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Background: Glioblastoma exhibits aggressive growth and poor outcomes despite treatment, and its marked variability renders therapeutic design and prognostication challenging. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling of 206 glioblastoma patients, providing opportunities to identify novel associations between molecular features and clinical outcomes., Methods: Survival analyses were performed using the Logrank test, and clinical features were evaluated using Wilcoxon and chi-squared tests with q -values derived via Benjamini-Hochberg correction. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test with Benjamini-Hochberg correction. Transcriptomic analyses utilized a student's t -test with Benjamini-Hochberg correction. Expression fold changes were processed with Ingenuity Pathway Analysis to determine pathway-level alterations between groups., Results: Key findings include an association of MUC17, SYNE1, and TENM1 mutations with prolonged overall survival (OS); decreased OS associated with higher epithelial growth factor receptor (EGFR) mRNA expression, but not with EGFR amplification or mutation; a 14-transcript signature associated with OS > 2 years; and 2 transcripts associated with OS < 1 year., Conclusions: Herein, we report the first clinical, genomic, and transcriptomic analysis of ORIEN glioblastoma cases, incorporating sample reclassification under updated 2021 diagnostic criteria. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of intractable diseases such as glioblastoma., Competing Interests: HC: Advisory Board/Consultant: Best Doctors/Teladoc, Orbus Therapeutics, Bristol Meyers Squibb, Regeneron, Novocure, PPD/Chimerix, AnHeart Therapeutics, Alpha Biopharma. Research Funding: Orbus, GCAR, Array BioPharma, Karyopharm Therapeutics, Nuvation Bio, Bayer, Bristol Meyer Squib, Sumitomo Dainippon Pharma Oncology, Samus Therapeutics, Erasca. DRO: Research funding: Integra, Servier. Medical advisory board: Longeviti. AND, FC, DWC, MGW, JB, AC, JLV, BPS, JKCL, MLC, GZ: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Common mitochondrial DNA (mtDNA) deletions are large structural variants in the mitochondrial genome that accumulate in metabolically active tissues with age and have been investigated in various diseases. We applied the Splice-Break2 pipeline (designed for high-throughput quantification of mtDNA deletions) to human RNA-Seq datasets and describe the methodological considerations for evaluating common deletions in bulk, single-cell, and spatial transcriptomics datasets. A robust evaluation of 1570 samples from 14 RNA-Seq studies showed: (i) the abundance of some common deletions detected in PCR-amplified mtDNA correlates with levels observed in RNA-Seq data; (ii) RNA-Seq library preparation method has a strong effect on deletion detection; (iii) deletions had a significant, positive correlation with age in brain and muscle; (iv) deletions were enriched in cortical grey matter, specifically in layers 3 and 5; and (v) brain regions with dopaminergic neurons (i.e., substantia nigra, ventral tegmental area, and caudate nucleus) had remarkable enrichment of common mtDNA deletions., (© 2024. The Author(s).)

The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.

Triple-negative breast cancer (TNBC) is an aggressive disease that disproportionately affects African American (AA) women. Limited targeted therapeutic options exist for patients with TNBC. Here, we employ spatial transcriptomics to interrogate tissue from a racially diverse TNBC cohort to comprehensively annotate the transcriptional states of spatially resolved cellular populations. A total of 38,706 spatial features from a cohort of 28 sections from 14 patients were analyzed. Intratumoral analysis of spatial features from individual sections revealed heterogeneous transcriptional substructures. However, integrated analysis of all samples resulted in nine transcriptionally distinct clusters that mapped across all individual sections. Furthermore, novel use of join count analysis demonstrated nonrandom directional spatial dependencies of the transcriptionally defined shared clusters, supporting a conserved spatio-transcriptional architecture in TNBC. These findings were substantiated in an independent validation cohort comprising 17,861 spatial features representing 15 samples from 8 patients. Stratification of samples by race revealed race-associated differences in hypoxic tumor content and regions of immune-rich infiltrate. Overall, this study combined spatial and functional molecular analyses to define the tumor architecture of TNBC, with potential implications in understanding TNBC disparities., Significance: Spatial transcriptomics profiling of a diverse cohort of triple-negative breast cancers and innovative informatics approaches reveal a conserved cellular architecture across cancers and identify proportional differences in tumor cell composition by race., (©2022 American Association for Cancer Research.)

Hepatocyte growth factor-overexpressing mice that harbor a deletion of the Ink4a/p16 locus (HP mice) form melanomas with low metastatic potential in response to UV irradiation. Here we report that these tumors become highly metastatic following hemizygous deletion of the Nme1 and Nme2 metastasis suppressor genes (HPN mice). Whole-genome sequencing of melanomas from HPN mice revealed a striking increase in lung metastatic activity that is associated with missense mutations in eight signature genes (Arhgap35, Atp8b4, Brca1, Ift172, Kif21b, Nckap5, Pcdha2, and Zfp869). RNA-seq analysis of transcriptomes from HP and HPN primary melanomas identified a 32-gene signature (HPN lung metastasis signature) for which decreased expression is strongly associated with lung metastatic potential. Analysis of transcriptome data from The Cancer Genome Atlas revealed expression profiles of these genes that predict improved survival of patients with cutaneous or uveal melanoma. Silencing of three representative HPN lung metastasis signature genes (ARRDC3, NYNRIN, RND3) in human melanoma cells resulted in increased invasive activity, consistent with roles for these genes as mediators of the metastasis suppressor function of NME1 and NME2. In conclusion, our studies have identified a family of genes that mediate suppression of melanoma lung metastasis, and which may serve as prognostic markers and/or therapeutic targets for clinical management of metastatic melanoma., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

We performed shallow single-cell sequencing of genomic DNA across 1475 cells from a cell-line, COLO829, to resolve overall complexity and clonality. This melanoma tumor-line has been previously characterized by multiple technologies and is a benchmark for evaluating somatic alterations. In some of these studies, COLO829 has shown conflicting and/or indeterminate copy number and, thus, single-cell sequencing provides a tool for gaining insight. Following shallow single-cell sequencing, we first identified at least four major sub-clones by discriminant analysis of principal components of single-cell copy number data. Based on clustering, break-point and loss of heterozygosity analysis of aggregated data from sub-clones, we identified distinct hallmark events that were validated within bulk sequencing and spectral karyotyping. In summary, COLO829 exhibits a classical Dutrillaux's monosomic/trisomic pattern of karyotype evolution with endoreduplication, where consistent sub-clones emerge from the loss/gain of abnormal chromosomes. Overall, our results demonstrate how shallow copy number profiling can uncover hidden biological insights.

Deletions in the 16.6 kb mitochondrial genome have been implicated in numerous disorders that often display muscular and/or neurological symptoms due to the high-energy demands of these tissues. We describe a catalogue of 4489 putative mitochondrial DNA (mtDNA) deletions, including their frequency and relative read rate, using a combinatorial approach of mitochondria-targeted PCR, next-generation sequencing, bioinformatics, post-hoc filtering, annotation, and validation steps. Our bioinformatics pipeline uses MapSplice, an RNA-seq splice junction detection algorithm, to detect and quantify mtDNA deletion breakpoints rather than mRNA splices. Analyses of 93 samples from postmortem brain and blood found (i) the 4977 bp 'common deletion' was neither the most frequent deletion nor the most abundant; (ii) brain contained significantly more deletions than blood; (iii) many high frequency deletions were previously reported in MitoBreak, suggesting they are present at low levels in metabolically active tissues and are not exclusive to individuals with diagnosed mitochondrial pathologies; (iv) many individual deletions (and cumulative metrics) had significant and positive correlations with age and (v) the highest deletion burdens were observed in major depressive disorder brain, at levels greater than Kearns-Sayre Syndrome muscle. Collectively, these data suggest the Splice-Break pipeline can detect and quantify mtDNA deletions at a high level of resolution., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The cardiac ventricular myocyte is a key experimental system for exploring the mechanical properties of the diseased and healthy heart. Millions of primary myocytes, which remain viable for 4-6 h, can be readily isolated from animal models. However, currently available instrumentation allows the mechanical properties of only a few physically loaded myocytes to be explored within 4-6 h. Here we describe a modular and inexpensive prototype instrument that could form the basis of an array of devices for probing the mechanical properties of single mammalian myocytes in parallel. This device would greatly increase the throughput of scientific experimentation and could be applied as a high-content screening instrument in the pharmaceutical industry. The instrument module consists of two independently controlled Lorentz force actuators-force transducers in the form of 0.025 x 1 x 5 mm stainless steel cantilevers with 0.5 m/N compliance and 360-Hz resonant frequency. Optical position sensors focused on each cantilever provide position and force resolution of <1 nm/ radicalHz and <2 nN/ radicalHz, respectively. The motor structure can produce peak displacements and forces of +/-200 mum and +/-400 microN, respectively. Custom Visual Basic.Net software provides data acquisition, signal processing, and digital control of cantilever position. The functionality of the instrument was demonstrated by implementation of novel methodologies for loading and attaching healthy mammalian ventricular myocytes to the force sensor and actuator and use of stochastic system identification techniques to measure their passive dynamic stiffness at various sarcomere lengths.

The suitability for low-coherence interferometry of a high-power, semiconductor laser line source operated at a forward bias current below threshold is demonstrated. Measurements of the important characteristics of the source are presented. For example, the source produces an output power of 1.3 mW and a spatially uniform coherence length of 16 mum at a bias current of 86% of threshold (250 mA) at 20 degrees C. The usefulness of the source is verified by measurement of the line profile of a contact lens.

Documented causes of biliary complications following orthotopic liver transplantation have been related to technical imperfections or insufficient arterial supply. Although anatomical variations of the extrahepatic biliary system are not infrequent, neither their incidence, surgical management nor possible association with complications have been reported in liver transplantation. At our institution, the global incidence of biliary complications following 357 consecutive liver transplants performed in 324 patients over a 2-yr period was 15.4% (55/357). Anomalous donor extrahepatic ducts were verified in 10 cases (2.8%) and they were recognized intraoperatively, prior to biliary reconstruction, in 7 cases. Technical complications occurred in 1 of these 7 and in 3 other cases where the anomalous ducts were not identified until later in the postoperative period when serious clinical problems ensued. We herein present a description of these 10 cases, with reference to the techniques employed to manage the anatomical anomalies and to treat complications. As in any hepatobiliary procedure, awareness of possible variations of the extrahepatic biliary system, intraoperative identification of the anomalous ducts and appropriate tailoring of the surgical technique are advisable in order to avoid serious postoperative complications in liver transplantation.

Ten patients with DSM-III-R obsessive-compulsive disorder (OCD) underwent the desipramine (DMI) growth hormone (GH) stimulation test as well as the dexamethasone suppression test (DST). The results were compared with the responses in a group of matched healthy controls. The GH response to DMI did not differ between patients and controls and 9 of 10 patients showed cortisol suppression in response to dexamethasone. The data suggest that neither alpha 2 adrenergic dysfunction nor DST non-suppression are features of primary OCD.

We report OCD and paraphilia in two male members of triplets (the two males being monozygotic twins), and discuss the possible aetiological factors for this previously unreported occurrence. We suggest that patients presenting with paraphilia should be examined for OCD and that a detailed sexual history should be obtained in all patients with OCD.

Barbiturate anaesthesia is modulated by brain noradrenergic (NA) function. As derangement of NA pathways is postulated to occur in depression, changes in anaesthetic sensitivity measured as producing loss of eyelash reflex were monitored in 29 depressed patients throughout a course of electroconvulsive therapy (ECT). Patients thus monitored were followed for 12 months after completing treatment. An increase in barbiturate induction dose over a course of ECT, indicating a decrease in anaesthetic sensitivity, was a powerful predictor of maintained wellbeing. All patients who increased their sensitivity to the anaesthetic either failed to respond to the course of ECT or relapsed within 12 months. The possible mechanism for this is discussed.

A clinical whole organ pancreas transplantation program for patients with insulin-dependent diabetes mellitus complicated by end-stage renal disease was initiated at Henry Ford Hospital in 1987. Five patients have received pancreatic allografts after a previous kidney transplant (phase 1), and six patients had simultaneous pancreas-kidney transplants (phase 2). Ten patients had functioning pancreatic grafts after surgery, and all of them had normal carbohydrate tolerance with appropriate plasma free insulin responses to an oral glucose tolerance test three months after transplantation. As long as 28 months postsurgery six patients remained free of insulin requirements; however, one patient rejected the pancreatic allograft, and three patients died because of cytomegalovirus pneumonia. Two of the latter patients had functioning pancreatic allografts at the time of their demise. These results compare favorably with those of the International Pancreas Transplant Registry which reflects the world experience. Pancreas transplantation is a unique experimental treatment with the potential of restoring euglycemia and improving the prognosis of insulin-dependent diabetic patients.

Brain-type creatine phosphokinase isoenzyme (CPK BB) was measured by radioimmunoassay in the serum of 31 depressed patients undergoing bilateral ECT. Samples were taken shortly before and at one hour, two hours, and six hours following ECT. ECT did not cause a significant alteration in serum CPK BB concentration during the six hours following the treatment. Similarly, there was no difference in mean pre-ECT concentration of serum CPK BB between patients receiving the first ECT of their current admission and those receiving subsequent treatments. These findings do not support suggestions that ECT causes alteration in permeability of the blood-brain barrier, nor that it causes detectable brain injury.

Rats exposed to ultraviolet light with maximum emission at 350 nm showed a stable intake of alcohol over water. A control group of animals exposed to white fluorescence light did not drink more alcohol than water.

Female rats, implanted with cerebrocortical EEG recording electrodes, were trained to self-administer cocaine and then ketamine under a fixed ratio 10 schedule of reinforcement, during limited access sessions. Periodically, a single unit dose of either phencyclidine (0.5 mg/kg), ketamine (4 mg/kg) or 1-(1-phenylcyclohexyl)morpholine (PCM 4 mg/kg) was substituted for ketamine, while the cortical EEG was recorded. Spectrum quantities of samples of EEG, taken immediately before and after each injection, were subjected to a discriminant analysis. For each drug, the preinjection state of the EEG could be classified separately from the postinjection state, using specific EEG spectrum quantities from the global frequency range (0.1-20 Hz). Furthermore, the relevant EEG parameters, which described the change from pre- to postinjection states, were unique for each drug (phencyclidine: total power and complexity; ketamine: peak frequency, relative power and mobility; PCM: all parameters except peak frequency), indicating potential differences in the EEG, occurring with a level of intake of drug which was controlled by the subject. Overall, these data serve to model the changes in the EEG that occur during the self-administration of three phencyclinoids. Furthermore, the combination of EEG spectrum analysis with discriminant analysis is useful in detecting subtle differences in the effects of these three drugs on the EEG.

Post-ECT blood pressure rise and its relationship to cognitive and affective change were studied in 29 depressed patients, using the Benton Visual Retention Test, the Hamilton Rating Scale for Depression, and the Leeds Self-Assessment Scale for Depression and Anxiety. No real difference was established in the Benton Test error scores before and after ECT, no correlation between rise in blood pressure and change in Benton Test error score with ECT was found, and no correlation was found between blood pressure rise and affective improvement following ECT. Previous studies which reported such correlations are not supported.

The case is described of a young man who repeatedly injured his left eye. There was a history of previous deliberate self-injury and of childhood epilepsy. A diagnosis of borderline personality disorder was made. Similarities to other reported patients who injured their eyes, to "wrist-cutters," and to "delicate self-cutters" are discussed.

Female Sprague-Dawley rats were trained to self-administer phencyclidine (PCP; 0.125, 0.25, or 0.5 mg/kg/injection) on a fixed ratio (FR) schedule of reinforcement under limited access conditions (3 h). Initial training began with cocaine, which was later replaced with ketamine and then one of the three unit doses of PCP. Baseline rates of injection were determined at FR 10. The size of the ratio was then incremented geometrically every fifth daily session. Increasing the ratio resulted in a decrease in the number of injections per session. Furthermore, this decrease was greater for the 0.25 mg/kg dose than for the 0.5 mg/kg unit dose. The self-administration of the 0.125 mg/kg dose was variable and rapidly extinguished upon the increase in fixed ratio. The results indicate that PCP is self-administered by rats under the conditions imposed in this study. Furthermore, the relative reinforcing efficacy of the different unit doses of PCP could be discriminated using this type of response cost procedure.

A 50-item questionnaire, designed to link attitudes to psychiatry directly with how these might influence a career choice of psychiatry, was administered to medical students before and after their clinical clerkship in psychiatry. Many of these changed in a positive direction, e.g. 'job satisfaction', 'life-style', 'training available' and 'multidisciplinary approach'. The influence of important people in their lives was predominantly negative; this may emphasize the impact of psychiatric 'role models'. Male and female students differed in how they changed. Males appeared influenced by external factors, e.g. 'work hours' and 'career structure', and females by internal ones, e.g. 'interest in knowing more about self'. Females were also more likely to wish for a career in psychiatry. Psychiatry was ranked higher in career choice at the end of the clerkship.