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Advancing CRISPR genome editing into gene therapy clinical trials: progress and future prospects.

Genome editing has recently evolved from a theoretical concept to a powerful and versatile set of tools. The discovery and implementation of CRISPR-Cas9 technology have propelled the field further into a new era. This RNA-guided system allows for specific modification of target genes, offering high accuracy and efficiency. Encouraging results are being announced in clinical trials employed in conditions like sickle cell disease (SCD) and transfusion-dependent beta-thalassaemia (TDT). The path finally led the way to the recent FDA approval of the first gene therapy drug utilising the CRISPR/Cas

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… Programmable nucleases enhance homologous recombination efficiency by at least 100-fold and/or activate the error-prone non-homologous end joining (NHEJ) mechanism (Ref 5 ). …

The mechanism of cytokine regulation of cancer occurrence and development in the tumor microenvironment and its application in cancer treatment: a narrative review.

Background and objectiveThe occurrence and development of tumors in human tissues widely depend on their surrounding environment, known as the tumor microenvironment (TME), which comprises various cells, molecules, and blood vessels. Through modifications, organization, and integration, these elements serve as potential therapeutic targets in anti-cancer therapy, supporting and promoting the proliferation, invasion, and metabolism of tumor cells. Cytokines within TME are responsible for immune cell activation, proliferation, and differentiation, thereby influencing the tumor's behavior. This a

Вирусная инфекция Эпштейна-Барра поощряет диагностику Т клеток в гуманизированной модели мыши множественного склероза.

Скрытая инфекция вируса Эпштейн-Барр (ЭБВ) является серьезным фактором риска для развития множественных склерозов (МС), хотя основополагающие механизмы остаются неясными. Для изучения этой связи мы спровоцировали экспериментальный аутоиммунный энцефаломиелит (EAE) в мышах с иммунодефицитными мышами, восстановленных с периферийными моноядерными клетками крови (PBMC) у лиц, которые имели или не имели историю заражения EBV и/или повторного образования MS (RMS). Мыши HuPBMC EAE, генерируемые EBV-серонегативными здоровыми донорами, были менее восприимчивы к возникновению серьезных неврологических с

Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function.

Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where it may function in regulating gene transcription. Using myeloma cell lines, we report here that heparanase enhances chromatin accessibility and confirm a previous report that it also upregulates the acetylation of histones. Employing the Multiple Myeloma Research Foundation CoMMpass datab

CS-6-induced p62 accumulation exacerbates DNA damage in colorectal cancer.

BACKGROUND: Gamabufotalin (CS-6), a bufadienolide derived from Chansu, has been reported to exhibit anti-tumor effects in various cancers, including glioblastoma, nonsmall cell lung cancer, and breast cancer. However,its role in colorectal cancer (CRC) remains unexplored. OBJECTIVE: Our study aimed to evaluate the inhibition of CS-6 to CRC cells by cell viability assay, colony formation assay, comet assay, and cell cycle analysis firstly. And its molecular mechanism was studied by immunofluorescence (IF) assay, western blot (WB) assay, siRNA transfection, protein-protein interaction (PPI) net

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… Furthermore, p62 exhibits dynamic associations with various pathways in case of severe DNA damage, associating with several DNA damage repair pathways, including homologous recombination repair, non-homologous recombination repair, and DNA damage response (DDR) pathways, activate autophagy to prevent …

Development and characterization of chimeric antigen receptor macrophages for amyloid clearance.

Systemic amyloidosis is a protein folding disorder characterized by the extracellular deposition of protein fibrils in tissues and vital organs, leading to dysfunction and mortality. While there are monoclonal antibody-based therapies that promote cell-mediated amyloid clearance in various stages of clinical development, there are currently no treatment options which focus on reducing the tissue amyloid burden. Therefore, the urgent need for a transformative approach to facilitate amyloid clearance and restore organ function remains paramount. We demonstrate that a short, polybasic peptide (p5

Monoclonal Antibodies Approved for Cancer Therapy

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Cytotoxicity of bendamustine, alone and in combination with novel agents, toward adult T-cell leukemia cells.

Adult T-cell leukemia/lymphoma (ATL) develops from the infection of T cells with human T lymphotropic virus type 1 (HTLV-1). There are an estimated 5-20 million HTLV-1 carriers worldwide and the patients are frequently observed in subtropical Africa, the Caribbean, Middle East, South America, and South West Japan. The prognosis of ATL remains dismal due to rapid acquired resistance to treatment with cytotoxic chemotherapeutic agents. In particular, the development of novel therapies for relapsed or refractory (R/R) ATL is an unmet need. Previous clinical trials revealed that bendamustine (BDM)

HMGB1: новая биомаркировка и лечебная цель аутоиммунной и аутовоспалительной кожных заболеваний.

Вставка 1 группы высокой подвижности (HMGB1) выражена почти во всех человеческих клетках. Во время активации клеток и клеточной смерти нуклеопротеин HMGB1 может перемещаться в внеклеточное пространство, тем самым посредничая ранним подстрекательским ответом как сигнализация или молекулярный рисунок, связанный с повреждением (DAMP). Внешнеклеточный HMGB1 взаимодействует с иммунными клетками, связываясь с системой распознавания рецепторов Toll-подобных (TLR), включая TLR2 и TLR4, и рецептором для современных продуктов для гликации (RAGE), тем самым содействуя иммунной реакции для защиты хоста от

Canine cancer immunotherapy studies: linking mouse and human.

Despite recent major clinical breakthroughs in human cancer immunotherapy including the use of checkpoint inhibitors and engineered T cells, important challenges remain, including determining the sub-populations of patients who will respond and who will experience at times significant toxicities. Although advances in cancer immunotherapy depend on preclinical testing, the majority of in-vivo testing currently relies on genetically identical inbred mouse models which, while offering critical insights regarding efficacy and mechanism of action, also vastly underrepresent the heterogeneity and co

Iron in the Tumor Microenvironment-Connecting the Dots.

Iron metabolism and tumor biology are intimately linked. Iron facilitates the production of oxygen radicals, which may either result in iron-induced cell death, ferroptosis, or contribute to mutagenicity and malignant transformation. Once transformed, malignant cells require high amounts of iron for proliferation. In addition, iron has multiple regulatory effects on the immune system, thus affecting tumor surveillance by immune cells. For these reasons, inconsiderate iron supplementation in cancer patients has the potential of worsening disease course and outcome. On the other hand, chronic im

Муриновая корреляция саркомы Эпштейна-Барра и саркомы Капози (MHV-68) представляет собой ценную модель для оценки чувствительности к антивирусным препаратам и взаимодействия в комбинаторных наркотиках.

Человеческие герпесвирусы представляют собой основные человеческие патогены. Особый интерес представляют члены подсемейства < < Герпесвирина > > , поскольку они вызывают хронические заболевания, такие, как рак, изменяя клеточные процессы и вводя клетки отдыха в непрерывно расширяющуюся фазу. Кроме того, в центре внимания постоянно находятся аутоиммунные заболевания, такие, как множественный склероз. Прототипический вирус человека - герпесвирус - вирус Эпштейна - Барра (ЭБВ) оказался трудно проанализировать в целях развития противовирусной терапии из-за проблем, связанных с распрост

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… Specifically, the luciferase cassette was integrated into the BAC-cloned MHV-68 genome through RecA-mediated homologous recombination, forming a cointegrate. …

γδ T cells: origin and fate, subsets, diseases and immunotherapy.

The intricacy of diseases, shaped by intrinsic processes like immune system exhaustion and hyperactivation, highlights the potential of immune renormalization as a promising strategy in disease treatment. In recent years, our primary focus has centered on γδ T cell-based immunotherapy, particularly pioneering the use of allogeneic Vδ2+ γδ T cells for treating late-stage solid tumors and tuberculosis patients. However, we recognize untapped potential and optimization opportunities to fully harness γδ T cell effector functions in immunotherapy. This review aims to thoroughly examine γδ T cell im

Acute Kidney Injury Associated with Anticancer Therapies: Small Molecules and Targeted Therapies.

Molecular targeted therapy has revolutionized cancer treatment by significantly improving patient survival compared with standard conventional chemotherapies. The use of these drugs targets specific molecules or targets, which block growth and spread of cancer cells. Many of these therapies have been approved for use with remarkable success in breast, blood, colorectal, lung, and ovarian cancers. The advantage over conventional chemotherapy is its ability to deliver drugs effectively with high specificity while being less toxic. Although known as "targeted," many of these agents lack specifici

Hematopoietic stem cell transplantation in Zagreb: the first 40 years.

Hematopoietic stem cell transplantation is the most effective treatment for acute leukemia, severe aplastic anemia, and some hereditary hematological disorders. The principal source of stem cells in this procedure are bone marrow and peripheral blood cells. In recent years, the transplantation outcome has significantly improved. The availability of the donor no longer poses a problem, as transplantation has been performed routinely from related, unrelated, and haploidentical donors. A high success rate has been reported in elderly patients transplanted with reduced-intensity conditioning. Impr

Safety Strategies of Genetically Engineered T Cells in Cancer Immunotherapy.

T-cell therapy using genetically engineered T cells modified with either T cell receptor or chimeric antigen receptor holds great promise for cancer immunotherapy. The concerns about its toxicities still remain despite recent successes in clinical trials. Temporal and spatial control of the engineered therapeutic T cells may improve the safety profile of these treatment regimens. To achieve these goals, numerous approaches have been tested and utilized including the incorporation of a suicide gene, the switch-mediated activation, the combinatorial antigen recognition, etc. This review will sum

Gambogic Acid as a Candidate for Cancer Therapy: A Review.

Gambogic acid (GA), a kind of dry resin secreted by the Garcinia hanburyi tree, is a natural active ingredient with various biological activities, such as anti-cancer, anti-inflammatory, antioxidant, anti-bacterial effects, etc. An increasing amount of evidence indicates that GA has obvious anti-cancer effects via various molecular mechanisms, including the induction of apoptosis, autophagy, cell cycle arrest and the inhibition of invasion, metastasis, angiogenesis. In order to improve the efficacy in cancer treatment, nanometer drug delivery systems have been employed to load GA and form mice

Current landscape of gene-editing technology in biomedicine: Applications, advantages, challenges, and perspectives.

The expanding genome editing toolbox has revolutionized life science research ranging from the bench to the bedside. These "molecular scissors" have offered us unprecedented abilities to manipulate nucleic acid sequences precisely in living cells from diverse species. Continued advances in genome editing exponentially broaden our knowledge of human genetics, epigenetics, molecular biology, and pathology. Currently, gene editing-mediated therapies have led to impressive responses in patients with hematological diseases, including sickle cell disease and thalassemia. With the discovery of more e

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… Expression of a site‐specific endonuclease stimulates homologous recombination in mammalian cells. Proc Natl Acad Sci U S A. 1994;91(13):6064‐6068. 5. O'Driscoll M, Jeggo PA. The role of double‐strand break repair–insights from human genetics. Nat Rev Genet. 2006;7(1):45‐54. 6. …

Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies.

Glucocorticoids (GCs) are a cornerstone in the treatment of lymphoid malignancies such as multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Yet, prolonged GC use is hampered by deleterious GC-related side effects and the emergence of GC resistance. To tackle and overcome these GC-related problems, the applicability of selective glucocorticoid receptor agonists and modulators was studied, in search of fewer side-effects and at least equal therapeutic efficacy as classic GCs. Compound A (CpdA) is a prototypical example of such a selective glucocorticoid receptor modulator and does no

Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect.

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high propensity for lymphatic spread and distant metastasis. It is prominent as an endemic malignancy in Southern China and Southeast Asia regions. Studies on NPC pathogenesis mechanism in the past decades such as through Epstein Barr Virus (EBV) infection and oncogenic molecular aberrations have explored several potential targets for therapy and diagnosis. The EBV infection introduces oncoviral proteins that consequently hyperactivate many promitotic pathways and block cell-death inducers. EBV infection is so prevalent in NPC pat