhibiting NFkB, STAT3, and ERK

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… . | Not specified | TRF, CA, and CIS synergistically enhanced late-phase apoptosis and improved cell cycle arrest in the G0/G1 phase. …

Chemotherapy-induced neuropathies-a growing problem for patients and health care providers.

IntroductionChemotherapy-induced neuropathies are one of the most common side effects of cancer treatment, surpassing bone marrow suppression and kidney dysfunction. Chemotherapy effects on the nervous system vary between different classes of drugs and depend on specific chemical and physical properties of the drug used. The three most neurotoxic classes of anti-cancer drugs are: platinum-based drugs, taxanes, and thalidomide and its analogs; other, less neurotoxic but also commonly used drugs are: bortezomib, ixabepilone, and vinca alkaloids.MethodsHere, in this paper, based on our experience

Lithium: A Promising Anticancer Agent.

Lithium is a therapeutic cation used to treat bipolar disorders but also has some important features as an anti-cancer agent. In this review, we provide a general overview of lithium, from its transport into cells, to its innovative administration forms, and based on genomic, transcriptomic, and proteomic data. Lithium formulations such as lithium acetoacetate (LiAcAc), lithium chloride (LiCl), lithium citrate (Li3C6H5O7), and lithium carbonate (Li2CO3) induce apoptosis, autophagy, and inhibition of tumor growth and also participate in the regulation of tumor proliferation, tumor invasion, and