👤 Martina Sj McDermott

CLN3 disease is a rare inherited neurodegenerative disease that typically starts in childhood. Given the progressive nature of the disease, it likely affects the health-related quality of life (HRQOL) of both the child and the family unit. In this study, we evaluated HRQOL and family function in individuals with CLN3 disease and their families. Data were obtained from longitudinal observational studies on CLN3 disease at the University of Rochester Batten Center. Assessments were completed at variable intervals from 2006 to 2024. Parents completed the PedsQL, which assesses child HRQOL, and the PedsQL FIM, which assess family impact. In a subset of participants, we concurrently administered the Unified Batten Disease Rating Scale, a global assessment of CLN3 disease. Data from 71 participants were included in this study, of which 21 participants had concurrent Unified Batten Disease Rating Scale data. Mean (SD) PedsQL Total (48.2 (19.7)) and PedsQL FIM Total (51.2 [16.5]) scores were low. Worse child HRQOL was associated with physical impairment from more severe CLN3 disease (r Children with CLN3 disease and their families are at high risk of impaired HRQOL and function. This information may provide important information for clinical care and trial design in CLN3 disease. Show less

There is an immunoreactive subtype of ovarian cancer with a favorable prognosis, but the majority of ovarian cancers have limited immune reactivity. The reason for this is poorly understood. This study aimed to approach this question by identifying prognostically relevant genes whose prognostic mRNA expression levels correlated with a genomic event. Expression microarray and 5-year survival data on 170 ovarian tumors and aCGH data on 45 ovarian cancer cell lines were used to identify amplified/deleted genes associated with prognosis. Three immune-response genes were identified mapping to epigenetically modified chromosome 6p21.3. Genes were searched for roles in epigenetic modification, identifying KANSL1. Genome-wide association studies were searched to identify genetic variants in KANSL1 associated with altered immune profile. Sensitivity to HDAC inhibition in cell lines with KANSL1 amplification/rearrangement was studied. Expression of 196 genes was statistically significantly associated with survival, and expression levels correlated with copy number variations for 82 of them. Among these, 3 immune-response genes (HCP5, PSMB8, PSMB9) clustered together at epigenetically modified chromosome 6p21.3 and their expression was inversely correlated to epigenetic modification gene KANSL1. KANSL1 is amplified/rearranged in ovarian cancer, associated with lymphocyte profile, a biomarker for response to HDAC inhibition, and may drive expression of immune-response genes. This study identifies 82 genes with prognostic relevance and genomic alteration in ovarian cancer. Among these, immune-response genes have correlated expression which is associated with 5-year survival. KANSL1 may be a master gene altering immune-response gene expression at 6p21.3 and drive response to HDAC inhibitors. Future research should investigate KANSL1 and determine whether targeting it alters the immune profile of ovarian cancer and improves survival, HDAC inhibition, and/or immunotherapy response. Show less

To enable hearing, the sensory hair cell contains specialized subcellular structures at its apical region, including the actin-rich cuticular plate and circumferential band. ACF7 (actin crosslinking family protein 7), encoded by the gene Show less

The dynamin-like protein, Vps1, is a GTPase involved in cargo sorting and membrane remodeling in multiple cellular trafficking pathways. Recently, Vps1 has been shown to genetically interact with ESCRT subunits. We tested the hypothesis that the functional connection of Vps1 with some of these subunits of ESCRT complexes occurs via a physical interaction. By utilizing the yeast two-hybrid system, we revealed that Vps1 physically interacts with the ESCRT-II subunits, Vps22 and Vps36, and the ESCRT-III subunit Vps24. We found that Vps1 and ESCRT-II components colocalize with Pep12, an endosomal marker. Additionally, loss of Vps1 or depletion of the GTPase activity of Vps1 results in a moderate defect in Cps1 targeting to the vacuole. Here, we discussed the potential implications of Vps1 and ESCRT interaction and their roles in the endosome-to-vacuole traffic. In summary, yeast dynamin interacts with ESCRT II and III complexes, and it functions in Cps1 trafficking toward the vacuole. Show less

Assessing whether next-generation DNA sequencing (NGS) can be used to screen prostate cancer for multiple gene alterations in men routinely diagnosed with this disease and/or who are entered into clinical trials. Previous studies are limited and have reported only low success rates. We marked areas of cancer on H&E-stained sections from formalin-fixed needle biopsies, and used these as templates to dissect cancer-rich tissue from adjacent unstained sections. DNA was prepared using a Qiagen protocol modified to maximise DNA yield. The DNA was screened simultaneously for mutations in 365 cancer-related genes using an Illumina HiSeq 2000 NGS platform. From 63 prostate cancers examined, 59(94%) of the samples yielded at least 30 ng of DNA, the minimum amount of DNA considered suitable for NGS analysis. Patients in the D'Amico high-risk group yielded an average of 1033 ng, intermediate-risk patients 401 ng, and low-risk patients 97 ng. NGS of eight samples selected from high-risk and intermediate-risk groups gave a median exon read depth of 962 and detected TMPRRS2-ERG fusions, as well as a variety of mutations including those in the SPOP, TP53, ATM, MEN1, NBPF10, NCOR2, PIK3CB and MAP2K5 (MEK5) genes. Using the methods presented here, NGS technologies can be used to screen a high proportion of patients with prostate cancer for mutations in cancer-related genes in tissue samples opening up its general use in the context of clinical trials or routine diagnosis. Show less

MEF2 plays a profound role in the regulation of transcription in cardiac and skeletal muscle lineages. To define the overlapping and unique MEF2A genomic targets, we utilized ChIP-exo analysis of cardiomyocytes and skeletal myoblasts. Of the 2783 and 1648 MEF2A binding peaks in skeletal myoblasts and cardiomyocytes, respectively, 294 common binding sites were identified. Genomic targets were compared to differentially expressed genes in RNA-seq analysis of MEF2A depleted myogenic cells, revealing two prominent genetic networks. Genes largely associated with muscle development were down-regulated by loss of MEF2A while up-regulated genes reveal a previously unrecognized function of MEF2A in suppressing growth/proliferative genes. Several up-regulated (Tprg, Mctp2, Kitl, Prrx1, Dusp6) and down-regulated (Atp1a2, Hspb7, Tmem182, Sorbs2, Lmod3) MEF2A target genes were chosen for further investigation. Interestingly, siRNA targeting of the MEF2A/D heterodimer revealed a somewhat divergent role in the regulation of Dusp6, a MAPK phosphatase, in cardiac and skeletal myogenic lineages. Furthermore, MEF2D functions as a p38MAPK-dependent repressor of Dusp6 in myoblasts. These data illustrate that MEF2 orchestrates both common and non-overlapping programs of signal-dependent gene expression in skeletal and cardiac muscle lineages. Show less

The precise morphology of the mechanosensitive hair bundle requires seamless integration of actin and microtubule networks. Here, we identify Acf7a (actin crosslinking family protein 7a) as a protein positioned to bridge these distinct cytoskeletal networks in hair cells. By imaging Acf7a-Citrine fusion protein in zebrafish and immunolabeling of vestibular and cochlear mouse hair cells, we show that Acf7a and ACF7 circumscribe, underlie, and are interwoven into the cuticular plate (CP), and they also encircle the basal body of the kinocilium. In cochlear hair cells, ACF7 localization is graded, with the highest concentration near each fonticulus--an area free of F-actin in the region of the CP that contains the basal body. During hair-cell development and regeneration, Acf7a precedes formation of the hair bundle and CP. Finally, electron tomography demonstrates that the ends of microtubules insert into the CP and are decorated with filamentous linkers connecting microtubules to the CP. These observations are consistent with ACF7 being a linker protein, which may shape the cytoskeleton of the hair cell early during hair-bundle genesis. Show less