scholarly journals Cancer missense mutations in the BRC repeats of BRCA2 protein disrupt RAD51 binding and activity leading to chemotherapeutic sensitivity

2021 ◽  
Author(s):  
Judit Jimenez-Sainz ◽  
Joshua Mathew ◽  
Jennifer Garbarino ◽  
Joseph P Eder ◽  
Ryan B Jensen
Keyword(s):  
Genome Stability ◽  
Treatment Options ◽  
Suppressor Gene ◽  
Current Treatment ◽  
Missense Mutations ◽  
Dna Double Strand Breaks ◽  
Clinical Databases ◽  
Brca2 Protein ◽  
Hypomorphic Alleles ◽  
The Impact

BRCA2 is a tumor suppressor gene that maintains genome stability by mediating the high fidelity repair of DNA double-strand breaks (DSBs) through homology-directed repair (HDR). Pathogenic mutations in BRCA2 predispose to breast, ovarian, pancreatic, prostate, and other cancers. Mutations in BRCA2 leading to severe protein truncation predict pathogenicity, however, missense mutations with unknown functional consequences, designated Variants of Uncertain Significance (VUS), comprise 60% of BRCA2 sequence changes deposited in clinical databases. Classifying BRCA2 VUS correctly is critical for relaying clinically actionable information to patients concerning future cancer risk or current treatment options. In this study, we identified and biochemically characterized three BRCA2 VUS located in BRC repeats to determine the impact on canonical HDR functions. Two of the germline variants, S1221P and T1980I, map to conserved residues in BRC2 and BRC7, disrupt RAD51 binding, and are diminished in their ability to stabilize RAD51-ssDNA complexes. We provide supporting cellular evidence that S1221P and T1980I are significantly compromised in their response to chemotherapeutics and ionizing radiation. The third variant, T1346I, lies within the spacer region between BRC2 and BRC3 but remains fully functional. We conclude that T1346I has a neutral impact on BRCA2 function, while S1221P and T1980I are hypomorphic alleles that disrupt the ability of BRCA2 to fully engage and stabilize RAD51 nucleoprotein filaments.

scholarly journals What does first-line therapy mean for paediatric multiple sclerosis in the current era?

2020 ◽  
pp. 135245852093764
Author(s):  
Yael Hacohen ◽  
Brenda Banwell ◽  
Olga Ciccarelli
Keyword(s):  
Multiple Sclerosis ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Cognitive Outcome ◽  
First Line ◽  
First Line Therapy ◽  
Highly Active ◽  
Paediatric Multiple Sclerosis ◽  
The Impact

Paediatric multiple sclerosis (MS) is associated with higher relapse rate, rapid magnetic resonance imaging lesion accrual early in the disease course and worse cognitive outcome and physical disability in the long term compared to adult-onset disease. Current treatment strategies are largely centre-specific and reliant on adult protocols. The aim of this review is to examine which treatment options should be considered first line for paediatric MS and we attempt to answer the question if injectable first-line disease-modifying therapies (DMTs) are still an optimal option. To answer this question, we review the effects of early onset disease on clinical course and outcomes, with specific considerations on risks and benefits of treatments for paediatric MS. Considering the impact of disease activity on brain atrophy, cognitive impairment and development of secondary progressive MS at a younger age, we would recommend treating paediatric MS as a highly active disease, favouring the early use of highly effective DMTs rather than injectable DMTs.

Characterization of tumor mutation load (TML) in solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11517-11517 ◽  
Author(s):  
Mohamed E. Salem ◽  
Joanne Xiu ◽  
Heinz-Josef Lenz ◽  
Michael B. Atkins ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Gene Mutations ◽  
Predictive Biomarker ◽  
Suppressor Gene ◽  
Older Age ◽  
Patient Treatment ◽  
Missense Mutations ◽  
Driver Genes ◽  
Primary Nsclc ◽  
The Impact

11517 Background: Rapid advances in immunotherapy have created a need for biomarkers to improve patient treatment selection. TML is proposed as a potential predictive biomarker due to its association with tumor immunogenicity. Methods: TML was assessed in 8020 tumors from 14 different cancers using somatic nonsynonymous missense mutations sequenced with a 592-gene panel. High TML was set at ≥ 17 mutations per megabase (mt/MB) based on an established concordance ( > 99%) with MSI-High in colorectal cancer (CRC). Results: Mean TML was highest in melanoma (Mel; 21 mt/MB), NSCLC (11 mt/MB), and bladder cancer (BLC; 11 mt/MB), whereas prostate cancer (PC), pancreas adenocarcinoma (PA), and renal cell carcinoma (RCC) had the lowest levels (all 6 mt/MB). High TML was seen most frequently in Mel (36%), NSCLC (15%), BLC (15%), and anal cancer (SCCA; 9%); and least frequently in PA (1.6%) and RCC (0.5%). Primary NSCLC carried lower TML than its brain metastases (11 vs. 16 mt/MB, p < 0.001). Older age was associated with higher TML in Mel (p = 0.001), CRC (p = 0.009), breast cancer (BC; p = 0.01), and NSCLC (p = 0.02). Higher TML was seen in males than in females for Mel (p = 0.002) and NSCLC (p < 0.001). Presence of mutations in oncogenic driver genes such as EGFR, ALK, ROS1 RET fusions, cMET exon 14 skipping correlated with lower TML in NSCLC (6.9 vs. 12 mt/MB, p < 0.001), as did BRAF and NRAS mutations in Mel (17 vs. 26, p = 0.003). Conversely, mutations in tumor suppressor genes such as ARID1A (CRC, NSCLC, and BLC) and NF1 (BC, CRC, Mel, BLC, and NSCLC) were associated with higher TML (p < 0.05). MSI-high was correlated with high TML in CRC and gastric cancers (p < 0.05). Conclusions: TML varied significantly among different cancers. High TML was associated with older age, absence of oncogenic mutations and presence of tumor suppressor gene mutations. Future studies will assess the impact of TML on clinical outcome and establish its role in selecting patients for immunotherapy. [Table: see text]

scholarly journals Classifying Variants of Undetermined Significance in BRCA2 with Protein Likelihood Ratios

2008 ◽  
Vol 6 ◽  
pp. CIN.S618 ◽  
Author(s):  
Rachel Karchin ◽  
Mukesh Agarwal ◽  
Andrej Sali ◽  
Fergus Couch ◽  
Mary S. Beattie
Keyword(s):  
Genetic Testing ◽  
Protein Structure ◽  
Tumor Suppressor ◽  
Likelihood Ratio ◽  
Cancer Susceptibility ◽  
Suppressor Gene ◽  
Medical Genetics ◽  
Missense Mutations ◽  
Likelihood Ratios ◽  
The Impact

Background Missense (amino-acid changing) variants found in cancer predisposition genes often create difficulties when clinically interpreting genetic testing results. Although bioinformatics has developed approaches to predicting the impact of these variants, many of these approaches have not been readily applicable in the clinical setting. Bioinformatics approaches for predicting the impact of these variants have not yet found their footing in clinical practice because 1) interpreting the medical relevance of predictive scores is difficult; 2) the relationship between bioinformatics “predictors” (sequence conservation, protein structure) and cancer susceptibility is not understood. Methodology/Principal Findings We present a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function. We apply the method to a tumor suppressor gene, BRCA2, whose loss of function is important to cancer susceptibility. Protein likelihood ratios are computed for 229 unclassified variants found in individuals from high-risk breast/ovarian cancer families. We map the variants onto a protein structure model, and suggest that a cluster of predicted deleterious variants in the BRCA2 OB1 domain may destabilize BRCA2 and a protein binding partner, the small acidic protein DSS1. We compare our predictions with variant “re-classifications” provided by Myriad Genetics, a biotechnology company that holds the patent on BRCA2 genetic testing in the U.S., and with classifications made by an established medical genetics model [ 1 ]. Our approach uses bioinformatics data that is independent of these genetics-based classifications and yet shows significant agreement with them. Preliminary results indicate that our method is less likely to make false positive errors than other bioinformatics methods, which were designed to predict the impact of missense mutations in general. Conclusions/Significance Missense mutations are the most common disease-producing genetic variants. We present a fast, scalable bioinformatics method that integrates information about protein sequence, conservation, and structure in a likelihood ratio that can be integrated with medical genetics likelihood ratios. The protein likelihood ratio, together with medical genetics likelihood ratios, can be used by clinicians and counselors to communicate the relevance of a VUS to the individual who has that VUS. The approach described here is generalizable to regions of any tumor suppressor gene that have been structurally determined by X-ray crystallography or for which a protein homology model can be built.

scholarly journals Back-translating a rodent measure of negative bias into humans: the impact of induced anxiety and unmedicated mood and anxiety disorders

2017 ◽  
Author(s):  
Jessica Aylward ◽  
Claire Hales ◽  
Emma Robinson ◽  
Oliver J Robinson
Keyword(s):  
Reaction Time ◽  
Anxiety Disorders ◽  
Computational Model ◽  
Treatment Options ◽  
Reaction Times ◽  
Current Treatment ◽  
Anxiety Symptoms ◽  
Mood And Anxiety Disorders ◽  
Affective Bias ◽  
The Impact

AbstractBackgroundMood and anxiety disorders are ubiquitous but current treatment options are ineffective for large numbers of sufferers. Moreover, recent years have seen a number of promising pre-clinical interventions fail to translate into clinical efficacy in humans. Improved treatments are unlikely without better animal-human translational pipelines. Here, we directly adapt–i.e. back-translate - a rodent measure of negative affective bias into humans, and explore its relationship with a)pathological mood and anxiety symptoms (study one) and b)transient induced anxiety (study two).MethodParticipants who met criteria for mood or anxiety disorder symptomatology according to a face-to-face neuropsychiatric interview were included in the symptomatic group. N = 77(47 asymptomatic; Female = 21; 30 symptomatic; Female = 25) participants completed study one and N = 47 asymptomatic participants (25 female) completed study two. Outcome measures were choice ratios, reaction times and parameters recovered from a computational model of reaction time; the drift diffusion model (DDM).ResultsSymptomatic individuals demonstrated increased negative affective bias relative to asymptomatic individuals (proportion high reward = 0.42(SD = 0.14), and 0.53(SD = 0.17), respectively) as well as reduced DDM drift rate (p = 0.004). No significant effects were observed for the within-subjects anxiety-induction in study 2.ConclusionHumans with pathological anxiety symptoms directly mimic rodents undergoing anxiogenic manipulation. The lack of sensitivity to transient anxiety suggests the paradigm may, moreover, be primarily sensitive to clinically relevant symptoms. Our results establish a direct translational pipeline (and candidate therapeutics screen) from negative affective bias in rodents to pathological mood and anxiety symptoms in humans, and link it to a computational model of reaction time.

scholarly journals Translating a rodent measure of negative bias into humans: the impact of induced anxiety and unmedicated mood and anxiety disorders

2019 ◽  
Vol 50 (2) ◽  
pp. 237-246 ◽  
Author(s):  
Jessica Aylward ◽  
Claire Hales ◽  
Emma Robinson ◽  
Oliver J. Robinson
Keyword(s):  
Anxiety Disorders ◽  
Treatment Options ◽  
Reaction Times ◽  
Current Treatment ◽  
Anxiety Symptoms ◽  
Mood And Anxiety Disorders ◽  
Affective Bias ◽  
Asymptomatic Individuals ◽  
Anxiety Induction ◽  
The Impact

AbstractBackgroundMood and anxiety disorders are ubiquitous but current treatment options are ineffective for many sufferers. Moreover, a number of promising pre-clinical interventions have failed to translate into clinical efficacy in humans. Improved treatments are unlikely without better animal–human translational pipelines. Here, we translate a rodent measure of negative affective bias into humans, exploring its relationship with (1) pathological mood and anxiety symptoms and (2) transient induced anxiety.MethodsAdult participants (age = 29 ± 11) who met criteria for mood or anxiety disorder symptomatology according to a face-to-face neuropsychiatric interview were included in the symptomatic group. Study 1 included N = 77 (47 = asymptomatic [female = 21]; 30 = symptomatic [female = 25]), study 2 included N = 47 asymptomatic participants (25 = female). Outcome measures were choice ratios, reaction times and parameters recovered from a computational model of reaction time – the drift diffusion model (DDM) – from a two-alternative-forced-choice task in which ambiguous and unambiguous auditory stimuli were paired with high and low rewards.ResultsBoth groups showed over 93% accuracy on unambiguous tones indicating intact discrimination, but symptomatic individuals demonstrated increased negative affective bias on ambiguous tones [proportion high reward = 0.42 (s.d. = 0.14)] relative to asymptomatic individuals [0.53 (s.d. = 0.17)] as well as a significantly reduced DDM drift rate. No significant effects were observed for the within-subjects anxiety-induction.ConclusionsHumans with pathological anxiety symptoms directly mimic rodents undergoing anxiogenic manipulation. The lack of sensitivity to transient anxiety suggests the paradigm might be more sensitive to clinically relevant symptoms. Our results establish a direct translational pipeline (and candidate therapeutics screen) from negative affective bias in rodents to pathological mood and anxiety symptoms in humans.

scholarly journals Advanced Gastric Cancer: Current Treatment Landscape and a Future Outlook for Sequential and Personalized Guide: Swiss Expert Statement Article

2021 ◽  
pp. 1-10
Author(s):  
Alexander R. Siebenhüner ◽  
Sara De Dosso ◽  
Daniel Helbling ◽  
Christoforos Astaras ◽  
Petr Szturz ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Systemic Treatment ◽  
Treatment Options ◽  
Current Treatment ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Her 2 ◽  
The Impact

<b><i>Background:</i></b> Gastric cancer is a leading cause of cancer-related deaths worldwide. Several treatment possibilities have been investigated, but only a few show clinically meaningful results. <b><i>Summary:</i></b> Systemic treatment options for advanced gastric cancer (aGC) have evolved over the recent years, implementing the growing molecular knowledge of this heterogeneous disease. Molecular profiling (at least for HER-2-expression, microsatellite instability status, <i>Epstein-Barr virus</i> expression, and programmed death ligand-1 expression/combined positive score [CPS]) is recommended for all therapy-fit patients prior to the start of a systemic treatment and is crucial for decisions on treatment strategy and drug selection. Various examples like the application of trastuzumab in the HER-2-positive subgroup underline the benefits of this approach starting from the first-line setting. A combination of platinum and fluoropyrimidine remains the first-line chemotherapy backbone in the treatment of advanced gastric cancer. Triplet combinations adding taxanes to the doublet regimen are reserved for certain scenarios. Unfortunately, almost all patients who receive first-line treatment (with or without anti-HER-2 blockade) progress and &#x3c;70% are eligible for a second-line therapy. The addition of monoclonal antibodies has substantially improved outcomes in this setting. As such, ramucirumab has led to significant and clinically meaningful advancements in the second-line treatment. Furthermore, immuno-oncology with checkpoint inhibition and immune stimulation has evolved in the field of aGC. Recent first-line data show a significant survival benefit in aGC patients with a CPS ≥ 5 under immunochemotherapy. Nonetheless, the impact of immunotherapy combinations and immunochemotherapy remains an area of investigation. <b><i>Key Message:</i></b> In this review, we highlight recent improvements in the treatment landscape of advanced gastric cancer, the heterogeneity of this disease, and possible personalized targets.

IMerge: A phase 3 study to evaluate imetelstat in transfusion-dependent subjects with IPSS low or intermediate-1 risk myelodysplastic syndromes that are relapsed/refractory to erythropoiesis-stimulating agent treatment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS7056-TPS7056
Author(s):  
Uwe Platzbecker ◽  
Rami S. Komrokji ◽  
Pierre Fenaux ◽  
Amer Methqal Zeidan ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Controlled Trial ◽  
Treatment Options ◽  
Current Treatment ◽  
International Prognostic Scoring System ◽  
Phase 2 ◽  
Phase 3 ◽  
Double Blind ◽  
The Impact ◽  
Rbc Transfusion

TPS7056 Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients (pts) with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in MDS pts across all disease stages. IMerge (MDS3001) is a Phase 2/3 global study of imetelstat for TD pts with non-del(5q) LR MDS post ESA therapy. The results from Phase 2 part indicated that imetelstat achieved durable RBC transfusion independence (RBC-TI) and the most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. Among 38 pts with median follow-up of 24 months, 8-week, 24-week and 1-year TI rates were 42%, 32% and 29%, respectively; these responses were seen across different LR MDS subtypes. Median TI duration was 20 months and the longest TI was 2.7 years. A high and durable hematologic improvement-erythroid (HI-E) rate of 68% for a median duration of 21 months were also achieved. Reduction of variant allele frequency of mutations by imetelstat treatment was observed in some pts and correlated with clinical benefits (Platzbecker et al EHA 2020; Steensma et al JCO 2020). These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 3 part of the study is open for enrollment to adult pts with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs placebo that will enroll approximately 170 pts and will be conducted at approximately 120 centers in North America, Europe, Asia and Middle East. Imetelstat is administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics, and quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. The study is currently recruiting pts. Clinical trial information: NCT02598661.

scholarly journals Towards a Unified Testing Framework for Single-Sided Deafness Studies: A Consensus Paper

2016 ◽  
Vol 21 (6) ◽  
pp. 391-398 ◽  
Author(s):  
Paul Van de Heyning ◽  
Dayse Távora-Vieira ◽  
Griet Mertens ◽  
Vincent Van Rompaey ◽  
Gunesh P. Rajan ◽  
...  
Keyword(s):  
Outcome Measures ◽  
Study Design ◽  
Hearing Aids ◽  
Treatment Options ◽  
Bone Conduction ◽  
Binaural Hearing ◽  
Current Treatment ◽  
Single Sided Deafness ◽  
High Level ◽  
The Impact

Background: While hearing aids for a contralateral routing of signals (CROS-HA) and bone conduction devices have been the traditional treatment for single-sided deafness (SSD) and asymmetric hearing loss (AHL), in recent years, cochlear implants (CIs) have increasingly become a viable treatment choice, particularly in countries where regulatory approval and reimbursement schemes are in place. Part of the reason for this shift is that the CI is the only device capable of restoring bilateral input to the auditory system and hence of possibly reinstating binaural hearing. Although several studies have independently shown that the CI is a safe and effective treatment for SSD and AHL, clinical outcome measures in those studies and across CI centers vary greatly. Only with a consistent use of defined and agreed-upon outcome measures across centers can high-level evidence be generated to assess the safety and efficacy of CIs and alternative treatments in recipients with SSD and AHL. Methods: This paper presents a comparative study design and minimum outcome measures for the assessment of current treatment options in patients with SSD/AHL. The protocol was developed, discussed, and eventually agreed upon by expert panels that convened at the 2015 APSCI conference in Beijing, China, and at the CI 2016 conference in Toronto, Canada. Results: A longitudinal study design comparing CROS-HA, BCD, and CI treatments is proposed. The recommended outcome measures include (1) speech in noise testing, using the same set of 3 spatial configurations to compare binaural benefits such as summation, squelch, and head shadow across devices; (2) localization testing, using stimuli that rove in both level and spectral content; (3) questionnaires to collect quality of life measures and the frequency of device use; and (4) questionnaires for assessing the impact of tinnitus before and after treatment, if applicable. Conclusion: A protocol for the assessment of treatment options and outcomes in recipients with SSD and AHL is presented. The proposed set of minimum outcome measures aims at harmonizing assessment methods across centers and thus at generating a growing body of high-level evidence for those treatment options.

scholarly journals The Impact of Selected Bacterial Sexually Transmitted Diseases on Pregnancy and Female Fertility

2021 ◽  
Vol 22 (4) ◽  
pp. 2170
Author(s):  
Katarzyna Smolarczyk ◽  
Beata Mlynarczyk-Bonikowska ◽  
Ewa Rudnicka ◽  
Dariusz Szukiewicz ◽  
Blazej Meczekalski ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Treatment Options ◽  
Mycoplasma Genitalium ◽  
Current Treatment ◽  
Female Fertility ◽  
Sexually Transmitted ◽  
Tubal Factor ◽  
Adverse Pregnancy ◽  
New Treatments ◽  
The Impact

Sexually transmitted infections (STIs) caused by Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium are a common cause of pelvic inflammatory disease (PID) which can lead to tubal factor infertility (TFI). TFI is one of the most common causes of infertility, accounting for 30% of female fertility problems. STIs can also have an impact on pregnancy, leading to adverse pregnancy outcomes. Escalating antibiotic resistance in Neisseria gonorrhoeae and Mycoplasma genitalium represents a significant problem and can be therapeutically challenging. We present a comprehensive review of the current treatment options, as well as the molecular approach to this subject. We have given special attention to molecular epidemiology, molecular diagnostics, current and new treatments, and drug resistance.

Factors that influence bidirectional long-tract homozygosis due to double-strand break repair in Candida albicans

Genetics ◽  
2021 ◽  
Author(s):  
Timea Marton ◽  
Murielle Chauvel ◽  
Adeline Feri ◽  
Corinne Maufrais ◽  
Christophe D’enfert ◽  
...  
Keyword(s):  
Dna Repair ◽  
Candida Albicans ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Strand Break ◽  
Genomic Rearrangements ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
Break Site ◽  
The Impact

Abstract Genomic rearrangements have been associated with the acquisition of adaptive phenotypes, allowing organisms to efficiently generate new favorable genetic combinations. The diploid genome of Candida albicans is highly plastic, displaying numerous genomic rearrangements that are often the by-product of the repair of DNA breaks. For example, DNA double-strand breaks (DSB) repair using homologous-recombination pathways are a major source of loss-of-heterozygosity (LOH), observed ubiquitously in both clinical and laboratory strains of C. albicans. Mechanisms such as break-induced replication (BIR) or mitotic crossover (MCO) can result in long tracts of LOH, spanning hundreds of kilobases until the telomere. Analysis of I-SceI-induced BIR/MCO tracts in C. albicans revealed that the homozygosis tracts can ascend several kilobases towards the centromere, displaying homozygosis from the break site towards the centromere. We sought to investigate the molecular mechanisms that could contribute to this phenotype by characterizing a series of C. albicans DNA repair mutants, including pol32-/-, msh2-/-, mph1-/- and mus81-/-. The impact of deleting these genes on genome stability revealed functional differences between Saccharomyces cerevisiae (a model DNA repair organism) and C. albicans. Additionally, we demonstrated that ascending LOH tracts towards the centromere are associated with intrinsic features of BIR and potentially involve the mismatch repair pathway which acts upon natural heterozygous positions. Overall, this mechanistic approach to study LOH deepens our limited characterization of DNA repair pathways in C. albicans and brings forth the notion that centromere proximal alleles from DNA break sites are not guarded from undergoing LOH.

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