BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair.

Tumor suppressor BRCA2 functions in homology-directed repair (HDR), the protection of stalled replication forks, and the suppression of replicative gaps, but their relative contributions to genome integrity and chemotherapy response are under scrutiny. Here, we report that mouse and human cells require a RAD51 filament stabilization motif in BRCA2 for fork protection and gap suppression but not HDR. In mice, the loss of fork protection/gap suppression does not compromise genome stability or shorten tumor latency. By contrast, HDR deficiency increases spontaneous and replication stress-induced chromosome aberrations and tumor predisposition. Unlike with HDR, fork protection/gap suppression defects are also observed in Brca2 heterozygous cells, likely due to reduced RAD51 stabilization at stalled forks/gaps. Gaps arise from PRIMPOL activity, which is associated with 5-hydroxymethyl-2'-deoxyuridine sensitivity due to the formation of SMUG1-generated abasic sites and is exacerbated by poly(ADP-ribose) polymerase (PARP) inhibition. However, HDR proficiency has the major role in mitigating sensitivity to chemotherapeutics, including PARP inhibitors.

Active p38α causes macrovesicular fatty liver in mice.

One third of the western population suffers from nonalcoholic fatty liver disease (NAFLD), which may ultimately develop into hepatocellular carcinoma (HCC). The molecular event(s) that triggers the disease are not clear. Current understanding, known as the multiple hits model, suggests that NAFLD is a result of diverse events at several tissues (e.g., liver, adipose tissues, and intestine) combined with changes in metabolism and microbiome. In contrast to this prevailing concept, we report that fatty liver could be triggered by a single mutated protein expressed only in the liver. We established a transgenic system that allows temporally controlled activation of the MAP kinase p38α in a tissue-specific manner by induced expression of intrinsically active p38α allele. Here we checked the effect of exclusive activation in the liver. Unexpectedly, induction of p38α alone was sufficient to cause macrovesicular fatty liver. Animals did not become overweight, showing that fatty liver can be imposed solely by a genetic modification in liver per se and can be separated from obesity. Active p38α-induced fatty liver is associated with up-regulation of MUC13, CIDEA, PPARγ, ATF3, and c-jun mRNAs, which are up-regulated in human HCC. Shutting off expression of the p38α mutant resulted in reversal of symptoms. The findings suggest that p38α plays a direct causative role in fatty liver diseases and perhaps in other chronic inflammatory diseases. As p38α activity was induced by point mutations, it could be considered a proto-inflammatory gene (proto-inflammagene).

Rapid interrogation of cancer cell of origin through CRISPR editing.

The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. Here we show, using prostate as a model tissue, that primary organoids and freshly isolated epithelial cells can be CRISPR edited ex vivo using Cas9-sgRNA (guide RNA) ribotnucleoprotein complex technology, then orthotopically transferred in vivo into immunocompetent or immunodeficient mice to generate cancer models with phenotypes resembling those seen in traditional genetically engineered mouse models. Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection, including in isolated subpopulations to address cell-of-origin questions.

Evaluation of the microbiological efficacy of cleaning agents for tracheostomy inner cannulas.

PURPOSE: Biofilms are a significant cause of morbidity in patients with indwelling medical devices. Biofilms pose a potential risk with reusable inner cannulas by increasing the risk of infections. Effective decontamination is thus vital in decreasing bioburden. The current guidelines for cleaning inner cannulas are varied, with multiple techniques being recommended, which are not supported by strong evidence. This randomized, controlled, cross-over study attempted to enumerate the bacterial count of inner cannulas used in tracheostomy patients (n = 60) pre-and post-decontamination with detergent (A) or sterile water (B). MATERIALS AND METHODS: The patients were randomly allocated to sequence A > B or B > A in 1:1 fashion. The saline flushing of the inner cannulas was plated on trypticase soy agar with 5 % sheep blood to enumerate the bacterial count. RESULTS: The mean ratio [Log (CFU)post/Log (CFU)pre]A/[Log (CFU)post/Log (CFU)pre]B based on 53 samples was 0.918 ± 0.470, two-sided 90 % confidence interval (CI) 0.812, 1.024. The equivalence criterion was met as the mean ratio after cleaning fell within the equivalence region of 0.8 and 1.25. CONCLUSION: This study demonstrated the microbiological efficacy of both detergent and sterile water in the decontamination of inner cannulas, and that sterile water was not less effective than detergent in reducing the bacterial load for safe re-use of inner cannulas. This has the potential to promote cost savings for patients with tracheostomy, both in the hospital and the community. The study findings may also be relevant in formulating tracheostomy care policies.

Spectrally Resolved Single Particle Photoluminescence Microscopy Reveals Heterogeneous Photocorrosion Activity of Cuprous Oxide Microcrystals.

Photocorrosion of cuprous oxide (Cu2O) has notably limited its application as an efficient photocatalyst. We report a facile approach to visualize in situ formation of copper and oxygen vacancies on the Cu2O surface under ambient condition. By imaging photoexcited single Cu2O particles, the resultant photoluminescence generated at Cu2O surface enable effective localization of copper and oxygen vacancies. Single particle photoluminescence imaging showed substantial heterogeneity in the rate of defect formation at different facets with the truncated corners achieving the fastest initial rate of photooxidation before subsequently changing to the face and edge sites as the photocorrosion proceeds. The generation of copper or oxygen vacancy is proportional to the photoexcitation power, while pH-dependent studies rationalized alkaline conditions for the formation of copper vacancy. Reaction in an electron-hole scavenger system showed that photooxidation and photoreduction will simultaneously occur, yet heterogeneously on the surface of Cu2O, with rate of copper vacancy formation being fastest.

Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia.

Erythroferrone (ERFE) is produced by erythroblasts in response to erythropoietin (EPO) and acts in the liver to prevent hepcidin stimulation by BMP6. Hepcidin suppression allows for the mobilization of iron to the bone marrow for the production of red blood cells. Aberrantly high circulating ERFE in conditions of stress erythropoiesis, such as in patients with ß-thalassemia, promotes the tissue iron accumulation that substantially contributes to morbidity in these patients. Here we developed antibodies against ERFE to prevent hepcidin suppression and to correct the iron loading phenotype in a mouse model of ß-thalassemia [Hbb(th3/+) mice] and used these antibodies as tools to further characterize ERFE's mechanism of action. We show that ERFE binds to BMP6 with nanomolar affinity and binds BMP2 and BMP4 with somewhat weaker affinities. We found that BMP6 binds the N-terminal domain of ERFE, and a polypeptide derived from the N terminus of ERFE was sufficient to cause hepcidin suppression in Huh7 hepatoma cells and in wild-type mice. Anti-ERFE antibodies targeting the N-terminal domain prevented hepcidin suppression in ERFE-treated Huh7 cells and in EPO-treated mice. Finally, we observed a decrease in splenomegaly and serum and liver iron in anti-ERFE-treated Hbb(th3/+) mice, accompanied by an increase in red blood cells and hemoglobin and a decrease in reticulocyte counts. In summary, we show that ERFE binds BMP6 directly and with high affinity, and that antibodies targeting the N-terminal domain of ERFE that prevent ERFE-BMP6 interactions constitute a potential therapeutic tool for iron loading anemias.

Age at diagnosis, anthropometry and birthweight in two ethnically different cohorts of children with type 1 diabetes living in Northwest England or Singapore.

AIM: To compare children with type 1 diabetes (T1D) living in the Northwest England, United Kingdom (UK) or Singapore, and to correlate age at diagnosis with birthweight and anthropometry at T1D diagnosis. METHODS: We included 166 T1D children of white ethnicity in England (UK-White) and 185 T1D children of East-Asian ethnicity origin in Singapore (SG-Asian) who were born between 2002 and 2020. RESULTS: The cohorts from UK-White and SG-Asian children differed significantly in FH of T1D (p < 0.001), FH of T2D (p < 0.001) and pubertal status at diagnosis (p = 0.01). Median interquartile range (IQR) for age at diagnosis was similar in the two groups. UK-White children had significantly higher birthweight SDS, height SDS, weight SDS and BMI SDS (all p < 0.001). Among the subgroup of 174 children who were prepubertal and diagnosed after age 5 years, the UK-White children were 11 months older than the SG-Asian children (p = 0.02) indicating that SG-Asian children at the time of T1D diagnosis were more likely to be in puberty compared with UK-White children (30% vs. 18%). CONCLUSION: These two cohorts have substantially different genetic and environmental backgrounds, yet age at the diagnosis of T1D was similar except for the prepubertal children who were diagnosed after 5 years old. Timing of puberty and other factors may influence how early T1D presents during childhood.

Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Overview of the Molecular and Cellular Mechanisms of Actions and Effects on Epithelial Ovarian Cancers.

Most patients with epithelial ovarian cancers (EOCs) are at advanced stages (stage III-IV), for which the recurrence rate is high and the 5-year survival rate is low. The most effective treatment for advanced diseases involves a debulking surgery followed by adjuvant intravenous chemotherapy with carboplatin and paclitaxel. Nevertheless, systemic treatment with intravenous chemotherapeutic agents for peritoneal metastasis appears to be less effective due to the poor blood supply to the peritoneal surface with low drug penetration into tumor nodules. Based on this reason, hyperthermic intraperitoneal chemotherapy (HIPEC) emerges as a new therapeutic alternative. By convection and diffusion, the hyperthermic chemotherapeutic agents can directly contact intraperitoneal tumors and produce cytotoxicity. In a two-compartment model, the peritoneal-plasma barrier blocks the leakage of chemotherapeutic agents from peritoneal cavity and tumor tissues to local vessels, thus maintaining a higher concentration of chemotherapeutic agents within the tumor tissues to facilitate tumor apoptosis and a lower concentration of chemotherapeutic agents within the local vessels to decrease systemic toxicity. In this review, we discuss the molecular and cellular mechanisms of HIPEC actions and the effects on EOCs, including the progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). For primary advanced ovarian cancers, more studies are agreeing that patients undergoing HIPEC have better surgical and clinical (PFS; OS) outcomes than those not, although one study reported no differences in the PFS and OS. For recurrent ovarian cancers, studies have revealed better DFS and OS in patients undergoing HIPEC than those in patients not undergoing HIPEC, although one study reported no differences in the PFS. HIPEC appears comparable to traditional intravenous chemotherapy in treating advanced EOCs. Overall, HIPEC has demonstrated some therapeutic benefits in many randomized phase III trials when combined with the standard cytoreductive surgeries for advanced EOCs. Nevertheless, many unknown aspects of HIPEC, including detailed mechanisms of actions, along with the effectiveness and safety for the treatment of EOCs, warrant further investigation.

Patient and Caregiver Considerations and Priorities When Selecting Hospitals for Complex Cancer Care.

BACKGROUND: Healthcare policies have focused on centralizing care to high-volume centers in an effort to optimize patient outcomes; however, little is known about patients' and caregivers' considerations and selection process when selecting hospitals for care. We aim to explore how patients and caregivers select hospitals for complex cancer care and to develop a taxonomy for their selection considerations. METHODS: This was a qualitative study in which data were gathered from in-depth interviews conducted from March to November 2019 among patients with hepatopancreatobiliary cancers who were scheduled to undergo a pancreatectomy (n = 20) at a metropolitan, urban regional, or suburban medical center and their caregivers (n = 10). RESULTS: The interviews revealed six broad domains that characterized hospital selection considerations: hospital factors, team characteristics, travel distance to hospital, referral or recommendation, continuity of care, and insurance considerations. The identified domains were similar between participants seen at the metropolitan center and urban/suburban medical centers, with the following exceptions: participants receiving care specifically at the metropolitan center noted operative volume and access to specific services such as clinical trials in their hospital selection; participants receiving care at urban/suburban centers noted health insurance considerations and having access to existing medical records in their hospital selection. CONCLUSIONS: This study delineates the many considerations of patients and caregivers when selecting hospitals for complex cancer care. These identified domains should be incorporated into the development and implementation of centralization policies to help increase patient access to high-quality cancer care that is consistent with their priorities and needs.

Effect of comorbid migraine on propranolol efficacy for painful TMD in a randomized controlled trial.

INTRODUCTION: The migraine-preventive drug propranolol is efficacious in reducing pain from temporomandibular disorder, suggesting potential modifying or mediating effects of comorbid migraine. METHODS: In this randomized controlled trial, myofascial temporomandibular disorder patients were treated with propranolol or placebo for 9 weeks. The primary endpoint was change in a facial pain index derived from daily symptom diaries. Linear and logistic regression models tested for a migraine × treatment-group interaction in reducing facial pain index. Counterfactual models explored changes in headache impact and heart rate as mediators of propranolol's efficacy. RESULTS: Propranolol's efficacy in reducing facial pain index was greater among the 104 migraineurs than the 95 non-migraineurs: For example, for the binary ≥ 30% reduction in facial pain index, odds ratios were 3.3 (95% confidence limits: 1.4, 8.1) versus 1.3 (0.5, 3.2), respectively, although the interaction was statistically non-significant (p = 0.139). Cumulative response curves confirmed greater efficacy for migraineurs than non-migraineurs (differences in area under the curve 26% and 6%, respectively; p = 0.081). While 9% of the treatment effect was mediated by reduced headache impact, 46% was mediated by reduced heart rate. CONCLUSIONS: Propranolol was more efficacious in reducing temporomandibular disorder pain among migraineurs than non-migraineurs, with more of the effect mediated by reduced heart rate than by reduced headache impact. STUDY IDENTIFICATION AND REGISTRATION: SOPPRANO; NCT02437383; https://clinicaltrials.gov/ct2/show/NCT02437383.

Validation of the Malay version of the p-QOL questionnaire.

INTRODUCTION: This study aimed to translate and validate the P-QOL questionnaire in the Malay language. METHODS: The P-QOL questionnaire was translated into the Malay language and subsequently back-translated to English. Test-retest reliability and internal consistency were tested. All patients who visited the gynecology outpatient clinic of UKMMC, UMMC and IIUM between January 2016 and May 2017 completed the P-QOL questionnaires and were assessed for POP-Q staging. RESULTS: One hundred twenty patients with symptomatic pelvic organ prolapse and 180 asymptomatic patients were included. The Cronbach's alpha for each domain was > 0.70, which confirmed that there was a highly acceptable internal consistency. The value varied between 0.88 (role limitation) and 0.912 (sleep/energy). Test-retest reliability showed a significant correlation between the total scores for each domain (p < 0.001). There was a significant correlation between P-QOL domain scores and vaginal examination findings (POP-Q). With a higher POP-Q stage, a higher impact on the quality of life was detected in symptomatic patients. The total scores from all domains were significantly higher in symptomatic patients. CONCLUSION: The Malay translated version of the P-QOL questionnaire is a reliable, consistent, and valid instrument for assessing the severity of the symptoms and impact on the quality of life among women with uterovaginal prolapse. It is easily understood, administered, and self-completed by patients.

Perineal skin tear repair following vaginal birth; skin adhesive versus conventional suture - a randomised controlled trial.

This was a prospective randomised controlled trial comparing the effects of first-degree perineal tear repair using adhesive glue versus conventional suturing in terms of pain score, wound complication and patient's satisfaction. One hundred and twenty one women were randomised. The skin adhesive group had a significantly lower pain score at rest as well as during sitting, walking and micturition during the first week of delivery compared to the suture group. The time taken to become pain free was significantly shorter in the tissue adhesive group (3.18 vs. 8.65 days, p < .001). Only two patients who had skin glue experienced wound gaping. No significant difference was observed in the level of satisfaction between the adhesive and suture groups. Tissue adhesive is better than subcuticular suture for repairing first-degree perineal tear as it causes less pain and has shorter recovery time.Impact statementWhat is already known on this subject. First- and second-degree tears following vaginal delivery are common and involved a third of women. Suturing of these tears is advocated to avoid wound gaping and poor healing.What the results of this study add. For first-degree tear repair, tissue adhesive is better than conventional suture in terms of pain reduction and recovery time.What the implications are of these findings for clinical practice and/or further research. Skin adhesive is an ideal method for first-degree perineal tear repair especially in out of hospital settings such as home birth or midwifery-led centre. A larger scale study is needed to establish its feasibility for second- and third-degree tears repair.

Clinical, psychological, and sensory characteristics associated with headache attributed to temporomandibular disorder in people with chronic myogenous temporomandibular disorder and primary headaches.

BACKGROUND: Headache attributed to Temporomandibular Disorder (HATMD) is a secondary headache that may have features resulting in diagnostic overlap with primary headaches, namely, tension-type (TTH) or migraine. This cross-sectional study of people with both chronic myogenous TMD and primary headaches evaluated characteristics associated with HATMD. METHODS: From a clinical trial of adults, baseline data were used from a subset with diagnoses of both TMD myalgia according to the Diagnostic Criteria for TMD (DC/TMD) and TTH or migraine according to the International Classification of Headache Disorders, 3rd edition. HATMD was classified based on the DC/TMD. Questionnaires and examinations evaluated 42 characteristics of facial pain, headache, general health, psychological distress, and experimental pain sensitivity. Univariate regression models quantified the associations of each characteristic with HATMD (present versus absent), headache type (TTH versus migraine), and their interaction in a factorial design. Multivariable lasso regression identified the most important predictors of HATMD. RESULTS: Of 185 participants, 114 (61.6%) had HATMD, while the numbers with TTH (n = 98, 53.0%) and migraine (n = 87, 47.0%) were similar. HATMD was more likely among migraineurs (61/87 = 70.1%) than participants with TTH (53/98 = 54.1%; odds ratio = 2.0; 95%CL = 1.1, 3.7). In univariate analyses, characteristics associated with HATMD included pain-free jaw opening and examination-evoked pain in masticatory muscles and temporomandibular joints (TMJ) as well as frequency and impact of headache, but not frequency or impact of facial pain. Lowered blood pressure but not psychological or sensory characteristics was associated with HATMD. Multiple characteristics of facial pain, headache, general health, and psychological distress differed between TTH or migraine groups. Few interactions were observed, demonstrating that most characteristics' associations with HATMD were consistent in TTH and migraine groups. The lasso model identified headache frequency and examination-evoked muscle pain as the most important predictors of HATMD. CONCLUSIONS: HATMD is highly prevalent among patients with chronic myogenous TMD and headaches and often presents as migraine. In contrast to primary headaches, HATMD is associated with higher headache frequency and examination-evoked masticatory muscle pain, but with surprisingly few measures of facial pain, general health, and psychological distress. A better understanding of HATMD is necessary for developing targeted strategies for its management. TRIAL IDENTIFICATION AND REGISTRATION: SOPPRANO; NCT02437383 . Registered May 7, 2015.

α-Amylase and dipeptidyl peptidase-4 (DPP-4) inhibitory effects of Melicope latifolia bark extracts and identification of bioactive constituents using in vitro and in silico approaches.

CONTEXT: Melicope latifolia (DC.) T. G. Hartley (Rutaceae) was reported to contain various phytochemicals including coumarins, flavonoids, and acetophenones. OBJECTIVE: This study investigates the antidiabetic and antioxidant effects of M. latifolia bark extracts, fractions, and isolated constituents. MATERIALS AND METHODS: Melicope latifolia extracts (hexane, chloroform, and methanol), fractions, and isolated constituents with varying concentrations (0.078-10 mg/mL) were subjected to in vitro α-amylase and dipeptidyl peptidase-4 (DPP-4) inhibitory assay. Molecular docking was performed to study the binding mechanism of active compounds towards α-amylase and DPP-4 enzymes. The antioxidant activity of M. latifolia fractions and compounds were determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging and ß-carotene bleaching assays. RESULTS: Melicope latifolia chloroform extract showed the highest antidiabetic activity (α-amylase IC50: 1464.32 µg/mL; DPP-4 IC50: 221.58 µg/mL). Fractionation of chloroform extract yielded four major fractions (CF1-CF4) whereby CF3 showed the highest antidiabetic activity (α-amylase IC50: 397.68 µg/mL; DPP-4 IC50: 37.16 µg/mL) and resulted in ß-sitosterol (1), halfordin (2), methyl p-coumarate (3), and protocatechuic acid (4). Isolation of compounds 2-4 from the species and their DPP-4 inhibitory were reported for the first time. Compound 2 showed the highest α-amylase (IC50: 197.53 µM) and ß-carotene (88.48%) inhibition, and formed the highest number of molecular interactions with critical amino acid residues of α-amylase. The highest DPP-4 inhibition was exhibited by compound 3 (IC50: 911.44 µM). DISCUSSION AND CONCLUSIONS: The in vitro and in silico analyses indicated the potential of M. latifolia as an alternative source of α-amylase and DPP-4 inhibitors. Further pharmacological studies on the compounds are recommended.

Clinical outcomes and quality of life in children and adolescents with primary brain tumors treated with pencil beam scanning proton therapy.

BACKGROUND: Long-term treatment-related toxicity may substantially impact well-being, quality of life (QoL), and health of children/adolescents with brain tumors (CBTs). Strategies to reduce toxicity include pencil beam scanning (PBS) proton therapy (PT). This study aims to report clinical outcomes and QoL in PBS-treated CBTs. PROCEDURE: We retrospectively reviewed 221 PBS-treated CBTs aged <18 years. Overall-free (OS), disease-free (DFS), and late-toxicity-free survivals (TFS), local control (LC) and distant (DC) brain/spinal control were calculated using Kaplan-Meier estimates. Prospective QoL reports from 206 patients (proxies only ≤4 years old [yo], proxies and patients ≥5 yo) were descriptively analyzed. Median follow-up was 51 months (range, 4-222). RESULTS: Median age at diagnosis was 3.1 years (range, 0.3-17.7). The main histologies were ependymoma (n = 88; 39.8%), glioma (n = 37; 16.7%), craniopharyngioma (n = 22; 10.0%), atypical teratoid/rhabdoid tumor (ATRT) (n = 21; 9.5%) and medulloblastoma (n = 15; 6.8%). One hundred sixty (72.4%) patients received chemotherapy. Median PT dose was 54 Gy(relative biological effectiveness) (range, 18.0-64.8). The 5-year OS, DFS, LC, and DC (95% CI) were 79.9% (74-85.8), 65.2% (59.8-70.6), 72.1% (65.4-78.8), and 81.8% (76.3-87.3), respectively. Late PT-related ≥G3 toxicity occurred in 19 (8.6%) patients. The 5-year ≥G3 TFS was 91.0% (86.3-95.7). Three (1.4%) secondary malignancies were observed. Patients aged ≤3 years at PT (P = .044) or receiving chemotherapy (P = .043) experienced more ≥G3 toxicity. ATRT histology independently predicted distant brain failure (P = .046) and death (P = .01). Patients aged ≥5 years self-rated QoL higher than their parents (proxy assessment). Both reported lower social functioning and cognition after PT than at baseline, but near-normal long-term global well-being. QoL was well below normal before and after PT in children ≤4 years. CONCLUSIONS: The outcome of CBTs was excellent after PBS. Few patients had late ≥G3 toxicity. Patients aged <5 years showed worse QoL and toxicity outcomes.

Outcomes of adolescents and young adults treated for brain and skull base tumors with pencil beam scanning proton therapy.

BACKGROUND: The use of proton therapy (PT) in adolescents and young adults (AYAs) is becoming increasingly popular. This study aims to assess the outcomes and late toxicity consequences in AYAs (15-39 years) with brain/skull base tumors treated with pencil beam scanning proton therapy. METHODS: One hundred seventy six AYAs treated curatively at the Paul Scherrer Institute (PSI) were identified. Median age was 30 years (range 15-39) and median prescribed dose was 70.0 Gy (relative biological effectiveness [RBE]) (range 50.4-76.0). The most common tumors treated were chordomas/chondrosarcomas (61.4%), followed by gliomas (15.3%), and meningiomas (14.2%). RESULTS: After a median follow up of 66 months (range 12-236), 24 (13.6%) local only failures and one (0.6%) central nervous system (CNS) distant only failure were observed. The 6-year local control, distant progression-free survival, and overall survival were 83.2%, 97.4%, and 90.2%, respectively. The 6-year high-grade (≥grade [G] 3) PT-related late toxicity-free survival was 88.5%. Crude late toxicity rates were 26.2% G1, 37.8% G2, 12.2% G3, 0.6% G4, and 0.6% G5. The one G4 toxicity was a retinopathy and one G5 toxicity was a brainstem hemorrhage. The 6-year cumulative incidences for any late PT-related pituitary, ototoxicity, and neurotoxicity were 36.3%, 18.3%, and 25.6%; whilst high-grade (≥G3) ototoxicity and neurotoxicity were 3.4% and 2.9%, respectively. No secondary malignancies were observed. The rate of unemployment was 9.5% pre-PT, increasing to 23.8% post-PT. Sixty-two percent of survivors were working whilst 12.7% were in education post-PT. CONCLUSIONS: PT is an effective treatment for brain/skull base tumors in the AYA population with a reasonable late toxicity profile. Despite good clinical outcomes, around one in four AYA survivors are unemployed after treatment.

Circadian rhythm and its association with birth and infant outcomes: research protocol of a prospective cohort study.

BACKGROUND: Circadian rhythm plays an important role as our internal body's clock that synchronizes behavior and physiology according to the external 24-h light-dark cycle. Past studies have associated disrupted circadian rhythm with higher risk of miscarriages, preterm birth and low birth weights. This paper described the protocol of a prospective cohort study which aims to determine the circadian rhythm in pregnant women, identify its association with maternal factors during pregnancy, gestational weight gain, birth and infant outcomes. METHODS: Ten government maternal and child health clinics in Kuala Lumpur, Malaysia will be randomly selected. Sample size of 438 first-trimester pregnant women will be followed-up until the birth of their infant. Salivary melatonin and cortisol concentration among subsample will be determined using enzyme-linked immunosorbent assay. Data on sleep quality, psychological distress and morningness/eveningness chronotype of pregnant women will be collected using validated questionnaires. Pedometer will be used to measure 5-day physical activity data. Total gestational weight gain will be determined at the end of pregnancy. Utilization of 3-day food record is to capture meal timing and nutrient intake. All measurements will be done in 2nd and 3rd trimester. Birth outcomes will be collected through clinic records and Centers for Disease Control and Prevention (CDC) Neonatal questionnaire. Infants will be followed-up at 6 and 12 months old to obtain anthropometric measurements. DISCUSSION: There is a growing recognition of the role of maternal circadian rhythm, which entrains fetal circadian rhythms that may subsequently have long-term health consequences. The present study will identify the effect of circadian rhythm on pregnancy outcomes and infant growth in the first year of life.

Identification of Dipeptidyl Peptidase-4 and α-Amylase Inhibitors from Melicope glabra (Blume) T. G. Hartley (Rutaceae) Using Liquid Chromatography Tandem Mass Spectrometry, In Vitro and In Silico Methods.

The present study investigated the antidiabetic properties of the extracts and fractions from leaves and stem bark of M. glabra based on dipeptidyl peptidase-4 (DPP-4) and α-Amylase inhibitory activity assays. The chloroform extract of the leaves was found to be most active towards inhibition of DPP-4 and α-Amylase with IC50 of 169.40 µg/mL and 303.64 µg/mL, respectively. Bioassay-guided fractionation of the leaves' chloroform extract revealed fraction 4 (CF4) as the most active fraction (DPP-4 IC50: 128.35 µg/mL; α-Amylase IC50: 170.19 µg/mL). LC-MS/MS investigation of CF4 led to the identification of trans-decursidinol (1), swermirin (2), methyl 3,4,5-trimethoxycinnamate (3), renifolin (4), 4',5,6,7-tetramethoxy-flavone (5), isorhamnetin (6), quercetagetin-3,4'-dimethyl ether (7), 5,3',4'-trihydroxy-6,7-dimethoxy-flavone (8), and 2-methoxy-5-acetoxy-fruranogermacr-1(10)-en-6-one (9) as the major components. The computational study suggested that (8) and (7) were the most potent DPP-4 and α-Amylase inhibitors based on their lower binding affinities and extensive interactions with critical amino acid residues of the respective enzymes. The binding affinity of (8) with DPP-4 (-8.1 kcal/mol) was comparable to that of sitagliptin (-8.6 kcal/mol) while the binding affinity of (7) with α-Amylase (-8.6 kcal/mol) was better than acarbose (-6.9 kcal/mol). These findings highlight the phytochemical profile and potential antidiabetic compounds from M. glabra that may work as an alternative treatment for diabetes.

Cytotoxic Activity of Christia vespertilionis Root and Leaf Extracts and Fractions against Breast Cancer Cell Lines.

Christia vespertilionis, commonly known as 'Daun Rerama', has recently garnered attention from numerous sources in Malaysia as an alternative treatment. Its herbal decoction was believed to show anti-inflammatory and anti-cancer effects. The present study investigated the cytotoxicity of the extract of root and leaf of C. vespertilionis. The plant parts were successively extracted using the solvent maceration method. The most active extract was further fractionated to afford F1-F8. The cytotoxic effects were determined using MTT assay against human breast carcinoma cell lines (MCF-7 and MDA-MB-231). The total phenolic content (TPC) of the extracts were determined. The antioxidant properties of the extract were also studied using DPPH and ß-carotene bleaching assays. The ethyl acetate root extract demonstrated selective cytotoxicity especially against MDA-MB-231 with the highest TPC and antioxidant properties compared to others (p < 0.05). The TPC and antioxidant results suggest the contribution of phenolic compounds toward its antioxidant strength leading to significant cytotoxicity. F3 showed potent cytotoxic effects while F4 showed better antioxidative strength compared to others (p < 0.05). Qualitative phytochemical screening of the most active fraction, F3, suggested the presence of flavonoids, coumarins and quinones to be responsible toward the cytotoxicity. The study showed the root extracts of C. vespertilionis to possess notable anti-breast cancer effects.

Reviewing the role of progesterone therapy in endometriosis.

Endometriosis is a benign, chronic inflammatory condition characterized by the presence and growth of endometrial implants outside the uterine cavity. The cause of endometriosis is multifactorial. It is due to the diversity of hypothesis and plausibility of hormonal alterations which could play a major role. Evidence has shown that progesterone resistance is a key factor for endometriosis sufferers. Medical therapy can avoid surgical intervention, which may lead to a reduced in ovarian reserve, and its effects of earlier menopause and reduced fecundity. Progesterone receptor isoform has provided new insight as the potential treatment. Progestin, anti-progestin and selective progesterone receptor modulators usage, which target these receptors, could avoid hypo-estrogenic side effects, which can be debilitating. Numerous types of these medications have been used on and off labeled to treat endometriosis with varying success. This review aims to consolidate series of clinical trials using progestins in endometriosis.