GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress.

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, which promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes nonhomologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard-of-care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in nonmalignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment. SIGNIFICANCE: A newly described GTP-dependent signaling axis is an unexpected link between nucleotide metabolism and DNA repair. Disrupting this pathway can overcome cancer resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues. This article is featured in Selected Articles from This Issue, p. 5.

Base Editor Scanning Reveals Activating Mutations of DNMT3A.

DNA methyltransferase 3A (DNMT3A) is a de novo cytosine methyltransferase responsible for establishing proper DNA methylation during mammalian development. Loss-of-function (LOF) mutations to DNMT3A, including the hotspot mutation R882H, frequently occur in developmental growth disorders and hematological diseases, including clonal hematopoiesis and acute myeloid leukemia. Accordingly, identifying mechanisms that activate DNMT3A is of both fundamental and therapeutic interest. Here, we applied a base editor mutational scanning strategy with an improved DNA methylation reporter to systematically identify DNMT3A activating mutations in cells. By integrating an optimized cellular recruitment strategy with paired isogenic cell lines with or without the LOF hotspot R882H mutation, we identify and validate three distinct hyperactivating mutations within or interacting with the regulatory ADD domain of DNMT3A, nominating these regions as potential functional target sites for pharmacological intervention. Notably, these mutations are still activating in the context of a heterozygous R882H mutation. Altogether, we showcase the utility of base editor scanning for discovering functional regions of target proteins.

Smoking Cessation Interventions Among Asian Americans: a Scoping Review.

BACKGROUND: Tobacco use is the leading cause of morbidity and mortality in the USA, with smoking rates remaining disproportionately high among Asian-Americans, particularly in males with limited English proficiency, including Vietnamese (43%), Korean (37%), and Chinese (29%) Americans. Barriers to smoking cessation in this population include high social acceptability of smoking in participants' countries of origin, low quit intention, and limited use of linguistically appropriate smoking cessation resources. This paper aims to conduct a systematic review of studies evaluating the effectiveness of smoking cessation interventions targeting Asian-Americans. METHODS: The researchers conducted a thorough search of Scopus, Medline, Cochrane Central, and Google Scholar from 2006 through March 2022, as well as reference lists of relevant articles. The inclusion criteria for the studies were that they described smoking cessation interventions for Asian-Americans and Asian immigrants, and reported outcomes related to feasibility, acceptability, usability, and smoking-related outcomes. RESULTS: The review identified 14 studies with a total of 5607 participants, with participant numbers ranging from 26 to 2277. The interventions varied across 14 distinct approaches, with individual counseling being a prominent component. These interventions were found to be feasible and culturally acceptable. All studies reported positive smoking-related outcomes, including abstinence rates ranging from 26.7 to 68% and an increase in quit attempts. Culturally sensitive components and linguistically tailored content played a significant role in promoting participant engagement. The retention rates in the studies ranged from 42 to 100%, highlighting the importance of partnership with the Asian community, cultural and ethnic congruence, and family involvement and support. CONCLUSION: The review highlighted the lack of direct in-language treatment as a disadvantage for Asian-American smokers in accessing evidence-based treatments. Despite this, the review reported the feasibility, acceptability, and effectiveness of a limited number of culturally targeted interventions for Asian-Americans, who are the fastest-growing racial-ethnic group. Future research should focus on exploring novel community-based and culturally adapted approaches for hard-to-reach and high-risk ethnic Asian subgroups to further improve smoking cessation outcomes in this population.

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress.

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.

Deciphering cell signaling networks with massively multiplexed biosensor barcoding.

Genetically encoded fluorescent biosensors are powerful tools for monitoring biochemical activities in live cells, but their multiplexing capacity is limited by the available spectral space. We overcome this problem by developing a set of barcoding proteins that can generate over 100 barcodes and are spectrally separable from commonly used biosensors. Mixtures of barcoded cells expressing different biosensors are simultaneously imaged and analyzed by deep learning models to achieve massively multiplexed tracking of signaling events. Importantly, different biosensors in cell mixtures show highly coordinated activities, thus facilitating the delineation of their temporal relationship. Simultaneous tracking of multiple biosensors in the receptor tyrosine kinase signaling network reveals distinct mechanisms of effector adaptation, cell autonomous and non-autonomous effects of KRAS mutations, as well as complex interactions in the network. Biosensor barcoding presents a scalable method to expand multiplexing capabilities for deciphering the complexity of signaling networks and their interactions between cells.

Rates and Risk Factors for Post-Traumatic Stress Disorder Symptomatology among Adult Hematopoietic Cell Transplant Recipients and Their Informal Caregivers.

Hematopoietic cell transplant (HCT) can cause significant distress in patients and their informal caregivers. Despite advances in reduced-intensity conditioning and supportive care, few recent studies have reported rates of clinically significant post-traumatic stress disorder (PTSD) symptomatology. Goals of the current study were to examine rates of PTSD and distress in patients and caregivers and to identify sociodemographic and clinical risk factors for PTSD. As part of an annual survivorship survey, 2157 HCT recipients and their caregivers were mailed self-report measures of PTSD and distress. Patients also completed self-report measures of sociodemographic information (eg, age, sex, employment status). Clinical variables (eg, time since transplant, transplant type) were captured in the transplant database. A total of 691 recipients (56% age 60 or above at the time of survey, 47% women, median 10.1 years post-HCT) and 333 caregivers provided PTSD data and were included in the current analyses. More caregivers reported PTSD (6.6%) than patients (3.3%; P = .02). Patients or caregivers who had PTSD reported significantly higher distress related to uncertainty, family strain, medical demands, finances, identity, and health burden (P < .0001) compared with those without PTSD. Patient but not caregiver PTSD was associated with more recent transplant (P = .01 and P = .16, respectively). Rates of PTSD are relatively low in long-term survivors of HCT and their caregivers. Nevertheless, results are consistent with other studies of cancer caregiving suggesting that caregivers often experience greater distress than patients. Timely referral to psychosocial services should be offered to both HCT recipients and caregivers reporting symptoms of PTSD.

Telemedicine and Mobile Health Technology Are Effective in the Management of Digestive Diseases: A Systematic Review.

BACKGROUND: Mobile applications and interactive websites are an increasingly used method of telemedicine, but their use lacks evidence in digestive diseases. AIM: This study aims to explore digestive disease studies that use telemedicine to effectively manage disease activity, help monitor symptoms, improve compliance to the treatment protocol, increase patient satisfaction, and enhance the patient-to-provider communication. METHODS: EBSCO, PubMed, and Web of Science databases were searched using Medical Subject Headings and other keywords to identify studies that utilized telemedicine in patients with digestive disease. The PRISMA guidelines were used to identify 20 research articles that had data aligning with 4 common overlapping themes including, patient compliance (n = 13), patient satisfaction (n = 11), disease activity (n = 15), and quality of life (n = 13). The studies focused on digestive diseases including inflammatory bowel disease (n = 7), ulcerative colitis (n = 4), Crohn's Disease (n = 1), irritable bowel syndrome (n = 6), and colorectal cancer (n = 2). RESULTS: From the studies included in this systematic review, patient compliance and patient satisfaction ranged between 25.7-100% and 74-100%, respectively. Disease activity, measured by symptom severity scales and physiological biomarkers, showed improvements following telemedicine interventions in several, but not all, studies. Similar to disease activity, general and disease-specific quality of life showed improvements following telemedicine interventions in as little as 12 weeks in some studies. CONCLUSION: Telemedicine and mobile health technology may be effective in managing disease activity and improving quality of life in digestive diseases. Future studies should explore both gastrointestinal and gastroesophageal diseases using these types of interventions.

Associations Between Parental BMI and the Family Nutrition and Physical Activity Environment in a Community Sample.

The purpose of this study was to examine the relationship between parental BMI and the family environment and determine if differences exist in child diet and physical activity related parenting behaviors by parental BMI in a community sample of families recruited through elementary schools in a local school district. We found an association between parental BMI category and family nutrition and physical activity (FNPA) score. Families with an underweight or normal weight parent had a larger proportion (64.3%) of high (indicating a healthier family environment) FNPA scores and families with an overweight or obese parent had a smaller proportion (45.2%) of high FNPA scores (χ 2 = 5.247, P = 0.022). Families with a parent who was overweight or obese had 2.18 times the odds (95% CI 1.11-4.27) of being in the low FNPA ("less healthy" environment) group. Further, underweight/normal weight parents reported higher levels of monitoring of child diet (Z = -3.652, P < 0.0001), higher levels of parental monitoring of child physical activity (Z = -3.471, p < 0.001), and higher levels of parental limit setting related to child sedentary activities compared to overweight/obese parents (Z = -2.443, P = 0.01). Parent BMI and parenting behaviors are known to have a major impact on childhood obesity. In this study, lower parent BMI and authoritative parenting behaviors were associated with a less obesogenic home environment and a positive parenting style related to child eating and physical activity behaviors.