Prevalence of PALB2 Mutations in Breast Cancer Patients in Multi-Ethnic Asian Population in Malaysia and Singapore

10.1371/journal.pone.0073638PLoS ONE88-POLN

Fission Yeast Methylenetetrahydrofolate Reductase Ensures Mitotic and Meiotic Chromosome Segregation Fidelity

10.3390/ijms22020639INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES22

Fission Yeast Methylenetetrahydrofolate Reductase Ensures Mitotic and Meiotic Chromosome Segregation Fidelity

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway, and its loss of function through polymorphisms is often associated with human conditions, including cancer, congenital heart disease, and Down syndrome. MTHFR is also required in the maintenance of heterochromatin, a crucial determinant of genomic stability and precise chromosomal segregation. Here, we characterize the function of a fission yeast gene met11+, which encodes a protein that is highly homologous to the mammalian MTHFR. We show that, although met11+ is not essential for viability, its disruption increases chromosome missegregation and destabilizes constitutive heterochromatic regions at pericentromeric, sub-telomeric and ribosomal DNA (rDNA) loci. Transcriptional silencing at these sites were disrupted, which is accompanied by the reduction in enrichment of histone H3 lysine 9 dimethylation (H3K9me2) and binding of the heterochromatin protein 1 (HP1)-like Swi6. The met11 null mutant also dominantly disrupts meiotic fidelity, as displayed by reduced sporulation efficiency and defects in proper partitioning of the genetic material during meiosis. Interestingly, the faithful execution of these meiotic processes is synergistically ensured by cooperation among Met11, Rec8, a meiosis-specific cohesin protein, and the shugoshin protein Sgo1, which protects Rec8 from untimely cleavage. Overall, our results suggest a key role for Met11 in maintaining pericentromeric heterochromatin for precise genetic inheritance during mitosis and meiosis

Pedigrees of families with germline mutations in <i>PALB2</i>.

<p>(A) Family pedigree of BRC945, carrier of c.1037_1041delAAGAA [STOP358]. (B) Family pedigree of BRC859, carrier of c.2606delC [S869X]. (C) Family pedigree of BRC1126, carrier of c.1050delAACA [STOP353]. Index patients are indicated with an arrow while individuals affected with breast cancer are indicated with filled symbol. Date of birth (DOB) and age of diagnosis (in bracket) foraffected individuals are indicated. Deceased individuals are indicated with a slash.</p

Optical coherence tomography angiography of the macula and optic nerve head: microvascular density and test-retest repeatability in normal subjects

Abstract Background Despite the potential usefulness of optical coherence tomography angiography in retinal and optic disc conditions, the reliability of the imaging modality remains unclear. This study set out to measure the microvascular density of macula and optic disc by mean of optical coherence tomography angiography and report the repeatability of the vessel density measurements. Methods Cross sectional observational cohort study. Subjects with normal eyes were recruited. Two sets of optical coherence tomography angiography images of macula and optic nerve head were acquired during one visit. Novel in-house developed software was used to count the pixels in each images and to compute the microvessel density of the macula and optic disc. Data were analysed to determine the measurement repeatability. Results A total of 176 eyes from 88 consecutive normal subjects were recruited. For macular images, the mean vessel density at superficial retina, deep retina, outer retina and choriocapillaries segment was OD 0.113 and OS 0.111, OD 0.239 and OS 0.230, OD 0.179 and OS 0.164, OD 0.237 and OS 0.215 respectively. For optic disc images, mean vessel density at vitreoretinal interface, radial peripapillary capillary, superficial nerve head and disc segment at the level of choroid were OD 0.084 and OS 0.085, OD 0.140 and OS 0.138, OD 0.216 and OS 0.209, OD 0.227 and OS 0.236 respectively. The measurement repeatability tests showed that the coefficient of variation of macular scans, for right and left eyes, ranged from 6.4 to 31.1% and 5.3 to 59.4%. Likewise, the coefficient of variation of optic disc scans, for right and left eyes, ranged from 14.3 to 77.4% and 13.5 to 75.3%. Conclusions Optical coherence tomography angiography is a useful modality to visualise the microvasculature plexus of macula and optic nerve head. The vessel density measurement of macular scan by mean of optical coherence tomography angiography demonstrated good repeatability. The optic disc scan, on the other hand, showed a higher coefficient of variation indicating a lower measurement repeatability than macular scan. Interpretation of optical coherence tomography angiography should take into account test-retest repeatability of the imaging system. Trial registration National Healthcare Group Domain Specific Review Board (NHG DSRB) Singapore. DSRB Reference: 2015/00301

Choroidal remodeling in age-related macular degeneration and polypoidal choroidal vasculopathy : a 12-month prospective study

Choroid thinning occurs in age-related macular degeneration (AMD). However, it remains unclear whether the reduction is due to reduction in choroidal vessels or shrinkage of choroidal stroma, or both. The purpose of this study was to evaluate the changes of the choroidal vascular and stromal area in 118 patients with typical AMD (t-AMD) and polypoidal choroidal vasculopathy (PCV) over a 12-month period. We used spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging (EDI) mode to measure the subfoveal choroidal thickness (CT), central retinal thickness (CRT) and choroidal vascularity index (CVI - ratio of luminal area to total choroidal area). At baseline, PCV eyes had higher CRT (471.6 µm vs 439.1 µm, p = 0.02), but comparable subfoveal CT and CVI, compared to t-AMD. Eyes with high CVI at baseline showed marked reduction in stromal area compared with eyes with average or low CVI. Over 12 months, CRT and subfoveal CT significantly decreased (p < 0.001) in both subtypes. Eyes with high baseline CVI showed significant CVI reduction from baseline to month 12 (p < 0.001), whereas eyes with average to low baseline CVI showed increase in CVI. These differences in choroidal vascularity may reflect different predominant pathogenic processes and remodeling in AMD eyes with varying spectrum.Published versio

Phenotypic bases of NOTCH2NLC

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60 to 500 copies in the 5'-untranslated region of NOTCH2NLC. The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long-read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92-138). Ten were Chinese and two of Malay ethnicity. Age at onset ranged from 50 to 69 years. Eight (66.7%) patients had dementia, while four (33.3%) patients were oligosymptomatic, without typical NIID symptoms of dementia, Parkinsonism, or muscle weakness. GGA interruptions within the GGC expansion were present in four patients; the number of GGA interruptions was highest (6.71%) in the patient with the earliest age at onset (50 years). Median plasma neurofilament light level was 47.3 pg/mL in seven patients (range 26-380 pg/mL). The highest level (380 pg/mL) was found in one patient who experienced an encephalitic episode. Overall, we describe a cohort of genetically confirmed NIID patients from Southeast Asia and provide further information that the presence of GGA interruptions within GGC repeat expansions may serve as a potential genetic modifier in NIID.National Medical Research Council (NMRC)This study was funded by Singapore's National Medical Research Council (ASLN by the Transition Award (MOH-TA18may-0003); ZC by the NMRC Centre Grant Seed Funding Programme-Pilot Grant (IRNMR17CPG02); CTL by the NNI Research Endowment Fund (NNI-HREF NRH16/001)

Multi-Center Validation of Pain Assessment in Advanced Dementia (PAINAD) Scale in Malaysia

The detection of pain in persons with advanced dementia is challenging due to their inability to verbally articulate the pain they are experiencing. Pain Assessment in Advanced Dementia (PAINAD) is an observer-rated pain assessment tool developed based on non-verbal expressions of pain for persons with severe dementia. This study aimed to perform construct validation of PAINAD for pain assessment in persons with severe dementia in Malaysia. This was a prospective cross-sectional study conducted from 27 April 2022 to 28 October 2022 in eight public hospitals in Malaysia. The PAINAD scale was the index test, and the Discomfort Scale—Dementia of the Alzheimer Type (DS-DAT) and Nurse-Reported Pain Scale (NRPS) were the reference tests for construct and concurrent validity assessment. Pain assessment for the study subjects was performed by two raters concurrently at rest and during activity. The PAINAD score was determined by the first rater, whereas the DS-DAT and NRPS were assessed by the second rater, and they were blinded to each other’s findings to prevent bias. PAINAD showed good positive correlations ranging from 0.325 to 0.715 with DS-DAT and NRPS at rest and during activity, with a p-value of <0.05. It also demonstrated statistically significant differences when comparing pain scores at rest and during activity, pre- and post-intervention. In conclusion, the PAINAD scale is a reliable observer-rated pain assessment tool for persons with severe dementia in Malaysia. It is also sensitive to changes in the pain level during activity and at rest, pre- and post-intervention