N 2-Alkyl-dG lesions elicit R-loop accumulation in the genome.

Humans are exposed to DNA alkylating agents through endogenous metabolism, environmental exposure and cancer chemotherapy. The resulting alkylated DNA adducts may elicit genome instability by perturbing DNA replication and transcription. R-loops regulate various cellular processes, including transcription, DNA repair, and telomere maintenance.

HMGB3 and SUB1 Bind to and Facilitate the Repair of -Alkylguanine Lesions in DNA.

-Alkyl-2'-deoxyguanosine (-alkyl-dG) is a major type of minor-groove DNA lesions arising from endogenous metabolic processes and exogenous exposure to environmental contaminants. The -alkyl-dG lesions, if left unrepaired, can block DNA replication and transcription and induce mutations in these processes. Nevertheless, the repair pathways for -alkyl-dG lesions remain incompletely elucidated.

DNA polymerase κ participates in early S-phase DNA replication in human cells.

Cycling cells replicate their DNA during the S phase through a defined temporal program known as replication timing. Mutation frequencies, epigenetic chromatin states, and transcriptional activities are different for genomic regions that are replicated early and late in the S phase. Here, we found from ChIP-Seq analysis that DNA polymerase (Pol) κ is enriched in early-replicating genomic regions in HEK293T cells.

The aflatoxin B-induced imidazole ring-opened guanine adduct: High mutagenic potential that is minimally affected by sequence context.

Dietary exposure to aflatoxin B (AFB) is a recognized risk factor for developing hepatocellular carcinoma. The mutational signature of AFB is characterized by high-frequency base substitutions, predominantly G>T transversions, in a limited subset of trinucleotide sequences. The 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B (AFB-FapyGua) has been implicated as the primary DNA lesion responsible for AFB-induced mutations.

Base excision repair of the N-(2-deoxy-d-erythro-pentofuranosyl)-urea lesion by the hNEIL1 glycosylase.

The N-(2-deoxy-d-erythro-pentofuranosyl)-urea DNA lesion forms following hydrolytic fragmentation of cis-5R,6S- and trans-5R,6R-dihydroxy-5,6-dihydrothymidine (thymine glycol, Tg) or from oxidation of 7,8-dihydro-8-oxo-deoxyguanosine (8-oxodG) and subsequent hydrolysis. It interconverts between α and β deoxyribose anomers. Synthetic oligodeoxynucleotides containing this adduct are efficiently incised by unedited (K242) and edited (R242) forms of the hNEIL1 glycosylase.

Recent Advances in DNA Lesion Mapping and Repair Mechanisms.

Recognition and repair of DNA lesions are critical for cell survival. Herein, we highlight recent advances in the sequencing, repair mechanisms, and biological consequences of DNA lesions presented at the 2022 Fall American Chemical Society meeting.

Conformation and Pairing Properties of an -Methyl-2'-deoxyguanosine-Directed Benzimidazole Nucleoside Analog in Duplex DNA.

-Methyl-2'-deoxyguanosine (-MeG) is one of the most common DNA lesions and arises as a consequence of both xenobiotic carcinogens and endogenous methylation by -adenosylmethionine. -MeG frequently causes G-to-A mutations during DNA replication due to the misincorporation of dTTP and continued DNA synthesis. Efforts to detect DNA adducts such as -MeG, and to understand their impacts on DNA structure and function, have motivated the creation of nucleoside analogs with altered base moieties to afford a more favorable interaction with the adduct as compared to the unmodified nucleotide.

Total Synthesis of (-)-Bastimolide A: A Showcase for Type I Anion Relay Chemistry.

A highly convergent total synthesis of (-)-bastimolide A (1), a polyhydroxy antimalarial macrolide, has been achieved via a longest linear sequence of twenty steps from commercially available glycidyl ethers. Type I Anion Relay Chemistry (ARC) coupling tactics enable rapid construction of the molecule's 1,5-polylol backbone. A late-stage B-alkyl Suzuki-Miyaura union and an Evans-modified Mukaiyama macrolactonization generate the forty-membered Z-α,β-unsaturated macrocyclic lactone.

Real-World Performance of a Comprehensive Genomic Profiling Test Optimized for Small Tumor Samples.

Purpose: Tissue-based comprehensive genomic profiling (CGP) is increasingly used for treatment selection in patients with advanced cancer; however, tissue availability may limit widespread implementation. Here, we established real-world CGP tissue availability and assessed CGP performance on consecutively received samples.

Materials And Methods: We conducted a post hoc, nonprespecified analysis of 32,048 consecutive tumor tissue samples received for StrataNGS, a multiplex polymerase chain reaction (PCR)-based comprehensive genomic profiling (PCR-CGP) test, as part of an ongoing observational trial (NCT03061305).

DNA Sequence Modulates the Efficiency of NEIL1-Catalyzed Excision of the Aflatoxin B-Induced Formamidopyrimidine Guanine Adduct.

Dietary exposure to aflatoxins is a significant risk factor in the development of hepatocellular carcinomas. Following bioactivation by microsomal P450s, the reaction of aflatoxin B (AFB) with guanine (Gua) in DNA leads to the formation of stable, imidazole ring-opened 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B (AFB-FapyGua) adducts. In contrast to most base modifications that result in destabilization of the DNA duplex, the AFB-FapyGua adduct increases the thermal stability of DNA via 5'-interface intercalation and base-stacking interactions.

Structure of a Stable Interstrand DNA Cross-Link Involving a β--Glycosyl Linkage Between an -dA Amino Group and an Abasic Site.

Abasic (AP) sites are one of the most common forms of DNA damage. The deoxyribose ring of AP sites undergoes anomerization between α and β configurations, via an electrophilic aldehyde intermediate. In sequences where an adenine residue is located on the opposing strand and offset 1 nt to the 3' side of the AP site, the nucleophilic -dA amino group can react with the AP aldehyde residue to form an interstrand cross-link (ICL).

Long-term participation in collaborative fisheries research improves angler opinions on marine protected areas.

Recent marine spatial planning efforts, including the management and monitoring of marine protected areas (MPAs), increasingly focus on the importance of stakeholder engagement. For nearly 15 years, the California Collaborative Fisheries Research Program (CCFRP) has partnered volunteer anglers with researchers, the fishing industry, and resource managers to monitor groundfishes in California's network of MPAs. While the program has succeeded in generating sustained biological observations, we know little about volunteer angler demography or the impact of participation on their perceptions and opinions on fisheries data or MPAs.

Psychosocial Impact and Disease Management in Patients with Congenital Factor VII Deficiency.

Purpose: Congenital factor VII (FVII) deficiency is a rare bleeding disorder of variable phenotype with predominantly mucocutaneous bleeding. The aim of this study was to identify the burden of FVII deficiency on patients and caregivers through a better understanding of the management and psychosocial impact of this disease.

Materials And Methods: A rare disease specialty recruiter from Comprehensive Health Education Services recruited participants for this online survey, which was conducted from January 31 to March 12, 2019.

Disease Burden in Patients with Glanzmann's Thrombasthenia: Perspectives from the Glanzmann's Thrombasthenia Patient/Caregiver Questionnaire.

Purpose: Glanzmann's thrombasthenia (GT) is a rare bleeding disorder caused by a mutation in the αIIbβ3 integrin essential for optimal platelet function and hemostasis. The aim of this study was to identify the burden of GT on patients and caregivers through better understanding of the management and psychosocial impact of this disorder.

Patients And Methods: Participants for this online survey were recruited using a rare disease specialty recruiter from Comprehensive Health Education Services.

Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial.

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability.

Evaluation of Diverse Community Asthma Interventions: Balancing Health Outcomes with Developing Community Capacity for Evidence-Based Program Measurement.

The challenge of evaluating community asthma management programs is complicated by balancing the emphasis on health outcomes with the need to build community process capacity for conducting and monitoring evidence-based programs. The evaluation of a Georgia Childhood Asthma Management Program, a Healthcare Georgia Foundation-supported initiative for multiple diverse programs and settings, provides an example of an approach and the results that address this challenge. A "developmental evaluation" approach was applied, using mixed methods of quantitative and qualitative data collection and analysis, to assess the progress of community asthma prevention programs in building community within the context of: where the community is starting, community-level systems changes, and the community's progress toward becoming more outcome measurement oriented and evidence based.

A merged model of quality improvement and evaluation: maximizing return on investment.

Quality improvement (QI) and evaluation are frequently considered to be alternative approaches for monitoring and assessing program implementation and impact. The emphasis on third-party evaluation, particularly associated with summative evaluation, and the grounding of evaluation in the social and behavioral science contrast with an emphasis on the integration of QI process within programs or organizations and its origins in management science and industrial engineering. Working with a major philanthropic organization in Georgia, we illustrate how a QI model is integrated with evaluation for five asthma prevention and control sites serving poor and underserved communities in rural and urban Georgia.

A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors.

Objectives: Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, has been shown to increase platelet counts in adults with chronic immune thrombocytopenia and chronic hepatitis C. This multicenter phase 2 study assessed the efficacy and safety of eltrombopag in patients receiving first-line carboplatin/paclitaxel for the treatment of advanced solid tumors.

Research Design And Methods: Patients (N = 183) were randomized to placebo or eltrombopag 50 mg, 75 mg, or 100 mg given orally following chemotherapy on days 2 through 11 of each 21-day cycle, for at least two cycles.

Bypass operation for post-cystectomy intestinal obstruction.

A method for an intestinal bypass operation is presented. The procedure has been valuable in patients with post-cystectomy intestinal obstruction who did not respond to non-operative measures. A discussion on the possible means to prevent further obstruction is included.