Genetic Categories Research Articles

Genetic Risk, Health-Associated Lifestyle, and Risk of Early-onset Total Cancer and Breast Cancer.

Early-onset cancer (diagnosed under age 50) generally manifests as an aggressive disease phenotype. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants remains unclear. We analyzed a prospective cohort of 66,308 participants who were under age 50 and free of cancer at baseline in the UK Biobank. Using Cox regression, we estimated Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer based on sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs). In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI: 1.83, 1.49-2.26) and males (2.03, 1.51-2.73) as well as early-onset breast cancer in females (3.06, 2.20-4.26). An unfavorable lifestyle (highest vs lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer and breast cancer was stronger in the highest genetic risk category than the lowest: HRs (95% CIs) were 1.55 (1.12, 2.14) and 1.69 (1.11, 2.57) in the highest genetic risk category and 1.03 (0.64, 1.67) and 0.81 (0.36, 1.85) in the lowest. Genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.

Healthy lifestyle practice correlates with decreased obesity prevalence in individuals with high polygenic risk: TMM CommCohort study.

Obesity and overweight, fundamental components of the metabolic syndrome, predispose individuals to lifestyle-related diseases. The extent to which adopting healthy lifestyles can reduce obesity risk, even in those with a high genetic risk, remains uncertain. Our aim was to assess the extent to which lifestyle modifications can improve outcomes in individuals with a high polygenic score (PGS) for obesity. We quantified the genetic risk of obesity using PGSs. Four datasets from the Tohoku Medical Megabank Community-Based Cohort (TMM CommCohort) were employed in the study. One dataset (n = 9958) was used to select the best model for calculating PGS. The remaining datasets (total n = 69,341) were used in a meta-analysis to validate the model and to evaluate associated risks. The odds ratio (OR) for obesity risk in the intermediate (11th-90th percentiles in the dataset) and high PGS categories (91st-100th) was 2.27 [95% confidence intervals: 2.12-2.44] and 4.83 [4.45-5.25], respectively, compared to that in the low PGS category (1st-10th). Trend analysis showed that an increase in leisure-time physical activity was significantly associated with reduced obesity risk across all genetic risk categories, representing an OR of 0.9 [0.87-0.94] even among individuals in the high PGS category. Similarly, sodium intake displayed a positive association with obesity across all genetic risk categories, yielding an OR of 1.24 [1.17-1.31] in the high PGS category. The risk of obesity was linked to the adoption of healthy lifestyles, even in individuals with high PGS. Our results may provide perspectives for integrating PGSs into preventive medicine.

Adherence to a planetary health diet, genetic susceptibility, and incident cardiovascular disease: a prospective cohort study from the UK Biobank

BackgroundThe influence of adherence to a planetary health diet (PHD) proposed by the EAT-Lancet Commission on cardiovascular disease (CVD) is inconclusive. Besides, whether genetic susceptibility to CVD can modify the association of PHD with CVD remains unknown. ObjectiveWe aimed to investigate the association between adherence to PHD and CVD, and to evaluate the interaction between PHD and genetic predisposition to CVD. MethodsThis study included 114,165 participants who completed at least two 24-h dietary recalls and were initially free of CVD from the UK Biobank. PHD score was calculated to assess adherence to PHD. Genetic risk was evaluated using the polygenic risk score. Incidence of total CVD, ischemic heart disease (IHD), atrial fibrillation (AF), heart failure (HF), and stroke were identified via electronic health records. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). ResultsDuring a median follow-up of 9.9 y, 10,071 (8.8%) incident CVD cases were documented. Compared with participants with the lowest adherence to PHD, HRs (95% CIs) for total CVD, IHD, AF, HF, and stroke among those with the highest adherence were 0.79 (0.74, 0.84), 0.73 (0.67, 0.79), 0.90 (0.82, 0.99), 0.69 (0.59, 0.82), and 0.88 (0.75, 1.04), respectively. No significant interaction between the genetic risk of CVD and PHD was observed. Participants with high genetic risk and low PHD score, as compared with those with low genetic risk and high PHD score, had a 48% (95% CI: 40%, 56%) higher risk of CVD. The population-attributable risk (95% CI) of CVD for poor adherence to PHD ranged from 8.79% (5.36%, 12.51%) to 14.00% (9.00%, 18.88%). ConclusionsThese findings suggest that higher adherence to PHD was associated with lower risk of total CVD, IHD, AF, and HF in populations across all genetic risk categories.

Quality of human-animal interactions during beef cattle auctions in Panama

This study aimed to determine the quality of human-animal interactions during cattle auctions in Panama and to assess the relationship between cattle reactivity, value paid, and time spent on commercialization. Data were recorded by watching video records of 4531 individual cattle sold in the main Panamanian auctions. Cattle reactivity was assessed by one previously trained observer when the animals entered the box where they were exposed for sale, assigning one of three scores: 1 = calm, 2 = reactive, and 3 = very reactive. Human-animal interactions were assessed using a binary score to assess the occurrence of hitting (1) or not (0) during commercialization. When cattle were hit to stimulate movement, their reactivity was assessed again to determine whether hitting altered their behavior. The value paid (USD/kg of live weight), and the time spent on commercialization (s) of each animal were also recorded in a subsample of 704 animals. Cattle reactivity, genetic group, animal category, auction location and phase of commercialization influenced the occurrence of hits (p<0.05). Hitting altered cattle reactivity (p<0.001); 95 % of the animals scored calm when they entered the auction box, dropped to 85 % after being hit. There was a significant effect of the reactivity score (p<0.05), genetic group (p=0.01), location (p<0.001) and auction phase (p=0.002) on the number of hits received by the cattle when inside the auction box. The median value paid for very reactive cattle tended to be higher than for calm cattle (1.85 vs 1.82 USD/kg; respectively; p=0.06). There were no differences in the time spent on commercialization according to cattle reactivity (p>0.05). In conclusion, cattle reactivity, and auction phase, in addition to other factors such as genetic group, animal category, and auction location, affected the frequency of negative human-animal interactions during commercialization. Cattle reactivity tended to affect the price paid per head of cattle but not the time spent in marketing.

Abstract PO4-08-10: Genetic mutations and associated rates of pathologic complete response among a diverse patient population with early stage triple negative breast cancer

Abstract Background: Combination treatment with chemotherapy and immunotherapy remains the standard of care for high risk, early-stage triple negative breast cancer (TNBC). Although the addition of immunotherapy improves rates of pathologic complete response (pCR) and event-free survival, approximately 50% of patients achieve pCR with neoadjuvant chemotherapy alone suggesting that some patients may safely avoid the potential toxicities of immunotherapy without compromising outcomes.1,2 Markers of immune activation including PD-L1 expression and tumor infiltrating lymphocytes have demonstrated prognostic significance; however, identifying a predictive biomarker to aid in selecting those patients most likely to benefit from immunotherapy remains an unmet need.3,4 Genetic mutations are suggestive of DNA susceptibility to damage and the role they may play as a potential marker of immune response is unclear.5,6 This study explores genetic analysis and mutation rates among a diverse cohort of patients with TNBC to identify patterns associated with and without pCR. Methods: We evaluated 105 women diagnosed with Stage I-III TNBC and treated with combination neoadjuvant chemotherapy and immunotherapy at Ochsner Cancer Center between December 2019 through June 2022. Exclusion criteria included ER+, PR+, HER2+, or unknown receptor status, no pembrolizumab in the neoadjuvant setting, no definitive surgery following neoadjuvant treatment, absence of documented race and age less than 18 years of age. Data was collected utilizing Epic Slicer Dicer program, in addition to chart review. Genetic analysis was performed using a variety of DNA-based next generation sequencing analysis platforms. Results: 91 patients met inclusion criteria. 17 patients were found to have pathogenic mutations (BRCA1/2, POLE and ATM), 38 patients had variants of undetermined significance (VUS) and 36 patients had neither. Among patients with pathogenic genetic mutations, 81.25% had a pCR following neoadjuvant treatment compared to 58.33% of those with a VUS and 47.06% of those with no known mutation (p=0.07). Before adjusting for age and stage, patients with a pathogenic mutation were 73% more likely to achieve pCR than those with no known genetic mutations (crude RR: 1.73, 95% CI: 1.13-2.65). After adjusting for age and stage, the relationship was not statistically significant (aRR: 1.15, 95% CI: 0.78-1.34). Among the 47 Black patients, 5 were found to have a pathogenic mutation and 29 had a VUS. 11 of the 39 White patients were found to have a pathogenic mutation while only 6 had a VUS. Across all genetic mutation categories, Black patients experienced lower rates of pCR than White patients. White patients with a known pathogenic mutation had the highest rate of pCR at 90.91%, while Black patients with no identified mutation had the lowest rate of pCR at 38.46%. The generalizability of these results may be limited due to small sample size. Conclusion: Our results demonstrating higher rates of genetic variants among patients achieving pCR regardless of race highlight the importance of better understanding how these variants correlate with tumor mutational burden (TMB) and further, the role this may play in predicting immune-response. Larger studies are needed to assess TMB as a predictive biomarker in early-stage TNBC as this may provide opportunities to further individualize treatment and minimize toxicity among this group of patients. Additionally, given differences in the prevalence of pathogenic mutations and VUS among Black patients, better understanding the relationship between mutation status and immune response is imperative to optimize outcomes in this high-risk population. Table. Citation Format: Caitlin Taylor, Melanie Sheen, Rabia Cattie, Victoria Chung, Melyssa Bratton, Meredith Lakey, Erin Biggs. Genetic mutations and associated rates of pathologic complete response among a diverse patient population with early stage triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-10.

ChatGPT accurately performs genetic counseling for gynecologic cancers

ObjectiveArtificial Intelligence (AI) systems such as ChatGPT can take medical examinations and counsel patients regarding medical diagnosis. We aim to quantify the accuracy of the ChatGPT V3.4 in answering commonly asked questions pertaining to genetic testing and counseling for gynecologic cancers. MethodsForty questions were formulated in conjunction with gynecologic oncologists and adapted from professional society guidelines and ChatGPT version 3.5 was queried, the version that is readily available to the public. The two categories of questions were genetic counseling guidelines and questions pertaining to specific genetic disorders. The answers were scored by two attending Gynecologic Oncologists according to the following scale: 1) correct and comprehensive, 2) correct but not comprehensive, 3) some correct, some incorrect, and 4) completely incorrect. Scoring discrepancies were resolved by additional third reviewer. The proportion of responses earning each score were calculated overall and within each question category. ResultsChatGPT provided correct and comprehensive answers to 33/40 (82.5%) questions, correct but not comprehensive answers to 6/40 (15%) questions, partially incorrect answers to 1/40 (2.5%) questions, and completely incorrect answers to 0/40 (0%) questions. The genetic counseling category of questions had the highest proportion of answers that were both correct and comprehensive with ChatGPT answering all 20/20 questions with 100% accuracy and were comprehensive in responses. ChatGPT performed equally in the specific genetic disorders category, with 88.2% (15/17) and 66.6% (2/3) correct and comprehensive answers to questions pertaining to hereditary breast and ovarian cancer and Lynch syndrome questions respectively. ConclusionChatGPT accurately answers questions about genetic syndromes, genetic testing, and counseling in majority of the studied questions. These data suggest this powerful tool can be utilized as a patient resource for genetic counseling questions, though more data input from gynecologic oncologists would be needed to educate patients on genetic syndromes.

Stirling engine multi-objective optimization using a genetic algorithm

With the growing demand of energy globally, the actual worrying state of the earth’s finite resources, namely fossil fuels, opens up the scope of energy researches to innovative and efficient solutions. Stirling engine has been an interesting subject of study since its invention, and many studies dealt with Stirling engine efficiency with attempts to optimize it in order to have a proper use of the engine in the real world, depending on the use cases. Stirling engine is an external combustion engine with a theoretical efficiency equivalent to that of Carnot. Alongside the global awareness to use efficient and less resource consuming solutions, there has been a spiking growth in the set of tools that are conceived to achieve that; specifically in the machine learning area. Among the various available algorithms, the one used in the hereby study is the non-sorted genetic algorithm II, which falls into the genetic algorithms category. This algorithm is well suited for multi-objective optimization problems; it consists of selecting the best design parameters that are contained in predefined upper and lower bounds, based on multiple objective functions.

FEATURES OF THE FORMATION, INTAKE AND DISTRIBUTION OF THE IRON-CONTAINING COMPONENT IN THE WATER SUSPENSION OF THE DNIEPER RIVER WITHIN ZAPORIZHZHIA CITY

The article presents the results of research devoted to one of the aspects of environmental issues, namely: the determination of the distribution features of the solid component of the river suspension containing iron oxide; investigation of the morphological characteristics of iron-containing particles; and the discovering of their genetic affiliation to various technological processes of metallurgical production. The results of many years of continuous comprehensive research on the distribution of iron in the suspended matter of the Dnieper water within Zaporizhzhia city are presented. Field observations were carried out by scientists of the Institute of Geological Sciences of the National Academy of Sciences of Ukraine (IGS) in cooperation with specialists from the State Institution “Scientific Hydrophysical Center of the National Academy of Sciences of Ukraine” (SHC). Analytical studies of the solid phase of the suspended matter were done in the Center for Collective Use of Scientific Equipment of the National Academy of Sciences of Ukraine and the Educational and Scientific Institute “Institute of Geology” of Taras Shevchenko Kyiv National University. The publication considers the seasonal features of the distribution of the total iron content in suspension and the relationship of its monthly changes with the distribution of concentrations of such heavy metals as copper, chromium, nickel, zinc. Considerable attention is paid to the examination of iron-containing particles present in suspension, their chemical and trace element composition and the allocation of their individual categories in accordance with the technogenic processes during which they were formed. Comprehensive analysis of suspension samples made it possible to identify and classify a group of typical iron-bearing formations that are inherent in the territory of Zaporizhzhia city. Based on a set of characteristics, three main genetic categories have been identified: spherical mineral aggregates represented by iron oxide; clastic fragments of Fe2O3, and aluminosilicate spherules (formation, the main or essential component of which is aluminum oxide with an admixture of iron). The obtained data showed a significant influence of the metallurgical industry on the chemical composition of the Dnieper suspension within Zaporizhzhia. Comparison of iron-containing particles observed in the Dnieper suspended matter with the substance filtered out by gas purification systems of various parts of metallurgical production and slag deposits showed that the most active emission to the environment occurs during the preparation and smelting of iron ore.

Abstract B062: Prevalence of pathogenic BRCA1/2 variants among Latinas in the All of Us Cohort

Abstract Latinas in the United States are disproportionately affected by breast cancer, but little is known about genetic risk factors for breast cancer in this population. Genetic variants in BReast CAncer genes 1 and 2 (BRCA1/2) are known to be associated with heritable cancer risk, yet the prevalence of BRCA1/2 pathogenic variants in the Latina population is not well characterized. This study aims to examine the prevalence of pathogenic BRCA1/2 variants among Latinas in the NIH All of Us research program, which includes a large number of individuals representative of the diversity of the United States population. Using data from the All of Us research program, we will analyze the prevalence of these variants among Latinas, in addition to all other racial and ethnic groups. To date, the All of Us cohort contains 245,400 genomes, and of those 41,940 (17%) are from self-identified Hispanic/Latino/or Spanish participants. We will compare the prevalence of pathogenic, or likely pathogenic, variants across self-reported race/ethnicity and continental genetic ancestry categories. Our study will leverage the diversity of All of Us and enable us to compare our data with those from more Eurocentric databases. With these data, we can potentially 1) identify novel variants that could predispose to increased cancer risk; and 2) clarify the previous designations of variants characterized to have undetermined/unknown significance due to the limitations of using a single Eurocentric reference genome. Identifying the actual prevalence of pathogenic BRCA1/2 variants among Latinas is important for improving breast cancer prevention, detection, and treatment in this population. The findings of this study have the potential to inform genetic counseling and testing recommendations for Latina patients at high risk of developing breast cancer, as well as others. This will also enable healthcare providers to better understand the unique genetic factors contributing to breast cancer risk among this population. Ultimately, this knowledge can improve the care of Latina patients and contribute to the broader effort to advance health equity and reduce disparities in breast cancer outcomes among Latinas. Citation Format: Cathy Samayoa, Erick Olivares, Catherine Gavile, Adriana Visbal. Prevalence of pathogenic BRCA1/2 variants among Latinas in the All of Us Cohort [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B062.

Analysis of Post-Transplant Clinical Outcomes and Prognostic Factors in FLT3-ITD Mutated Acute Myeloid Leukemia Patients Under ELN 2022 Risk Stratification

Background In 2022 European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML), one of the most important changes made to the genetic risk classification of AML is that the FLT3-ITD allelic ratio (AR) is no longer considered in the risk classification; consequently, AML with FLT3-ITD (without adverse-risk genetic lesions) are now categorized in the intermediate-risk group, irrespective of the allelic ratio or concurrent presence of NPM1 mutation. Aims To investigate the survival outcomes of FLT3-ITD mutated AML patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), based on prognostic stratification defined by the 2017 and 2022 ELN guidelines, and to analyze the risk factors affecting transplant prognosis. Methods A total of 163 FLT3-ITD mutated AML patients underwent allo-HSCT were enrolled in this study. Bone marrow aspirates were obtained, cytogenetic and molecular characteristics were collected at the time of diagnosis. Genetic risk category was classified according to the 2017 and 2022 edition of the European LeukemiaNet (ELN) recommendations. HLA-haploidentical donor transplants were performed if no HLA matched sibling or unrelated donor was available. Patients received myeloablative conditioning with a modified Bu/Cy/Flu/Ara-c (busulfan/cyclophosphamide/fludarabine/cytarabine) or MCBC (melphalan/cladribine/busulfan/cyclophosphamide) preparative regimen. The therapeutic process and clinical outcomes were retrospectively analyzed. Results We assessed 163 adults with FLT3-mutated AML (median age 37 years) allografted between 2017 and 2022 in our clinical center. The median follow-up of alive patients was 24.9 months. The 2-year relapse-free survival (RFS) and overall survival (OS) were 67.2% and 71.9%, respectively. The 2-year incidences of relapse and non-relapse mortality were 27.9% and 12.5%, respectively. There was no significant difference in survival outcomes between the intermediate and high-risk groups after transplantation, both defined by the 2017 and 2022 ELN guidelines. High FLT3-ITD allelic ratio (≥0.5) at initial diagnosis was associated with elevated WBC counts ( P&amp;lt;0.001), but did not affect the response ratefollowing induction chemotherapy ( P=0.059) . Patients with high allelic ratio were more likely to benefit from maintenance therapy after transplantation ( P=0.048 for OS). In univariate analysis, presence of NPM1 mutation and the allelic ratio of FLT3-ITD did not affect any of the transplant outcomes. In multivariate analysis, MRD-negative at transplantation, occurrence of chronic GVHD and posttransplant maintenance therapy improved OS and RFS. Conclusion Allo-HSCT can overcome the poor prognosis in patients with FLT3-ITD mutated AML. Neither the presence of NPM1 mutation nor the FLT3-ITD allelic ratio affected survival. Prevention of disease relapse after transplantation remains a challenge. The main prognostic factors affecting transplant outcomes included pre-transplant MRD status and the application of maintenance therapy. Thus, introduction of FLT3 inhibitors as post-transplant maintenance therapy and the development of highly sensitive MRD assays will further reduce disease recurrence and improve survival.

Comparing the Efficacy and Safety of Venetoclax Combined with Decitabine Versus Conventional Chemotherapy As Induction Therapy for Young Adults with Newly Diagnosed Acute Myeloid Leukemia - Interim Analysis of a Multicenter, Randomized, Phase 2b Trial

Introduction: Venetoclax in combination with hypomethylating agents (HMAs) is a first-line induction regimen recommended by NCCN guidelines for older or unfit AML patients. In a phase 2 study (NCT04752527) from our group, venetoclax plus decitabine (VEN-DAC) resulted in a 93% of response rate in young adult patients with newly diagnosed (ND) ELN adverse-risk AML. Currently, there is a lack of data on the VEN-DAC regimen in ND young adults with favorable or intermediate risk AML who are fit for intensive chemotherapy. There are also no studies directly comparing the VEN-DAC regimen with intensive chemotherapy in patients with ND AML. Here, we report the results of an interim analysis of a multicenter, randomized, phase 2b trial (NCT05177731) , which explored the efficacy and safety of VEN-DAC versus intensive chemotherapy (idarubicin and cytarabine) in ND AML patients. Methods: Adult patients with newly diagnosed AML aged between 18 and 59 years were enrolled. The diagnosis was made according to the WHO 2016 criteria. Risk stratification was performed according to the 2017 ELN recommendations. Eligible patients were randomized in a 1:1 ratio to the VEN-DAC group (decitabine 20mg/m 2 on days 1-5 and venetoclax at an escalated dose of 100mg, 200mg and 400mg by day 28) or the IA-12 group (idarubicin 12mg/m 2 on days 1-3 and cytarabine 100mg/m 2 on days 1-7). Patients who did not respond to the treatment were allowed to receive another cycle of the original induction regimen. Intermediate-dose cytarabine (2g/m 2, q12h, days 1-3) were applied as consolidation therapy. The primary endpoint was the composite complete remission (CRc, including complete remission, CR and complete remission with incomplete hematologic recovery, CRi). The secondary endpoints included measurable residual disease (MRD) negative remission (defined as &amp;lt;1×10 -3 by flow cytometry), event-free survival (EFS) , overall survival (OS) and adverse events. Results: Since March, 2022, a total of 163 patients with AML were screened and 116 patients were randomized. Sixty patients received the VEN-DAC regimen and 55 patients received the IA-12 regimen. There were no differences in baseline characteristics between the two groups of patients (Table 1). Bythe cut-off date of July 11, 2023, a total of 102 patients have been evaluated, 55 in the VEN-DAC group and 47 in the IA-12 group. The overall CRc rate in the VEN-DAC group was 85.5%, which was comparable to that of the IA-12 group (78.7%, P=0.37). The MRD-negative CR rate in the VEN-DAC group was 67.3%, which was much higher than that in the IA-12 group (53.2%) ( P=0.147). According to univariate analysis, efficacy of the VEN-DAC regimen did not differ from that of the IA-12 regimen with respect to sex, age, initial bone marrow blast count, genetic risk category, and major molecular markers (Figure 1A). Notably, the CRc rate and MRD-negative CR rate were significantly higher in the VEN-DAC group than in the IA-12 group for intermediate-risk and adverse-risk patients, especially those with adverse risk ( P=0.031 for CRc, P=0.029 for MRD-negative CR) (Figure 1A). At median follow-ups of 7.8 months (range, 0.9-16.6), the EFS and OS were not reached in both groups. The median time for platelets to recovery to 20×10 9/L or above in the VEN-DAC group was 12 days after induction in the VEN-DAC group, which was shorter than that in the IA-12 group (21 days) ( P&amp;lt;0.01). In addition, patients in the VEN-DAC group required fewer platelet (5 U vs 7 U, P&amp;lt;0.01) and red blood cell infusions (3 U vs 5 U, P=0.023) during induction as compared with that in the IA-12 group. In addition, the incidence of grade 3 or higher febrile neutropenia (41.8% vs. 83.0%), infection (27.3% vs. 72.3%) and sepsis (5.5% vs. 31.9%) were all significantly lower in the VEN-DAC group than in the IA-12 group ( P&amp;lt;0.01) (Figure 1B). Conclusion: In newly diagnosed young AML patients, venetoclax in combination with decitabine as an induction regimen had comparable efficacy and a higher safety profile compared to IA-12 regimen. In particular, patients with adverse-risk AML showed higher and deeper remission rate in the venetoclax plus decitabine group as compared with the IA-12 group.

Use of Geriatric Assessment and Genetic Profiling to Personalize Selection of Intensive Versus Low Intensity Chemotherapy in Older Adults with Acute Myeloid Leukemia (AML): Final Results of a Phase II Trial

Introduction: Geriatric assessment can predict the risk of toxicities of chemotherapy in older adults. Genetic risk categories are associated with survival following intensive chemotherapy in AML. Integrating geriatric assessment for patient profiling and genetic profiling of leukemic cells represents an innovative precision medicine approach to personalize therapy selection in older adults with AML. We report final results of a pragmatic phase II trial using such strategy, aiming to reduce early mortality (NCT03226418). Methods: Patients ≥60 years with a new diagnosis of AML underwent geriatric assessment prior to initiation of treatment. Geriatric assessment of physical function, cognitive function and comorbidity burden were used to determine fitness for intensive chemotherapy (Table 1). Additional assessment included Karnofsky Performance Scale (KPS), Patient Health Questionnaire-9 (PHQ-9), and Mini Nutritional Assessment-Short Form (MNA). Genetic profiling for therapy selection relied on karyotyping and followed the 2017 European LeukemiaNet criteria. While available mutation test results were incorporated to risk stratify, the study did not require waiting for the results prior to therapy initiation, given an anticipated turnaround time of 1-2 weeks for mutation test results. Therapy selection followed the algorithm in Figure 1. Patients with good or intermediate-risk AML received intensive chemotherapy such as 7+3 +/- gemtuzumab or midostaurin if determined to be fit. Patients with high-risk AML received low-intensity chemotherapy such as a hypomethylating agent with or without venetoclax or novel drugs (based on timing of FDA approval of these drugs), or CPX 351 if they were fit and met the FDA-approved indications. Patients with organ dysfunction (e.g. creatinine ≥2 mg/dl) and those requiring chemotherapy for other malignancy were eligible for low-intensity chemotherapy. Chemotherapy could be administered in community oncology settings. Patients were followed for quality of life assessments, as well as functional and oncologic outcomes. Results: Between July 2017-October 2022, 75 patients were consented; 2 patients were considered screen failure. Baseline characteristics of 73 eligible patients included a median age of 69 years (range 60-87 years), 49% female, 92% white, and a median KPS of 80 (range 60-100). As presented in Table 1, most had ≥3 comorbidities (55%), impaired physical function measured by Short Physical Performance Battery (70% had a score of 9 or less) and impaired cognition measured by Montreal Cognitive Assessment (64% had a score of 25 or less). Genetic risk categories included adverse (62%), intermediate (22%), and good-risk AML (16%). Patients had one or more of the following mutations: TET2 (26%), NPM1 (22%), RUNX1 (19%), ASXL1 (19%), TP53 (19%), DNMT3A (16%), IDH2 (15%), IDH1 (11%), FLT3 ITD (10%), FLT3 TKD (10%), biallelic CEBPA (4%), EZH2 (2%). Seven patients (10%) received intensive chemotherapy; CPX 351 (n=4) or 7+3 based regimen (n=3). Other patients received low-intensity chemotherapy: azacitidine or decitabine and venetoclax (n=43, 59%), decitabine or azacitidine alone (n=18, 24%) prior to approval of venetoclax, and other (n=5, 7%). The median time from diagnosis to therapy initiation was 6 days and from enrollment to therapy initiation was 1 day (range 0-13). Mortality at 30 days from diagnosis was 6.8% (95% confidence interval, CI 3.0-15.1%) and at 90 days was 21.9% (95% CI 14.0-32.7%). Mortality compared favorably to an unmatched historical cohort of patients ≥60 years treated at our center between 2011-2016, where 30-day mortality was 30% (95% CI 22-40%) and 90-day was 41% (95% CI 32-52%) (Future Oncol. 2019;15:1989-95). Conclusions: Our model to personalize AML therapy selection represents an innovative approach to precision medicine that incorporates both geriatric assessment for patient profiling and genetic profiling of leukemia cells. Geriatric assessment demonstrated high frequency of impairment in objective physical and cognitive function. Patients were able to start therapy within a median of 1 day following enrollment. Pragmatic aspects of the trial included broad eligibility criteria and co-management of patients with community oncologists. The results from our final analysis appear promising with lower rates of early mortality compared to unmatched historical controls.

Education counteracts the genetic risk of Alzheimer's disease without an interaction effect.

Alzheimer's disease (AD) is a major cause of disability and mortality in older adults. This study aimed to investigate the association of AD with education and genetic factors. We conducted a prospective cohort study using data from the UK Biobank. Genetic risk was assessed using a polygenic risk score for AD. The educational level was categorized as either low, intermediate, or high. AD was defined using the International Classification of Diseases and Related Health Problems, 10th revision. Logistic regression models were used to investigate the independent and combined effects of genetic factors and educational levels on the risk of AD. We included 318,535 participants in this study (age: 56.53 ± 8.09 years; male: 44.81%). Compared with a low genetic risk, a high genetic risk was associated with a significantly greater risk of AD (OR = 7.09, 95% CI: 6.09-8.26). A high educational level was associated with a 30% lower risk of AD compared with a low educational level (OR = 0.70, 95% CI: 0.60-0.81). Combining genetic risk and education categories, individuals with a low genetic risk and high educational level had a more than 90% (OR = 0.09, 95% CI: 0.05-0.16) lower risk of AD compared to those with a high genetic risk and low educational level. There was no significant interaction between genetic risk and educational level regarding AD risk (p for interaction = 0.359). Education counteracts the genetic risk of AD, without an interaction effect. Increasing education to reduce the incidence of AD is of same importance across individuals with different genetic risk.

Possible genetic relationship between Mesozoic magmatic rocks and gold mineralization in the Jiaodong Peninsula (Eastern China): constraints of magmatic evolution and physicochemical conditions

The Jiaodong Peninsula is China’s largest gold province and the third largest in the world. Although gold mineralization is associated with Mesozoic granites temporally and spatially, the specific genetic association remains unclear, leading to ambiguity regarding the genetic type of gold deposits. To address this issue, we conducted whole-rock major and trace elements, LA–ICP–MS zircon U–Pb geochronology and trace elements geochemical analyses on the Linglong (Linglong suite), Yashan, and Nansu (Weideshan suite) plutons, and compiled contemporaneous magmatic rock data. Our results show that the granites were emplaced at 161 ± 2, 118 ± 1, and 121 ± 2 Ma, respectively. Geochemically, these rocks exhibit high Al2O3 (12.73–14.10 wt%) content and Sr/Y (35.54–136.50) ratio, and low Y (3.26–11.20 ppm) and Yb (0.33–0.97 ppm) contents, indicating the adakitic rock properties. They were formed through partial melting of the thickened lower crust associated with subduction of the paleo-Pacific Plate. The Early Cretaceous granites contain a large amount of mafic microgranular enclaves, indicating the presence of mantle material mixing in the source area. Zircon trace elements show that the pre-mineralization magma (Linglong) had relatively low oxygen fugacity and temperature (ΔFMQ = −2.5 to +1.9, T-Ti in zircon (mean) = 740°C) compared to the mineralization magma (ΔFMQ = +0.5 to +3.9, T-Ti in zircon (mean) = 755°C). The physicochemical conditions in the pre-mineralization magma source area may be favorable for sulfide accumulation (may including gold). During the Early Cretaceous, North China Craton decratonization reached its climax, and a large number of adakitic crust-mantle mixed oxidized magma upwells, allowing for the migration and mineralization of a large amount of sulfides and gold. This model helps explain the transient, explosive, and genetic categories in Jiaodong gold deposits.

Long-term exposure to ambient air pollution, genetic susceptibility, and the incidence of bipolar disorder: A prospective cohort study

There is mounting recent evidence showing that air pollution exposure may be related to the risk of mental health, yet the association between long-term exposure to air pollution and the risk of incident bipolar disorder (BD) remains unclear. Thus we aim to identify associations between air pollution and the incidence of BD in a prospective population-based cohort. In total, 482,726 participants who were free of BD from the UK Biobank were included in this prospective study. We applied time-varying Cox proportional hazards models, accounting for relevant confounders, and used annual-year moving averages of air pollution as time-varying exposures. The genetic risk for BD was categorized into three categories (low, intermediate, and high) according to the tertiles of polygenic risk score. During a median of 10.79-year follow-up, 923 incident BD events were recorded. Long-term exposures to PM2.5, PM10, NO2, and NOx were associated with increased BD risk. Estimated HRs (95% CIs) for each interquartile range increase in PM2.5, PM10, NO2, and NOx concentrations were 1.31 (1.18–1.45), 1.19 (1.09–1.31), 1.19 (1.08–1.30), and 1.16 (1.07–1.26), respectively. Associations were still observed and even stronger at pollutant concentrations lower than WHO air quality guideline. In subgroup analysis stratified by genetic risk, we observed consistent associations between all pollutants and BD risk in intermediate and high genetic risk groups, but not in low genetic risk group. For example, the HRs (95% CIs) for PM2.5 were 1.00 (0.94–1.53), 1.30 (1.06–1.59), and 1.34 (1.16–1.54) in low, intermediate, and high genetic groups, respectively. In conclusion, long-term exposure to air pollution was significantly associated with an elevated risk of BD. Associations of air pollution with BD occurred only within intermediate and high genetic risk categories and were even stronger at the pollutants levels below WHO air quality guidelines. These findings could help inform policy makers regarding ambient air quality standards and BD management.

Quantifying uncertainty in inferences of landscape genetic resistance due to choice of individual-based genetic distance metric.

Estimates of gene flow resulting from landscape resistance inferences frequently inform conservation management decision-making processes. Therefore, results must be robust across approaches and reflect real-world gene flow instead of methodological artefacts. Here, we tested the impact of 32 individual-based genetic distance metrics on the robustness and accuracy of landscape resistance modelling results. We analysed three empirical microsatellite datasets and 36 simulated datasets that varied in landscape resistance and genetic spatial autocorrelation. We used ResistanceGA to generate optimised multi-feature resistance surfaces for each of these datasets using 32 different genetic distance metrics. Results of the empirical dataset demonstrated that the choice of genetic distance metric can have strong impacts on inferred optimised resistance surfaces. Simulations showed accurate parametrisation of resistance surfaces across most genetic distance metrics only when a small number of environmental features was impacting gene flow. Landscape scenarios with many features impacting gene flow led to a generally poor recovery of true resistance surfaces. Simulation results also emphasise that choosing a genetic distance metric should not be based on marginal R2 -based model fit. Until more robust methods are available, resistance surfaces can be optimised with different genetic distance metrics and the convergence of results needs to be assessed via pairwise matrix correlations. Based on the results presented here, high correlation coefficients across different genetic distance categories likely indicate accurate inference of true landscape resistance. Most importantly, empirical results should be interpreted with great caution, especially when they appear counter-intuitive in light of the ecology of a species.

Variability in Cochlear Implantation Outcomes in a Large German Cohort With a Genetic Etiology of Hearing Loss.

The variability in outcomes of cochlear implantation is largely unexplained, and clinical factors are not sufficient for predicting performance. Genetic factors have been suggested to impact outcomes, but the clinical and genetic heterogeneity of hereditary hearing loss makes it difficult to determine and interpret postoperative performance. It is hypothesized that genetic mutations that affect the neuronal components of the cochlea and auditory pathway, targeted by the cochlear implant (CI), may lead to poor performance. A large cohort of CI recipients was studied to verify this hypothesis. This study included a large German cohort of CI recipients (n = 123 implanted ears; n = 76 probands) with a definitive genetic etiology of hearing loss according to the American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines and documented postoperative audiological outcomes. All patients underwent preoperative clinical and audiological examinations. Postoperative CI outcome measures were based on at least 1 year of postoperative audiological follow-up for patients with postlingual hearing loss onset (>6 years) and 5 years for children with congenital or pre/perilingual hearing loss onset (≤6 years). Genetic analysis was performed based on three different methods that included single-gene screening, custom-designed hearing loss gene panel sequencing, targeting known syndromic and nonsyndromic hearing loss genes, and whole-genome sequencing. The genetic diagnosis of the 76 probands in the genetic cohort involved 35 genes and 61 different clinically relevant (pathogenic, likely pathogenic) variants. With regard to implanted ears (n = 123), the six most frequently affected genes affecting nearly one-half of implanted ears were GJB2 (21%; n = 26), TMPRSS3 (7%; n = 9), MYO15A (7%; n = 8), SLC26A4 (5%; n = 6), and LOXHD1 and USH2A (each 4%; n = 5). CI recipients with pathogenic variants that influence the sensory nonneural structures performed at or above the median level of speech performance of all ears at 70% [monosyllable word recognition score in quiet at 65 decibels sound pressure level (SPL)]. When gene expression categories were compared to demographic and clinical categories (total number of compared categories: n = 30), mutations in genes expressed in the spiral ganglion emerged as a significant factor more negatively affecting cochlear implantation outcomes than all clinical parameters. An ANOVA of a reduced set of genetic and clinical categories (n = 10) identified five detrimental factors leading to poorer performance with highly significant effects ( p < 0.001), accounting for a total of 11.8% of the observed variance. The single strongest category was neural gene expression accounting for 3.1% of the variance. The analysis of the relationship between the molecular genetic diagnoses of a hereditary etiology of hearing loss and cochlear implantation outcomes in a large German cohort of CI recipients revealed significant variabilities. Poor performance was observed with genetic mutations that affected the neural components of the cochlea, supporting the "spiral ganglion hypothesis."

Association Between Glucosamine Use and the Risk of Incident Heart Failure: The UK Biobank Cohort Study and Mendelian Randomization Analysis

ObjectiveTo evaluate the association between regular glucosamine intake and heart failure (HF) and to explore whether the association is mediated by relevant cardiovascular disease. Patients and MethodsWe included 479,650 participants with data available for supplement use and without HF at baseline from the UK Biobank study. Using 12 single-nucleotide polymorphisms linked to HF, a weighted genetic risk score was calculated. We evaluated the association between glucosamine use and HF by Cox regression models after inverse probability of treatment weighting. A validation and mediation analysis were performed through two-sample Mendelian randomization. The study was from May 18, 2006, to February 16, 2018. ResultsDuring a median follow-up of 9.0 (IQR, 8.3-9.8) years, we documented 5501 incident cases of HF. In multivariable analysis, the HR of glucosamine users for HF was 0.87 (95% CI, 0.81 to 0.94). The inverse associations were stronger in males and participants with unfavorable lifestyle (P<.05 for interaction). Genetic risk categories did not modify this association (P>.05 for interaction). Multivariable Mendelian randomization showed that taking glucosamine was protective against HF (HR, 0.92; 95% CI, 0.87 to 0.96). The mediated proportion of coronary heart disease and stroke were 10.5% (95% CI, 7.6% to 13.4%) and 14.4% (95% CI, 10.8% to 18.0%), respectively. The two-mediator combination accounted for 22.7% (95% CI, 17.2% to 28.2%) of the effect of glucosamine use. ConclusionRegular glucosamine supplementation was associated with a lower risk of HF regardless of genetic risk status, and to a lesser extent, coronary heart disease and stroke mediated this effect. The results may inform novel pathway for prevention and intervention toward HF.

Mode of transport, genetic susceptibility, and incidence of coronary heart disease

BackgroundCar use has been associated with higher risk of coronary heart disease (CHD). However, whether the associations of transport modes with CHD vary by genetic susceptibility to CHD are unknown. This study aims to investigate the associations of genetic susceptibility and modes of transport with incidence of CHD.MethodsWe included 339,588 white British participants from UK Biobank with no history of CHD or stroke at baseline or within two years of follow-up (52.3% in work). Genetic susceptibility to CHD was quantified through weighted polygenic risk scores derived from 300 single-nucleotide polymorphisms related to CHD risk. Categories of transport mode included exclusive car use and alternatives to the car (e.g., walking, cycling and public transport), separately for non-commuting (e.g., getting about [n=339,588] excluding commuting for work), commuting (in the sub-set in work [n=177,370] who responded to the commuting question), and overall transport (transport mode for both commuting and non-commuting [n=177,370]). We used Cox regression with age as the underlying timescale to estimate hazard ratios (HR) of CHD (n=13,730; median 13.8-year follow-up) and tested the interaction between genetic susceptibility and travel modes with adjustment for confounders.ResultsCompared to those using alternatives to the car, hazards of CHD were higher for exclusive use of cars for overall transport (HR: 1.16, 95% confidence interval (CI): 1.08-1.25), non-commuting (HR: 1.08, 95% CI: 1.04-1.12) and commuting (HR: 1.16, 95% CI: 1.09-1.23), after adjusting for confounders plus genetic susceptibility. HRs of CHD were 1.45 (95% CI: 1.38-1.52) and 2.04 (95% CI: 1.95-2.12) for the second and third tertile of genetic susceptibility to CHD, respectively, compared to the first. There was, in general, no strong evidence of interactions between genetic susceptibility and categories of overall, non-commuting and commuting transport. Estimated 10-year absolute risk of CHD was lower for the alternatives to the car across strata of genetic susceptibility, compared with exclusive use of cars for overall, non-commuting and commuting transport.ConclusionExclusive use of cars was associated with a relatively higher risk of CHD across all strata of genetic susceptibility. Using alternatives to the car should be encouraged for prevention of CHD for the general population including individuals at high genetic risk.

Quantitative analysis of parent-of-origin effect in reproductive and morphological selection criteria in the Pura Raza Española horse.

It is generally assumed that parents make a genetically equal contribution to their offspring, but this assumption might not always hold. This is because the expression of a gene can be blocked by methylation during gametogenesis, and the degree of methylation can depend on the origin of the parental gene (imprinting) or by preferential management associated with genetic merit. The first consequences of this for quantitative genetics is that the mean phenotypes of reciprocal heterozygotes need no longer be the same, as would be expected according to Mendelian heritage. We analysed three mare reproductive traits (reproductive efficiency, age at first foaling and foaling number) and three morphological traits (height at withers, thoracic circumference, and scapula-ischial length) in the Pura Raza Española (PRE) horse population, which possesses a deep and reliable pedigree, making it a perfect breed for analysing the quantitative effect of parent-of-origin. The number of animals analysed ranged from 44,038 to 144,191, all of them with both parents known. The model comparison between a model without parent-of-origin effects and three different models with parent-of-origin effects revealed that both maternal and paternal gametic effects influence all the analysed traits. The maternal gametic effect had a higher influence on most traits, accounting for between 3% and 11% of the total phenotypic variance, while the paternal gametic effect accounted for a higher proportion of variance in one trait, age at first foaling (4%). As expected, the Pearson's correlations between additive breeding values of models that consider parent-of-origin and that do not consider parent-of-origin were very high; however, the percentage of coincident animals slightly decreases when comparing animals with the highest estimated breeding values. Ultimately, this work demonstrates that parent-of-origin effects exist in horse gene transmission from a quantitative point of view. Additionally, including an estimate of the parent-of-origin effect within the PRE horse breeding program could be a great tool for a better parent's selection and that could be of interest for breeders, as this value will determine whether the animals acquire genetic categories and are much more highly valued.