Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. RESULTS: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. CONCLUSIONS: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

Navigating changes: A qualitative study exploring the health-related quality of life of breast cancer survivors during the coronavirus disease 2019 pandemic.

AIMS: To explore the impact of the coronavirus disease 2019 pandemic on the health-related quality of life (HRQoL) of breast cancer survivors. DESIGN: We utilized a qualitative descriptive approach to facilitate interviews among 25 participants, all of whom are survivors of breast cancer and have received treatment in Hong Kong within the preceding 3 years. METHODS: Content analysis was performed to understand how patients' HRQoL views and experiences changed during coronavirus disease 2019 pandemic. RESULTS: The results included six themes delineating the impact of the coronavirus disease 2019 pandemic: (i) survivor sensitivities in pandemic times, (ii) coping and conditioning in pandemic times, (iii) transforming work and home dynamics in pandemic times, (iv) cognitive resilience and adaptation to the COVID-19 protective measures, (v) social resilience in pandemic times and (vi) healthcare adaptation and coping in pandemic times. CONCLUSION: This study provides insights into the experiences and challenges of breast cancer survivors during the coronavirus disease 2019 pandemic. Some survivors had new physical and psychological symptoms, including fear and anxiety, isolation, pain, lymphoedema and burnout, which potentially have long-term impact upon HRQoL. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: This study highlights the unique challenges faced by breast cancer survivors during the coronavirus disease 2019 pandemic, including accessing healthcare services and the impact of social isolation. Healthcare providers should consider the holistic needs of breast cancer survivors in the provision of health care and develop supportive interventions, including telehealth services and online support groups, to address these challenges and improve their HRQoL. IMPACT: Surgery aimed at treating breast cancer or reducing its risk generally influences the appearance of breast areas and donor sites. The continuing effects of these changes on body image and HRQoL are well-reported, although studies have ineffectively examined the initial experiences of women regarding their postoperative appearance, particularly during the pandemic. REPORTING METHOD: The checklist of consolidated criteria for reporting qualitative research (COREQ) was utilized. PATIENT OR PUBLIC CONTRIBUTION: A small selection on breast cancer survivors contributed to the design of this study, in particular the content of the semi-structured interviews.

Targeting ATR in Cancer Medicine.

As a key component of the DNA Damage Response, the Ataxia telangiectasia and Rad3-related (ATR) protein is a promising druggable target that is currently widely evaluated in phase I-II-III clinical trials as monotherapy and in combinations with other rational antitumor agents, including immunotherapy, DNA repair inhibitors, chemo- and radiotherapy. Ongoing clinical studies for this drug class must address the optimization of the therapeutic window to limit overlapping toxicities and refine the target population that will most likely benefit from ATR inhibition. With advances in the development of personalized treatment strategies for patients with advanced solid tumors, many ongoing ATR inhibitor trials have been recruiting patients based on their germline and somatic molecular alterations, rather than relying solely on specific tumor subtypes. Although a spectrum of molecular alterations have already been identified as potential predictive biomarkers of response that may sensitize to ATR inhibition, these biomarkers must be analytically validated and feasible to measure robustly to allow for successful integration into the clinic. While several ATR inhibitors in development are poised to address a clinically unmet need, no ATR inhibitor has yet received FDA-approval. This chapter details the underlying rationale for targeting ATR and summarizes the current preclinical and clinical landscape of ATR inhibitors currently in evaluation, as their regulatory approval potentially lies close in sight.

No-biopsy strategy for coeliac disease is applicable in adult patients: a 'real-world' Scottish experience.

Objective: Emergency interim guidance from the British Society for Gastroenterology (BSG) states that a no-biopsy strategy is possible to diagnose coeliac disease (CD) in adults with elevated transglutaminase IgA antibody (TGA-IgA) levels. We aimed to determine if the suggested TGA-IgA ≥10× ULN is safe and robust in making the diagnosis in adult patients in Scotland. We also aimed to establish if any important co-diagnoses would be missed if no biopsy was performed. Method: All positive coeliac serology results for patients aged >15 years in Scotland in 2016 (Grampian 2019) were accessed. Data were collected on demographics, TGA-IgA titres, D1 sampling, histology and macroscopic findings at upper and lower gastrointestinal (GI) endoscopy. Results: 1037/1429 patients with positive serology proceeded to biopsy, of which 796/1037 (76.8%) were diagnosed as CD. A total of 320/322 (99.37%) patients with TGA-IgA ≥10× ULN were diagnosed as CD giving the cut-off a positive predictive value of 99.38%. No significant co-pathology was found at endoscopy in these patients. Conclusion: Our results show that a no-biopsy strategy using a cut-off of TGA-IgA ≥10× ULN is safe to diagnose CD and that no important pathology would be missed. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition 2020 and BSG COVID-19 interim guidelines are applicable to adult patients in Scotland.

Management of obesity across women's life course: FIGO Best Practice Advice.

Obesity is a chronic, progressive, relapsing, and treatable multifactorial, neurobehavioral disease. According to the World Health Organization, obesity affects 15% of women and has long-term effects on women's health. The focus of care in patients with obesity should be on optimizing health outcomes rather than on weight loss. Appropriate and common language, considering cultural sensitivity and trauma-informed care, is needed to discuss obesity. Pregnancy is a time of significant physiological change. Pre-, ante-, and postpartum clinical encounters provide opportunities for health optimization for parents with obesity in terms of, but not limited to, fertility and breastfeeding. Pre-existing conditions may also be identified and managed. Beyond pregnancy, women with obesity are at an increased risk for gastrointestinal and liver diseases, impaired kidney function, obstructive sleep apnea, and venous thromboembolism. Gynecological and reproductive health of women living with obesity cannot be dismissed, with accommodations needed for preventive health screenings and consideration of increased risk for gynecologic malignancies. Mental wellness, specifically depression, should be screened and managed appropriately. Obesity is a complex condition and is increasing in prevalence with failure of public health interventions to achieve significant decrease. Future research efforts should focus on interprofessional care and discovering effective interventions for health optimization.

Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models.

PURPOSE: DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy. EXPERIMENTAL DESIGN: We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo. RESULTS: Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone. CONCLUSIONS: These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.

POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells.

POLQ is a key effector of DSB repair by microhomology-mediated end-joining (MMEJ) and is overexpressed in many cancers. POLQ inhibitors confer synthetic lethality in HR and Shieldin-deficient cancer cells, which has been proposed to reflect a critical dependence on the DSB repair pathway by MMEJ. Whether POLQ also operates independent of MMEJ remains unexplored. Here, we show that POLQ-deficient cells accumulate post-replicative ssDNA gaps upon BRCA1/2 loss or PARP inhibitor treatment. Biochemically, cooperation between POLQ helicase and polymerase activities promotes RPA displacement and ssDNA-gap fill-in, respectively. POLQ is also capable of microhomology-mediated gap skipping (MMGS), which generates deletions during gap repair that resemble the genomic scars prevalent in POLQ overexpressing cancers. Our findings implicate POLQ in mutagenic post-replicative gap sealing, which could drive genome evolution in cancer and whose loss places a critical dependency on HR for gap protection and repair and cellular viability.

Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta.

Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ. The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility.

A retrospective observational research study to describe the real-world use of bosutinib in patients with chronic myeloid leukemia in the United Kingdom and the Netherlands.

OBJECTIVES: To describe the real-world effectiveness and safety of bosutinib in patients with chronic myeloid leukemia (CML). METHODS: This was a multi-center, retrospective, non-interventional chart review study conducted in 10 hospitals in the United Kingdom and the Netherlands. RESULTS: Eighty-seven patients were included. Bosutinib was the third-line tyrosine kinase inhibitor (TKI) in 33 (38%) and fourth-line in 44 (51%) patients. Median treatment duration was 15.6 months. Among 84 patients in chronic phase (CP) at baseline, 26 (31%) switched to bosutinib due to resistance and 57 (68%) due to intolerance to prior TKIs. Cumulative complete cytogenetic and major molecular response rates in CP patients were 67% and 55%, respectively. After a median follow-up of 21.5 months, nine (11%) patients in CP died; estimated overall survival rates at 1 and 2 years postbosutinib initiation were 95% and 91%, respectively. Overall, 33/87 (38%) patients discontinued bosutinib due to either lack of efficacy/disease progression (17%), adverse events (14%), death (2%), or other reasons (5%). Eighty-two (94%) patients experienced ≥1 adverse event possibly related to bosutinib, most commonly diarrhea (52%). CONCLUSIONS: Bosutinib used in routine clinical practice in heavily pretreated patients with CML is an effective treatment for patients in CP and is generally tolerable.

Predictors of Adverse Pregnancy Outcomes in Pregnant Women Living with Obesity: A Systematic Review.

Obesity is a well-recognized risk factor for pregnancy complications. Most studies to date are in large cohorts, with results presented in a way that assumes all women living with obesity are at equal risk. This study investigates which women living with obesity are at higher risk of specific pregnancy complications. A systematic search of MEDLINE and Embase identified 7894 prospective or retrospective cohort studies exploring predictors of adverse outcomes among pregnant women living with obesity. Following screening, 61 studies were deemed eligible. Studies were selected if the effects of exposure to any predictor amongst pregnant women living with obesity could be collected. Maternal characteristics assessed for association with adverse outcomes included maternal age, race/ethnicity, maternal height, mode of conception, complement activation factors, and history of various comorbidities/procedures. Gestational diabetes mellitus was the most studied outcome (n = 32), followed by preterm birth (n = 29), preeclampsia (n = 27), low birthweight infants (n = 20), small for gestational age newborns (n = 12), and stillbirth (n = 7). This review identified important characteristics that should be considered during the screening and follow-up sessions of pregnant women living with obesity, including pre-existing type 1 diabetes, maternal age < 20 years or ≥35 years, non-White ethnicity, abdominal adiposity obesity, and history of bariatric surgery.

The Canadian Women's Heart Health Alliance Atlas on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women - Chapter 4: Sex- and Gender-Unique Disparities: CVD Across the Lifespan of a Woman.

Women have unique sex- and gender-related risk factors for cardiovascular disease (CVD) that can present or evolve over their lifespan. Pregnancy-associated conditions, polycystic ovarian syndrome, and menopause can increase a woman's risk of CVD. Women are at greater risk for autoimmune rheumatic disorders, which play a role in the predisposition and pathogenesis of CVD. The influence of traditional CVD risk factors (eg, smoking, hypertension, diabetes, obesity, physical inactivity, depression, anxiety, and family history) is greater in women than men. Finally, there are sex differences in the response to treatments for CVD risk and comorbid disease processes. In this Atlas chapter we review sex- and gender-unique CVD risk factors that can occur across a woman's lifespan, with the aim to reduce knowledge gaps and guide the development of optimal strategies for awareness and treatment.

Les femmes présentent des facteurs de risque de maladies cardiovasculaires (MCV) uniques, liés au sexe et au genre, qui peuvent se manifester ou évoluer tout au long de leur vie. Les troubles médicaux associés à la grossesse, le syndrome des ovaires polykystiques et la ménopause peuvent augmenter le risque de MCV chez une femme. Les femmes sont plus exposées aux troubles rhumatologiques auto-immuns, qui jouent un rôle dans la prédisposition et dans la pathogenèse des MCV. L'influence des facteurs de risque traditionnels pour les MCV (par exemple, le tabagisme, l'hypertension, le diabète, l'obésité, la sédentarité, la dépression, l'anxiété et les antécédents familiaux) est plus importante chez les femmes que chez les hommes. Enfin, il existe des différences entre les sexes dans la réponse aux traitements du risque de MCV et des processus pathologiques comorbides. Dans ce chapitre de l'Atlas, nous passons en revue les facteurs de risque de MCV propres au sexe et au genre qui peuvent survenir tout au long de la vie d'une femme, dans le but de réduire les lacunes dans les connaissances et d'orienter l'élaboration de stratégies optimales de sensibilisation et de traitement.

Spousal Concordance of Cardiovascular Risk Factors in Newly Married Couples in China.

Importance: Several studies have shown that older married couples share a propensity for accruing the same cardiovascular risk factors such as hypertension and dyslipidemia. However, it remains unclear if these spousal associations reflect their shared home environment and lifestyle or the tendency to choose a partner with a similar perspective on lifestyle choices and behaviors (assortative mating). Evaluating these associations in young, newly married couples may help to differentiate between these 2 possibilities. Objective: To evaluate the spousal concordance of cardiovascular risk factors in young, newly married couples. Design, Setting, and Participants: This prospective cohort study recruited 831 couples around the time of marriage registration in Liuyang, China, from February 1, 2009, to November 4, 2015. Statistical analysis was performed from April to May 2021. Main Outcomes and Measures: Spousal concordance of cardiovascular risk factors. Both partners underwent systematic assessment of cardiovascular risk factors, including evaluation of anthropometrics, blood pressure, and fasting lipids. Results: Among the 831 participating couples, mean (SD) age was 24 (3) years in the women and 26 (4) years in the men. There were significant correlations between spouses in systolic blood pressure (r = 0.43; P < .001), diastolic blood pressure (r = 0.36; P < .001), total cholesterol (r = 0.13; P < .001), low-density lipoprotein cholesterol (r = 0.11; P = .003), high-density lipoprotein (HDL) cholesterol (r = 0.22, P < .001), and triglycerides (r = 0.13; P = .001). After adjustment for covariates (age, household income, education level, smoking, and either body mass index or waist circumference), significant correlations persisted between spouses in their systolic blood pressure (r = 0.42; P < .001), diastolic blood pressure (r = 0.34; P < .001), HDL cholesterol (r = 0.17; P < .001), and triglycerides (r = 0.10; P = .04). Conclusions and Relevance: This cohort study found spousal concordance of cardiovascular risk factors among young newly married couples. Assortative mating based on these concordant risk factors at the time of marriage may partially explain the shared vascular risk profile of older marital partners and raises the possibility of couple-based care.

Paternal weight prior to conception and infant birthweight: a prospective cohort study.

BACKGROUND/OBJECTIVE: Previous studies have consistently demonstrated that maternal weight status both before and during pregnancy is associated with infant birthweight. However, a fundamental limitation across this literature remains that previous studies have not evaluated the concomitant impact of paternal weight at conception, owing to the paucity of studies in which fathers were assessed prior to pregnancy. Thus, we established a cohort of preconception couples to prospectively evaluate the associations of maternal and paternal weight prior to pregnancy with infant birthweight at delivery. METHODS: In this prospective observational cohort study, 1292 newly-married women and their partners in Liuyang, China, were assessed at median of 23.3 weeks before a singleton pregnancy, thereby enabling concomitant assessment of preconception maternal and paternal body mass index (BMI) in relation to infant birthweight. RESULTS: Mean birthweight was 3294 ± 450 g with 147 neonates (11.4%) born large-for-gestational-age (LGA) and 94 (7.3%) small-for-gestational-age (SGA). After adjustment for maternal and paternal factors prior to conception (age, education, smoking, BMI, household income), length of gestation, total gestational weight gain, gestational diabetes, preeclampsia, and infant sex, it was noted that infant birthweight increased by 42.2 g (95% CI 29.5-54.8; p < 0.0001) per unit increase in maternal pregravid BMI and 10.7 g (95% CI 0.5-20.9; p = 0.04) per unit increase in paternal pregravid BMI. Maternal pregravid BMI explained 6.2% of the variance in birthweight whereas paternal BMI explained only 0.7%. Independent predictors of LGA delivery were maternal pregravid BMI (aOR = 1.91, 95% CI 1.50-2.44), maternal age (aOR = 1.48, 95% CI 1.09-2.00), and gestational weight gain (aOR = 1.80, 95% CI 1.40-2.30). Paternal pregravid BMI was not independently associated with LGA or SGA. CONCLUSION: Paternal BMI prior to conception is associated with infant birthweight but only modestly so, in contrast to the dominant impact of maternal weight.

Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target.

Amino Acids Whose Intracellular Levels Change Most During Aging Alter Chronological Life Span of Fission Yeast.

Amino acid deprivation or supplementation can affect cellular and organismal life span, but we know little about the role of concentration changes in free, intracellular amino acids during aging. Here, we determine free amino acid levels during chronological aging of nondividing fission yeast cells. We compare wild-type with long-lived mutant cells that lack the Pka1 protein of the protein kinase A signalling pathway. In wild-type cells, total amino acid levels decrease during aging, but much less so in pka1 mutants. Two amino acids strongly change as a function of age: glutamine decreases, especially in wild-type cells, while aspartate increases, especially in pka1 mutants. Supplementation of glutamine is sufficient to extend the chronological life span of wild-type but not of pka1Δ cells. Supplementation of aspartate, on the other hand, shortens the life span of pka1Δ but not of wild-type cells. Our results raise the possibility that certain amino acids are biomarkers of aging, and their concentrations during aging can promote or limit cellular life span.

Carbon monoxide increases utero-placental angiogenesis without impacting pregnancy specific adaptations in mice.

BACKGROUND: Cigarette smokers have a reduced risk of developing preeclampsia, possibly attributed to an increase in carbon monoxide (CO) levels. Carbon monoxide is a gasotransmitter that has been implicated in maintaining vascular tone, increasing angiogenesis, and reducing inflammation and apoptosis at physiological concentrations. Moderately increasing CO concentrations may have therapeutic potential to prevent or treat preeclampsia; however, the effects of CO on pregnancy are under studied. Our objective was to investigate the effect of CO on major angiogenic and inflammatory markers in pregnancy, and to evaluate the effect of CO on indicators of placental health. FINDINGS: Pregnant CD-1 mice were constantly exposed to either ambient air or 250 ppm CO from conception until gestation day (GD)10.5 or GD16.5. Using a qRT-PCR array, we identified that CO increased expression of major angiogenic genes at the implantation site on GD10.5, but not GD16.5. Pro-inflammatory cytokines in the plasma and tissue lysates from implantation sites in treated mice were not significantly different compared to controls. Additionally, CO did not alter the implantation site phenotype, in terms of proliferative capacity, invasiveness of trophoblasts, or abundance of uterine natural killer cells. CONCLUSIONS: This study suggests that CO exposure is pro-angiogenic at the maternal-fetal interface, and is not associated with demonstrable concerns during murine pregnancy. Future studies are required to validate safety and efficacy of CO as a potential therapeutic for vascular insufficiency diseases such as preeclampsia and intrauterine growth restriction.

Experiences of living with chronic myeloid leukaemia and adhering to tyrosine kinase inhibitors: A thematic synthesis of qualitative studies.

PURPOSE: To investigate the experiences of adults living with chronic myeloid leukaemia and treated with tyrosine kinase inhibitors, with particular reference to factors influencing adherence. METHODS: A thematic synthesis of all published qualitative studies examining adults with chronic myeloid leukaemia, receiving tyrosine kinase inhibitors. Eligible publications were identified by searching five electronic databases using defined criteria. The synthesis involved complete coding of extracted data and inductive theme development. RESULTS: Nine studies were included and three overarching themes defined. Overarching themes were: 1) Disease impacts whole life; 2) Disease management strategies; and 3) Valued aspects of care. Side-effects often required physical and psychological adaptation. Patients developed individual decision-making processes to promote adherence and manage side effects. Unintentional non-adherence occurred due to forgetfulness and system failures. Intentional omission also occurred, which together with side effects, was unlikely to be reported to healthcare professionals (HCPs). HCP reassurance about missed doses could reinforce non-adherence. Information needs varied over time and between individuals. Knowledge among patients about treatment was often lacking and could lead to misunderstandings. Patients valued psychological support from HCPs and suggested an individualised approach, facilitating discussion of symptoms, adherence and their perspectives about living with chronic myeloid leukaemia, would improve care. CONCLUSIONS: Patients with chronic myeloid leukaemia experienced significant side-effects from treatment and changes to their psychological and physical well-being. They developed their own strategies to manage their disease and treatment. This should be recognised in interventions to improve education, support and the delivery of care that is compassionate and adequately resourced.

The determinants of maternal homocysteine in pregnancy: findings from the Ottawa and Kingston Birth Cohort.

OBJECTIVE: Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population. DESIGN: Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration. SETTING: Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009. PARTICIPANTS: Women were recruited when presenting for prenatal care in the early second trimester. RESULTS: In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration. CONCLUSIONS: We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically.

AZD0156 is a potent and selective, bioavailable inhibitor of ataxia-telangiectasia mutated (ATM) protein, a signaling kinase involved in the DNA damage response. We present preclinical data demonstrating abrogation of irradiation-induced ATM signaling by low doses of AZD0156, as measured by phosphorylation of ATM substrates. AZD0156 is a strong radiosensitizer in vitro, and using a lung xenograft model, we show that systemic delivery of AZD0156 enhances the tumor growth inhibitory effects of radiation treatment in vivo Because ATM deficiency contributes to PARP inhibitor sensitivity, preclinically, we evaluated the effect of combining AZD0156 with the PARP inhibitor olaparib. Using ATM isogenic FaDu cells, we demonstrate that AZD0156 impedes the repair of olaparib-induced DNA damage, resulting in elevated DNA double-strand break signaling, cell-cycle arrest, and apoptosis. Preclinically, AZD0156 potentiated the effects of olaparib across a panel of lung, gastric, and breast cancer cell lines in vitro, and improved the efficacy of olaparib in two patient-derived triple-negative breast cancer xenograft models. AZD0156 is currently being evaluated in phase I studies (NCT02588105).