Identification of RAD51 foci in cancer-associated circulating cells of patients with high-grade serous ovarian cancer: Association with treatment outcomes

Data availability statement: Data are available upon reasonable request. Datasets will be made available on reasonable request from the corresponding author.Supplementary Data are available online at https://ijgc.bmj.com/content/33/9/1427#supplementary-materials .Objective Fifty percent of patients with high-grade serous ovarian cancer harbor defects in the homologous recombination repair pathway. RAD51 foci form where DNA is damaged, indicating its involvement in repairing double-stranded breaks. High levels of RAD51 in ovarian cancer tissue have been associated with a poorer prognosis. Objective To demonstrate RAD51 foci in circulating cancer-associated cells of patients with ovarian cancer and their association with clinical outcomes. Methods One hundred and twenty-four patients with high-grade serous ovarian cancer had blood samples taken at strategic points during treatment and follow-up. Cells were stained using WT1 and RAD51 antibodies with immunofluorescence and reviewed under Leica camera microscopy; RAD51 foci were counted. Correlations were made between numbers of RAD51 foci and treatment response, BRCA status, and progression-free survival. Results RAD51 foci were identified in all patients (n=42) with wild-type BRCA. BRCA mutant/homologous recombination deficiency-positive patients (n=8) had significantly lower numbers of RAD51 foci (p=0.009). Responders to treatment (n=32) had a reduction in circulating cells (p=0.02) and RAD51 foci (p=0.0007). Numbers of RAD51 foci were significantly higher in the platinum-resistant population throughout treatment: At the start of treatment, in 56 platinum-sensitive patients there was a mean of 3.6 RAD51 foci versus 6.2 in 15 platinum-resistant patients (p=0.02). Patients with a high number of RAD51 foci had worse median progression-free survival: in 39 patients with a mean of 3 RAD51 foci whose progression-free survival was 13 months (p=0.04). Conclusions Levels of RAD51 foci in circulating cancer-associated cells of patients with high-grade serous ovarian cancer are associated with clinical outcomes and may be a more pragmatic method of determining a homologous repair-deficient population.John Bush Academic Fund, Mount Vernon Cancer Centre, and the Cancer Treatment Research Trust

The addition of genetic testing and cardiovascular magnetic resonance to routine clinical data for stratification of aetiology in dilated cardiomyopathy

Background: Guidelines recommend genetic testing and cardiovascular magnetic resonance (CMR) for the investigation of dilated cardiomyopathy (DCM). However, the incremental value is unclear. We assessed the impact of these investigations in determining etiology. Methods: Sixty consecutive patients referred with DCM and recruited to our hospital biobank were selected. Six independent experts determined the etiology of each phenotype in a step-wise manner based on (1) routine clinical data, (2) clinical and genetic data and (3) clinical, genetic and CMR data. They indicated their confidence (1-3) in the classification and any changes to management at each step. Results: Six physicians adjudicated 60 cases. The addition of genetics and CMR resulted in 57 (15.8%) and 26 (7.2%) changes in the classification of etiology, including an increased number of genetic diagnoses and a reduction in idiopathic diagnoses. Diagnostic confidence improved at each step (p < 0.0005). The number of diagnoses made with low confidence reduced from 105 (29.2%) with routine clinical data to 71 (19.7%) following the addition of genetics and 37 (10.3%) with the addition of CMR. The addition of genetics and CMR led to 101 (28.1%) and 112 (31.1%) proposed changes to management, respectively. Interobserver variability showed moderate agreement with clinical data (κ = 0.44) which improved following the addition of genetics (κ = 0.65) and CMR (κ = 0.68). Conclusion: We demonstrate that genetics and CMR, frequently changed the classification of etiology in DCM, improved confidence and interobserver variability in determining the diagnosis and had an impact on proposed management

INFLUENCE OF INCREASING FLUORIDE DOSE RATES ON SELECTED LIVER AND KIDNEY ENZYMES PROFILE IN DOMESTIC CHICKEN (Gallus domesticus)

ABSTRACT Fluoride has been considered to cause hepatic and renal tissue damages in animals and humans. The present study investigated the effect of varying concentrations of fluoride on hepatic and renal enzyme profile in domestic chicken (n=80). Chicken were distributed into 4 groups. Group A was kept unexposed while group B, C and D were exposed to 10, 20 and 30 µg/g body weight of NaF respectively on weekly basis for four weeks. Alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine amino-transferase (ALT) and bilirubin were determined as indicators of liver function test (LFT), while uric acid was as a parameter for renal function test (RFT). All LFT and RFT parameters showed high values (P&lt; 0.05) after one, two three and four weeks in all groups. 579.4 ± 1.55, 355.0 ± 2.13, 246.2 ± 2.45 and 0.83 ± 1.46 were the ALP, AST, ALAT and bilirubin values for LFT and uric acid was 6.74 ± 2.92 in D group at the end of four weeks. All these results indicate the probability of severe effect on the physiology of the liver and kidneys in the exposed birds

INFLUENCE OF INCREASING FLUORIDE DOSE RATES ON SELECTED LIVER AND KIDNEY ENZYMES PROFILE IN DOMESTIC CHICKEN (Gallus domesticus)

ABSTRACT Fluoride has been considered to cause hepatic and renal tissue damages in animals and humans. The present study investigated the effect of varying concentrations of fluoride on hepatic and renal enzyme profile in domestic chicken (n=80). Chicken were distributed into 4 groups. Group A was kept unexposed while group B, C and D were exposed to 10, 20 and 30 µg/g body weight of NaF respectively on weekly basis for four weeks. Alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine amino-transferase (ALT) and bilirubin were determined as indicators of liver function test (LFT), while uric acid was as a parameter for renal function test (RFT). All LFT and RFT parameters showed high values (P&lt; 0.05) after one, two three and four weeks in all groups. 579.4 ± 1.55, 355.0 ± 2.13, 246.2 ± 2.45 and 0.83 ± 1.46 were the ALP, AST, ALAT and bilirubin values for LFT and uric acid was 6.74 ± 2.92 in D group at the end of four weeks. All these results indicate the probability of severe effect on the physiology of the liver and kidneys in the exposed birds

Assessment of myocardial microstructural dynamics by in vivo diffusion tensor cardiac magnetic resonance

Background: Cardiomyocytes are organized in microstructures termed sheetlets that reorientate during left ventricular thickening. Diffusion tensor cardiac magnetic resonance (DT-CMR) may enable noninvasive interrogation of in vivo cardiac microstructural dynamics. Dilated cardiomyopathy (DCM) is a condition of abnormal myocardium with unknown sheetlet function. Objectives: This study sought to validate in vivo DT-CMR measures of cardiac microstructure against histology, characterize microstructural dynamics during left ventricular wall thickening, and apply the technique in hypertrophic cardiomyopathy (HCM) and DCM. Methods: In vivo DT-CMR was acquired throughout the cardiac cycle in healthy swine, followed by in situ and ex vivo DT-CMR, then validated against histology. In vivo DT-CMR was performed in 19 control subjects, 19 DCM, and 13 HCM patients. Results: In swine, a DT-CMR index of sheetlet reorientation (E2A) changed substantially (E2A mobility ∼46°). E2A changes correlated with wall thickness changes (in vivo r2 = 0.75; in situ r2 = 0.89), were consistently observed under all experimental conditions, and accorded closely with histological analyses in both relaxed and contracted states. The potential contribution of cyclical strain effects to in vivo E2A was ∼17%. In healthy human control subjects, E2A increased from diastole (18°) to systole (65°; p < 0.001; E2A mobility = 45°). HCM patients showed significantly greater E2A in diastole than control subjects did (48°; p < 0.001) with impaired E2A mobility (23°; p < 0.001). In DCM, E2A was similar to control subjects in diastole, but systolic values were markedly lower (40°; p < 0.001) with impaired E2A mobility (20°; p < 0.001). Conclusions: Myocardial microstructure dynamics can be characterized by in vivo DT-CMR. Sheetlet function was abnormal in DCM with altered systolic conformation and reduced mobility, contrasting with HCM, which showed reduced mobility with altered diastolic conformation. These novel insights significantly improve understanding of contractile dysfunction at a level of noninvasive interrogation not previously available in humans

EFFECT OF FEEDING FREQUENCY ON THE GROWTH PERFORMANCE OF BEETAL GOAT KIDS DURING WINTER SEASON

ABSTRACT Eighteen Beetal goat kids of about same age (one month) and average weight (3.2 kg) were selected from the prevailing flock and were divided randomly into three groups with 6 replicates in each group. These kids were kept separately to study the effect of feeding frequency on the growth performance during winter season. Green fodder was offered adlibitum and concentrate was given @ 1% of the body weight to each kid. Group A (control), B and C were fed two, three and four times daily, respectively. The parameters studied were feed intake, weight gain, body measurements like height, girth and length, environmental temperature and relative humidity. There was a significant difference in the DMI (P&lt;0.01), weight gain (P&lt;0.05), body height (P&lt;0.01) between treatments (feeding frequency). Body girth and body length also had a significant difference (P&lt;0.05) for group A with B and C where as non significant results were found between kids of group B and C on fortnightly basis. The kids of group C performed well in terms of weekly body weight gain, daily dry matter intake, and body measurement as compared to group A and B

Association between mid-wall late gadolinium enhancement and sudden cardiac death in patients with dilated cardiomyopathy and mild and moderate left ventricular systolic dysfunction

Background—Current guidelines only recommend the use of an implantable cardioverter defibrillator (ICD) in patients with dilated cardiomyopathy (DCM) for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF)35%. Patients with a LVEF>35% also have low competing risks of death from non-sudden causes. Therefore, those at high-risk of SCD may gain longevity from successful ICD therapy. We investigated whether late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) identified patients with DCM without severe LV systolic dysfunction at high-risk of SCD. Methods—We prospectively investigated the association between mid-wall late gadolinium enhancement (LGE) and the pre-specified primary composite outcome of SCD or aborted SCD amongst consecutive referrals with DCM and a LVEF≥40% to our center between January 2000 and December 2011, who did not have a pre-existing indication for ICD implantation. Results—Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the pre-specified end-point, compared to 7 of 298 (2.3%) without (HR 9.2; 95% CI 3.9-21.8; p5% compared to those without LGE were 10.6 (95%CI 3.9-29.4), 4.9 (95% CI 1.3-18.9) and 11.8 (95% CI 4.3-32.3) respectively. Conclusions—Mid-wall LGE identifies a group of patients with DCM and LVEF≥40% at increased risk of SCD and low-risk of non-sudden death who may benefit from ICD implantation

Description of a Retrospective Cohort of Epithelial Ovarian Cancer Patients with Brain Metastases: Evaluation of the Role of PARP Inhibitors in this Setting

Data Availability Statement: Data will be available upon reasonable request.Copyright © 2023 by the authors. Background: The incidence of brain metastases (BM) in patients with epithelial ovarian cancer (EOC) is low: 0.3–11%. The onset of BM has been regarded as a late event with limited treatment options and poor prognosis. This retrospective case series aims to explore the current management strategies with particular emphasis on the use of PARP inhibitors and outcomes, as well as identification of other prognostic indicators. Methods: A total of 39 ovarian cancer patients with brain metastases were identified from eight cancer centres in the UK. Clinical characteristics, details of management, and survival data were collected. Results: A total of 14/39 had BM as their first site of relapse. The majority (29 patients) received systemic treatments in addition to local radiotherapy (RT)/surgery. Nineteen patients had BRCA mutations (one somatic), one had a RAD51C mutation, and eighteen were BRCA wild type; one was unknown. A total of 14/39 patients received maintenance PARP inhibitors. As is well known, patients who received PARPi had consistently better outcomes. This was no different for those who received PARPi as part of the management of their BM. Platinum sensitivity and receiving more than one modality of therapy (e.g., radiation +/− chemotherapy and PARPi) for BM were also good prognostic indicators. Median PFS/OS for those treated with chemotherapy and either RT or surgery, then PARP inhibitor maintenance, have not been reached after a median of 33 months follow up. Conclusions: As with abdominal relapse, maintenance treatment with PARP inhibitors also has a valuable role in managing BMs in EOC patients.This research received no extra funding

Phenotype, outcomes and natural history of early-stage non-ischaemic cardiomyopathy

Aims To characterize the phenotype, clinical outcomes and rate of disease progression in patients with early-stage non-ischaemic cardiomyopathy (early-NICM). Methods and results We conducted a prospective observational cohort study of patients with early-NICM assessed by late gadolinium enhancement cardiovascular magnetic resonance (CMR). Cases were classified into the following subgroups: isolated left ventricular dilatation (early-NICM H−/D+), non-dilated left ventricular cardiomyopathy (early-NICM H+/D−), or early dilated cardiomyopathy (early-NICM H+/D+). Clinical follow-up for major adverse cardiovascular events (MACE) included non-fatal life-threatening arrhythmia, unplanned cardiovascular hospitalization or cardiovascular death. A subset of patients (n = 119) underwent a second CMR to assess changes in cardiac structure and function. Of 254 patients with early-NICM (median age 46 years [interquartile range 36–58], 94 [37%] women, median left ventricular ejection fraction [LVEF] 55% [52–59]), myocardial fibrosis was present in 65 (26%). There was no difference in the prevalence of fibrosis between subgroups (p = 0.90), however fibrosis mass was lowest in early-NICM H−/D+, higher in early-NICM H+/D− and highest in early-NICM H+/D+ (p = 0.03). Over a median follow-up of 7.9 (5.5–10.0) years, 28 patients (11%) experienced MACE. Non-sustained ventricular tachycardia (hazard ratio [HR] 5.1, 95% confidence interval [CI] 2.36–11.00, p < 0.001), myocardial fibrosis (HR 3.77, 95% CI 1.73–8.20, p < 0.001) and diabetes mellitus (HR 5.12, 95% CI 1.73–15.18, p = 0.003) were associated with MACE in a multivariable model. Only 8% of patients progressed from early-NICM to dilated cardiomyopathy with LVEF <50% over a median of 16 (11–34) months. Conclusion Early-NICM is not benign. Fibrosis develops early in the phenotypic course. In-depth characterization enhances risk stratification and might aid clinical management

Relationship Between Nutritional Habits and Hair Calcium Levels in Young Women

The present study was conducted to investigate whether hair calcium levels are related to nutritional habits, selected status parameters, and life-style factors in young women. Eighty-five healthy female students neither pregnant nor lactating, using no hair dyes or permanents were recruited for the study. Food consumption data, including fortified products and dietary supplements were collected with 4-day records. The calcium levels in hair and serum were analyzed by atomic absorption spectroscopy. Serum osteocalcin and the C-terminal telopeptide of type I collagen were assayed by ELISA. The women were divided into four groups according to their total vitamin D and calcium intakes and hair calcium levels. At adequate calcium intake and comparable serum bone biomarker levels, supplemental vitamin D increased the hair calcium levels. On the other hand, at lower than estimated adequate requirement of vitamin D intake the hair calcium levels were comparable in women with low calcium intakes but consuming high amounts of meat products or those whose diets were rich in dairy products, possibly due to homeostatic mechanisms. Elevated hair calcium was seen in 25% of subjects and could not be related to nutritional or life-style factors. The results show that the hair calcium levels were weakly related to the quality of diet, with some synergistic interactions between nutrients, especially vitamin D and magnesium