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PTH1R-CaSR Cross Talk: New Treatment Options for Breast Cancer Osteolytic Bone Metastases.

Metastatic breast cancer (BrCa) is currently incurable despite great improvements in treatment of primary BrCa. The incidence of skeletal metastases in advanced BrCa occurs up to 70%. Recent findings have established that the distribution of BrCa metastases to the skeleton is not a random process but due to the favorable microenvironment for tumor invasion and growth. The complex interplay among BrCa cells, stromal/osteoblastic cells, and osteoclasts in the osseous microenvironment creates a bone-tumor vicious cycle (a feed-forward loop) that results in excessive bone destruction and progressi

Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes.

The complex mechanistic array underlying the pathogenesis of myelodysplastic syndrome (MDS) is still unclear. Although dysregulations of different signaling pathways involved in MDS have been described, the identification of specific biomarkers and therapy targets remains an important task in order to establish novel therapeutic approaches. Here, we demonstrated that the Shh signaling pathway is active in MDS and correlated it with disease progression. Additionally, the knockdown of Gli1 significantly inhibited cell proliferation in vitro and in vivo. Gli1 silencing also induced apoptosis and

Natural-History Mapping of Lysosomal Storage Disorders (LSDs): Gaucher Disease as a Model for Precision Care.

Natural-history datasets have become pivotal for drug development and for shaping clinical-practice guidelines in rare diseases, yet many lysosomal storage disorders would benefit from deep phenotyping and modern analytic methods. Our objective was to integrate the past decade of genomic, cellular, treatment-outcome, and regulatory advances into a practical framework for capturing and interpreting natural-history data, using Gaucher disease (GD) as a paradigm. We reviewed more than 300 peer-reviewed articles (2005-2025), FDA guidance documents, and output from large real-world registries. Part

Strategies for p53 Activation and Targeted Inhibitors of the p53-Mdm2/MdmX Interaction.

p53 is a tumor suppressor gene and is regarded as one of the most crucial genes in protecting humans against cancer. The protein Mdm2 and its homolog MdmX serve as negative regulators of p53. In nearly half of cancer cells, there is an overexpression of Mdm2 and MdmX, which inhibit p53 activity. Furthermore, Mdm2's E3 ubiquitin ligase activity promotes the ubiquitination and degradation of p53. Therefore, blocking the interaction between p53 and Mdm2/MdmX to prevent the degradation of wild-type p53 is an effective strategy for inhibiting tumor growth. This paper primarily discusses the regulat

Генетическая основа болезни.

Генетика в той или иной степени играет определенную роль во всех заболеваниях. Изменения в нашей ДНК и различия в том, как эта ДНК функционирует (одиночка или комбинация), наряду с окружающей средой (которая включает образ жизни), способствуют болезнетворным процессам. В рамках этого обзора изучается генетическая основа человеческих заболеваний, включая однородные генетические расстройства, хромосомные диспропорции, эпигенетические, раковые и сложные расстройства, и рассматривается вопрос о том, каким образом наше понимание и технологические достижения могут быть использованы для обеспечения н

The insulin-like growth factor system and its receptors: A potential novel anticancer target.

The current generation of novel anticancer therapies that are in preclinical and clinical development are based on exploiting our increasing understanding of the molecular and cellular basis of cancer development and progression. Accelerated rates of cell division and proliferation have been postulated to predispose to the development of malignant disease. The insulin-like growth factor (IGF) signaling system has an important physiological role in regulating cellular proliferation and apoptosis. This function has led to considerable interest in its relevance to neoplasia over the last decade.

Targeting Macrophage Migration Inhibitory Factor in Acute Pancreatitis and Pancreatic Cancer.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of inflammation and cancer. It is produced by various cells and circulating MIF has been identified as a biomarker for a range of diseases. Extracellular MIF mainly binds to the cluster of differentiation 74 (CD74)/CD44 to activate downstream signaling pathways. These in turn activate immune responses, enhance inflammation and can promote cancer cell proliferation and invasion. Extracellular MIF also binds to the C-X-C chemokine receptors cooperating with or without CD74 to activate chemokine

FDA-Approved Drugs for Hematological Malignancies-The Last Decade Review.

Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug

Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis.

BackgroundZalypsis(®) is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing's sarcoma. However, the determinants of the response to Zalypsis are not well known. The identification of biomarkers for Zalypsis activity would also contribute to broaden the spectrum of tumors by selecting those patients more likely to respond to this therapy.MethodsUsing in vitro drug sensitivity data coupled with a set of molecular data from a panel of sarcoma cell lines, we developed molecular signatures that predict sensitivity to Zalypsis. We verified

CD47-Targeted Therapy in Cancer Immunotherapy: At a Crossroads of Promise and Challenge.

Cluster of differentiation 47 (CD47), an immune checkpoint commonly referred to as the "don't eat me" signal, plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells (DCs). Although early enthusiasm drove broad clinical development, recent discontinuations of major CD47-targeted programs have prompted re-evaluation of its therapeutic potential. The purpose of this commentary is to contextualize the setbacks observed with first-generation CD47 inhibitors and to highlight strategie

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… PARP inhibition synergizes with CD47 blockade to promote phagocytosis by tumor-associated macrophages in homologous recombination-proficient tumors. Life Sci. 2023;326(4):121790. doi: 10.1016/j.lfs.2023.121790; 49. Bian H, Shen Y, Zhou Y, Nagle D, Guan Y, Zhang W, et al. …

Role of Dietary Antioxidants in p53-Mediated Cancer Chemoprevention and Tumor Suppression.

Cancer arises through a complex interplay between genetic, behavioral, metabolic, and environmental factors that combined trigger cellular changes that over time promote malignancy. In terms of cancer prevention, behavioral interventions such as diet can promote genetic programs that may facilitate tumor suppression; and one of the key tumor suppressors responsible for initiating such programs is p53. The p53 protein is activated by various cellular events such as DNA damage, hypoxia, heat shock, and overexpression of oncogenes. Due to its role in cell fate decisions after DNA damage, regulato

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… All these factors lead to the moderation of nucleotide bases of DNA, resulting in DNA strand breakage [ 33 , 46 ]. p53 is active in regulating DNA damage, and its key function is to promote nonhomologous end joining (NHEJ) and suppress homologous recombination (HR). …

Current Status of COVID-19 Therapies and Drug Repositioning Applications.

The rapid and global spread of a new human coronavirus (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Drug repositioning is an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. Here, we review current information concerning the global health issue of COVID-19 including promising approved drugs and ongoing clinical trials for prospective treatment options. In addition, we describe computational approaches to be used in dru

New Insights and Future Perspectives of APRIL in IgA Nephropathy.

IgA nephropathy (IgAN) is characterized by immune-mediated glomerulonephritis, with the accumulation of galactose-deficient IgA1 (Gd-IgA1) in the glomeruli and increased levels of circulating Gd-IgA1 and Gd-IgA1-containing immune complexes. An incomplete understanding of the underlying mechanisms and differences in clinical and pathological features between individuals and ethnicities has contributed to the lack of established treatments for IgAN. A tumor necrosis factor (TNF) family member, a proliferation-inducing ligand (APRIL), is a crucial cytokine essential for the generation and surviva

Механистические понимания и достижения биконкретной T-клетки, использующей антителную терапию в мультимиеломе.

Множественная миелома (ММ) — клональная порча неизмеримо дифференцированных плазменных клеток, характеризующаяся инфильтрацией костного мозга и чрезмерным производством моноклонных иммуноглобулинов, что приводит к повреждению конечной формы, например остеолитических повреждений костей. Несмотря на значительный терапевтический прогресс, достигнутый с протеаозными ингибиторами, иммуномодуляционными препаратами и anti-CD38 Моноклональные антитела, множественная миелома остаются неизлечимыми, а результаты для трехклассных пациентов-восстановителей остаются мрачными, при этом медиана выживаемости н

New understanding of the damage of SARS-CoV-2 infection outside the respiratory system.

Since early December 2019, a number of pneumonia cases associated with unknown coronavirus infection were identified in Wuhan, China, and many additional cases were identified in other regions of China and in other countries within 3 months. Currently, more than 80,000 cases have been diagnosed in China, including more than 3000 deaths. The epidemic is spreading to the rest of the world, posing a grave challenge to prevention and control. On February 12, 2020, the International Committee on Taxonomy of Viruses and the World Health Organization officially named the novel coronavirus and associa

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear o

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… EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient Ovarian Cancers to PARP Inhibition. Cancer Cell. 2020;37:157–167.e156. doi: 10.1016/j.ccell.2019.12.015. 39. … Panobinostat enhances olaparib efficacy by modifying expression of homologous recombination repair and immune transcripts in ovarian cancer. Neoplasia. 2022;24:63–75. doi: 10.1016/j.neo.2021.12.002. 79. Berdeja J.G., Laubach J.P., Richter J., Stricker S., Spencer A., Richardson P.G., Chari A. …

The Proliferative and Apoptotic Landscape of Basal-like Breast Cancer.

Basal-like breast cancer (BLBC) is an aggressive molecular subtype that represents up to 15% of breast cancers. It occurs in younger patients, and typically shows rapid development of locoregional and distant metastasis, resulting in a relatively high mortality rate. Its defining features are that it is positive for basal cytokeratins and, epidermal growth factor receptor and/or c-Kit. Problematically, it is typically negative for the estrogen receptor and human epidermal growth factor receptor 2 (HER2), which means that it is unsuitable for either hormone therapy or targeted HER2 therapy. As

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… Dysfunction in the BRCA1 gene results in ineffective homologous recombination, and in addition, defects in the homologous recombination repair mechanisms can also be present in BLBCs that do not present with BRCA1 mutation, a concept termed ‘BRCAness’ [ 13 ]. … BLBCs also have a high frequency of BRCA1 mutation and promoter methylation [ 74 ], which exacerbates DNA damage by disabling homologous recombination. A consequence of this is that DNA damage checkpoints are dysregulated in BLBC to protect the cells from excessive cell death. …

Структурная основа для селективного метилирования 5-carboxymethoxyuridine В модификацию tRNA.

Постранарные модификации tRNA широко сохранены во всех сферах жизни. Особенно те из них, которые происходят в антикодоне, часто модифицируют эффективность перевода. Производственные показатели 5-hydroxyuridine конкретно встречаются в бактериальных тРНК, где 5-methoxyuridine и 5-carboxymethoxyuridine , являются основными видами бактерий с положительной и отрицательной массой, соответственно. В некоторых видах тРНК, 5- Карбоксиметоксиуридин может быть дополнительно метилирован CMOM для образования метилэстера. В этом докладе мы представляем рентгеновскую кристаллическую структуру Escherichia col

Profile of eliglustat tartrate in the management of Gaucher disease.

Gaucher disease (GD) is a lysosomal storage disorder caused by the deficient activity of acid beta glucosidase, with consequent accumulation of glucosylceramide in the spleen, liver, bone marrow, and various organs and tissues. Currently, the gold standard for GD treatment is enzyme replacement therapy (ERT). The efficacy of ERT in improving or stabilizing the visceral and hematological symptoms of GD is well-proven. However, since ERT has to be administered by frequent intravenous infusions, this therapeutic approach has an important impact on the patient's quality of life. Eliglustat tartrat

Current advances of CRISPR-Cas technology in cell therapy.

CRISPR-Cas is a versatile genome editing technology that has been broadly applied in both basic research and translation medicine. Ever since its discovery, the bacterial derived endonucleases have been engineered to a collection of robust genome-editing tools for introducing frameshift mutations or base conversions at site-specific loci. Since the initiation of first-in-human trial in 2016, CRISPR-Cas has been tested in 57 cell therapy trials, 38 of which focusing on engineered CAR-T cells and TCR-T cells for cancer malignancies, 15 trials of engineered hematopoietic stem cells treating hemog

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… Regulation of homologous recombination in eukaryotes. Annu. Rev. Genet. 2010;44:113–139. doi: 10.1146/annurev-genet-051710-150955. Hoban M.D., Lumaquin D., Kuo C.Y., Romero Z., Long J., Ho M., Young C.S., Mojadidi M., Fitz-Gibbon S., Cooper A.R., et al. …