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What's your poison? Impact of individual repair capacity on the outcomes of genotoxic therapies in cancer. Part II - information content and validity of biomarkers for individual repair capacity in the assessment of outcomes of anticancer therapy.

The individual variance in the efficiency of repair of damage induced by genotoxic therapies may be an important factor in the assessment of eligibility for different anticancer treatments, the outcomes of various treatments and the therapy-associated complications, including acute and delayed toxicity and acquired drug resistance. The second part of this paper analyses the currently available information about the possibilities of using experimentally obtained knowledge about individual repair capacity for the purposes of personalised medicine and healthcare.

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… Abbreviations cyclin H global genome repair human epidermal growth factor receptor 2 hereditary non-polyposis colorectal carcinoma MutS homologue MutL homologue nucleotide excision repair non-homologous end joining tumour protein 53 (p53) Individual repair capacity and eligibility for different … repair and mismatch repair (10 , 47 , 57) . …

Molecular Targeting and Rational Chemotherapy in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a molecularly complex disease with multiple aberrant genetic pathways involved in its pathogenesis. Approximately one-third to one-half of patients with AML would relapse, and no standard therapy is established for relapsing and/or refractory AML (RR-AML) yet. It is unlikely that blockage of only one specific pathway will lead to prolonged remissions and cures in all fractions of the AML patients population. Nowadays, novel therapeutic agents with rational combination are being recognized which improve the cure rate for relapsed AML. These drugs and their metabo

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… repair, nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR) ( Figure 2 ). … Abbreviations: AML, acute myeloid leukemia; NER, nucleotide excision repair; BER, base excision repair; HDR, homology-directed repair; FA, Fanconi anemia; HR, homologous recombination; DDR, DNA damage response; NHEJ, non-homologous end joining; SSBs, single-strand breaks; DSB, double-strand breaks; PARP …

Fanconi anemia pathway as a prospective target for cancer intervention.

Fanconi anemia (FA) is a recessive genetic disorder caused by biallelic mutations in at least one of 22 FA genes. Beyond its pathological presentation of bone marrow failure and congenital abnormalities, FA is associated with chromosomal abnormality and genomic instability, and thus represents a genetic vulnerability for cancer predisposition. The cancer relevance of the FA pathway is further established with the pervasive occurrence of FA gene alterations in somatic cancers and observations of FA pathway activation-associated chemotherapy resistance. In this article we describe the role of th

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… While intrastrand crosslinks are readily repaired by the nucleotide excision repair (NER) pathway [ 13 ], ICLs represent a highly cytotoxic lesion that is primarily repaired by the FA pathway [ 14 ]. … Abbreviations Fanconi anemia Base excision repair Nucleotide excision repair Chromosomal instability Interstrand crosslink Non-homologous end joining Microhomology mediated end joining DNA damage response Single-stranded annealing Authors’ contributions All authors read and approved the final …

Expert consensus on resection of chest wall tumors and chest wall reconstruction.

Chest wall tumors are a relatively uncommon disease in clinical practice. Most of the published studies about chest wall tumors are usually single-center retrospective studies, involving few patients. Therefore, evidences regarding clinical conclusions about chest wall tumors are lacking, and some controversial issues have still to be agreed upon. In January 2019, 73 experts in thoracic surgery, plastic surgery, science, and engineering jointly released the Chinese Expert Consensus on Chest Wall Tumor Resection and Chest Wall Reconstruction (2018 edition). After that, numerous experts put forw

Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic.

Reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease (Ref-1/APE1) is a critical node in tumor cells, both as a redox regulator of transcription factor activation and as part of the DNA damage response. As a redox signaling protein, Ref-1/APE1 enhances the transcriptional activity of STAT3, HIF-1α, nuclear factor kappa B, and other transcription factors to promote growth, migration, and survival in tumor cells as well as inflammation and angiogenesis in the tumor microenvironment. Ref-1/APE1 is activated in a variety of cancers, including prostate, colon, pancreatic, ovarian, lung an

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… The DNA repair function is responsible for the endonuclease activity in base excision repair, cutting the phosphodiester backbone of DNA at abasic sites created by glycosylases. … Exploiting base excision repair to improve therapeutic approaches for pancreatic cancer. Front. Nutr. 2015;2:10. doi: 10.3389/fnut.2015.00010. 27. Fishel ML, Colvin ES, Luo M, Kelley MR, Robertson KA. …

Insights into platinum-induced peripheral neuropathy-current perspective.

Cancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously explored, platinum based chemotherapy agents remain in use due to their efficiency and availability. Unfortunately, all cancer therapies affect normal tissues as well as cancer, and more than 40 specific side effects of platinum based drugs documented so far decrease the quality of life of cancer survivors. Chemotherapy-induced peripheral neuropathy is a frequent side effects of plat

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… These complex DNA lesions inhibit the DNA base excision repair (Kelley et al., 2014) as well as transcription (Yan et al., 2015). … Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy. PLoS One. 2014;9:e106485. doi: 10.1371/journal.pone.0106485. 44. Kelley MR, Wikel JH, Guo C, Pollok KE, Bailey BJ, Wireman R, Fishel ML, Vasko MR. …

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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… Other DNA repair pathways, such as base excision repair (BER) and mismatch repair (MMR), resolve perturbations induced by base editing, whereas those induced by prime editing (PE) are resolved by flap excision, thoroughly reviewed elsewhere (Ref 21 ). …

Osteogenic protein-1 for long bone nonunion: an evidence-based analysis.

OBJECTIVE: To assess the efficacy of osteogenic protein-1 (OP-1) for long bone nonunion. CLINICAL NEED: Although most fractures heal within a normal period, about 5% to 10% do not heal and are classified as delayed or nonunion fractures. Nonunion and segmental bone loss after fracture, reconstructive surgery, or lesion excision can present complex orthopedic problems, and the multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life. Many factors contribute to the pathogenesis of a delayed union or nonunion fractures, including deficiencies of

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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… H4K20me2: Orchestrating the recruitment of DNA repair factors in nucleotide excision repair. Nucleus. 2018;9:212–215. doi: 10.1080/19491034.2018.1444327. 48. Chitale S., Richly H. DICER- and MMSET-catalyzed H4K20me2 recruits the nucleotide excision repair factor XPA to DNA damage sites. J. … SIRT1 deacetylates APE1 and regulates cellular base excision repair. Nucleic Acids Res. 2010;38:832–845. doi: 10.1093/nar/gkp1039. 104. Liu T., Liu P.Y., Marshall G.M. The critical role of the class III histone deacetylase SIRT1 in cancer. …

Strategies to Improve Sensitivity to Radiotherapy in Pediatric Solid Tumors.

The primary goal in the treatment of pediatric malignancies is to maintain effective cancer control while minimizing toxicities and late effects. Radiotherapy is a component of standard therapy against many pediatric cancers, but tumor cell DNA damage repair mechanisms and the hypoxic tumor microenvironment may limit the effectiveness of this modality. Additionally, irradiated cancer cells often acquire resistance to radiotherapy that permits cancer cell survival or stimulates tumor regrowth after treatment, further limiting the efficacy of radiotherapy. Various preclinical studies have invest

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… The DNA damage is repaired by base excision repair (BER), nucleotide excision repair (NER), non-homologous end joining (NHEJ), or homologous recombination (HR) [ 24 ]. If the damage is irreparable, the cell activates apoptosis to prevent propagation of damaged DNA. … Abbreviations The following abbreviations are used in this manuscript: ATM | Ataxia-Telangiectasia Mutated Protein ATR | Ataxia-Telangiectasia Mutated and Rad3-Related Protein BER | Base Excision Repair CNS | Central Nervous System CRT | Conformal Radiotherapy CSI | Craniospinal Irradiation CTLA-4 …

Advances of DNA Damage Repair-Related Drugs and Combination With Immunotherapy in Tumor Treatment.

Cancer therapy has been an important and popular area in cancer research. With medical technology developing, the appearance of various targeted drugs and immunotherapy offer more choices to cancer treatment. With the increase in drug use, people have found more and more cases in which tumors are resistant to DNA damage repair (DDR)-based drugs. Recently, the concept of combination therapy has been brought up in cancer research. It takes advantages of combining two or more therapies with different mechanisms, aiming to benefit from the synergistic effects and finally rescue patients irresponsi

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… DNA single-strand repair pathway mainly responds to impaired or mismatched basic groups (e.g., base excision repair, nucleotide excision repair, direct repair, and mismatch repair), while DNA double-strand repair pathway is mainly in charge of DNA double-strand breaks (DSBs) (e.g., homologous recombination …

Synthetic lethality and DNA damage response targeting in cancer stem cells: a comprehensive review.

This comprehensive review explores the critical intersection of Synthetic Lethality (SL) and DNA Damage Response (DDR) targeting within Cancer Stem Cells (CSCs), a subpopulation central to tumor initiation, metastasis, and therapeutic resistance. CSCs exhibit unique biological properties, including enhanced DNA repair mechanisms and metabolic plasticity, rendering them intrinsically resistant to conventional therapies. The fundamental mechanisms of DDR pathways and their dysregulation in cancer are delineated, highlighting how these vulnerabilities can be exploited through SL. The review synth

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… The DNA damage response (DDR) engages multiple repair pathways, including nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end-joining (NHEJ). … The DNA damage response (DDR) engages multiple repair pathways, including nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end-joining (NHEJ). …

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

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… It has been shown that the trabectedin chemical scaffold forms a covalent bond with DNA [ 8 ], and the appended ring has been proposed to directly interact with the nucleotide excision repair (NER) endonuclease XPG [ 9 , 10 ]. … Experiments in isogenic cell lines have indicated that the cytotoxic effect of this compound is independent of functional nucleotide excision repair system properties [ 7 ]. …

Principles of Management of Extremity Skeletal Metastasis.

Understanding the epidemiology of extremity skeletal metastasis and the factors deciding the treatment decision-making are essential in developing a diagnostic and treatment strategy. This leads to optimum care and reduces disease-related burden. With the evolution of medical, radiation therapy, and surgical methods, cancer care has improved the quality of life for patients with improved survival and functional status in patients with skeletal metastasis. Based on the currently available literature, we have described a step-wise evaluation and management strategy of metastatic extremity bone d

Periacetabular Osteotomy Improves Pain and Function in Patients With Lateral Center-edge Angle Between 18° and 25°, but Are These Hips Really Borderline Dysplastic?

BACKGROUND: The treatment of mild or borderline acetabular dysplasia is controversial with surgical options including both arthroscopic labral repair with capsular closure or plication and periacetabular osteotomy (PAO). The degree to which improvements in pain and function might be achieved using these approaches may be a function of acetabular morphology and the severity of the dysplasia, but detailed radiographic assessments of acetabular morphology in patients with a lateral center-edge angle (LCEA) of 18° to 25° who have undergone PAO have not, to our knowledge, been performed. QUESTIONS

Ультрафиолетовое излучение и нейродегенерация: молекулярные механизмы, лежащие в основе двойного нейрозащитного и нейротоксичного воздействия.

Ультрафиолетовое излучение имеет сложную, зачастую противоречивую связь с риском/прогрессом нейродегенерации, охватывающую клинически диагностированные заболевания [Заболевания Паркинсона (PD), болезни Альцгеймера (AD), множественный склероз (MS) и амиотропический боковой склероз (ALS)] или промежуточные фенотипы (уменьшенный нейрогенесис, потеря гиппокампального объема). Цель этого обзора заключается в выявлении двойного воздействия УФ-излучения путем сбора и обобщения экспериментальных (доклинических и переводческих) данных, а также эпидемиологических данных. Нынешняя литература демонстрируе

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… The Base Excision Repair (BER) pathway is a crucial pathway required to combat formation of these oxidative DNA bases via DNA glycosylases, particularly 8-oxoguanine glycosylase ( Jacobs and Schär, 2012 ). … Decreased base excision repair and increased helicase activity in Alzheimer’s disease brain. Brain Res. 855 116–123. 10.1016/s0006-8993(99)02335-5 MacLaughlin J., Anderson R., Holick M. (1982). …

CRISPR-Cas9 Therapeutics in Early Clinical Development: Delivery and Molecular Diagnostics.

CRISPR-Cas9 has progressed from an experimental tool to a therapeutic modality, marked by the first regulatory approvals of an ex vivo-edited autologous CD34+ hematopoietic stem cell product that induces fetal hemoglobin (CASGEVY/exa-cel). In this narrative review, we synthesize modality-specific molecular diagnostic strategies used across early CRISPR clinical translation. In parallel, early clinical experience has begun to demonstrate the feasibility of in vivo editing, including subretinal delivery for CEP290-associated inherited retinal degeneration (EDIT-101 programme) and hepatocyte-targ

Chemotherapy Side-Effects: Not All DNA Damage Is Equal.

Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence of numerous features of accelerated aging, seriously affecting quality of life, has now become one of the most pressing problems associated with (pediatric) cancer treatment. Chemotherapies frequently target and damage the DNA, causing mutations or genome instability, a major hallmark

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… These include amongst others homologous recombination (HR) and non-homologous end joining (NHEJ) for the repair of double-stranded DNA breaks [ 158 ], base excision repair (BER) for the removal of subtle base modifications [ 159 ], global genome-nucleotide excision repair (GG-NER) and transcription-coupled … Mammalian DNA base excision repair: Dancing in the moonlight DNA Repair 2020 93 102921 10.1016/j.dnarep.2020.102921 33087262 160. Marteijn J.A. Lans H. Vermeulen W. Hoeijmakers J.H. Understanding nucleotide excision repair and its roles in cancer and ageing Nat. Rev. Mol. …

CRISPR-Cas: Converting A Bacterial Defence Mechanism into A State-of-the-Art Genetic Manipulation Tool.

Bacteriophages are pervasive viruses that infect bacteria, relying on their genetic machinery to replicate. In order to protect themselves from this kind of invader, bacteria developed an ingenious adaptive defence system, clustered regularly interspaced short palindromic repeats (CRISPR). Researchers soon realised that a specific type of CRISPR system, CRISPR-Cas9, could be modified into a simple and efficient genetic engineering technology, with several improvements over currently used systems. This discovery set in motion a revolution in genetics, with new and improved CRISPR systems being

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… Single nicked DNA is preferably repaired through base excision repair [ 127 ], thus Cas9n can be used to improve the efficiency of the process by reducing the number of indel mutations resulting from unwanted NHEJ repairs. … Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity. Sci. Adv. 2017;3:1–9. doi: 10.1126/sciadv.aao4774. 84. Kim Y.B., Komor A.C., Levy J.M., Packer M.S., Zhao K.T., Liu D.R. …

Innovative Approaches in Bone Tissue Engineering: Strategies for Cancer Treatment and Recovery.

Cancer has rapidly emerged as a leading global cause of premature mortality, with significant economic implications projected to reach USD 25.2 trillion from 2020 to 2050. Among the various types of cancer, primary bone cancers, though uncommon, are projected to see nearly 4000 new cases diagnosed in the United States in 2024. The complexity of treating bone cancer arises from its rarity, diversity, and the challenges associated with surgical interventions, metastatic spread, and post-operative complications. Advancements in bone tissue engineering (BTE) have introduced innovative therapeutic