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Found 35740 matches. Displaying 91-100
Edlow BL, Barra ME, Zhou DW, Foulkes AS, Snider SB, Threlkeld ZD, Chakravarty S, Kirsch JE, Chan ST, Meisler SL, Bleck TP, Fins JJ, Giacino JT, Hochberg LR, Solt K, Brown EN, Bodien YG
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Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit

NEUROCRITICAL CARE 2020 OCT; 33(2):364-375
There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTIvation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network ( NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.
Sinha A, Chang JC, Xu P, Gindinova K, Cho Y, Sun WL, Wu XZ, Li YM, Greengard P, Kelly JW, Sinha SC
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Brain Permeable Tafamidis Amide Analogs for Stabilizing TTR and Reducing APP Cleavage

Tafamidis, 1, a potent transthyretin kinetic stabilizer, weakly inhibits the gamma-secretase enzyme in vitro. We have synthesized four amide derivatives of 1. These compounds reduce production of the A beta peptide in N2a695 cells but do not inhibit the gamma-secretase enzyme in cell-free assays. By performing fluorescence correlation spectroscopy, we have shown that TTR inhibits A beta oligomerization and that addition of tafamidis or its amide derivative does not affect TTR's ability to inhibit A beta oligomerization. The piperazine amide derivative of tafamidis (1a) efficiently penetrates and accumulates in mouse brain and undergoes proteolysis under physiological conditions in mice to produce tafamidis.
Sakata S, Tsumura M, Matsubayashi T, Karakawa S, Kimura S, Tamaura M, Okano T, Naruto T, Mizoguchi Y, Kagawa R, Nishimura S, Imai K, Le Voyer T, Casanova JL, Bustamante J, Morio T, Ohara O, Kobayashi M, Okada S
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Autosomal recessive complete STAT1 deficiency caused by compound heterozygous intronic mutations

Autosomal recessive (AR) complete signal transducer and activator of transcription 1 (STAT1) deficiency is an extremely rare primary immunodeficiency that causes life-threatening mycobacterial and viral infections. Only seven patients from five unrelated families with this disorder have been so far reported. All causal STAT1 mutations reported are exonic and homozygous. We studied a patient with susceptibility to mycobacteria and virus infections, resulting in identification of AR complete STAT1 deficiency due to compound heterozygous mutations, both located in introns: c.128+2 T>G and c.542-8 A>G. Both mutations were the first intronic STAT1 mutations to cause AR complete STAT1 deficiency. Targeted RNA-seq documented the impairment of STAT1 mRNA expression and contributed to the identification of the intronic mutations. The patient's cells showed a lack of STAT1 expression and phosphorylation, and severe impairment of the cellular response to IFN-gamma and IFN-alpha. The case reflects the importance of accurate clinical diagnosis and precise evaluation, to include intronic mutations, in the comprehensive genomic study when the patient lacks molecular pathogenesis. In conclusion, AR complete STAT1 deficiency can be caused by compound heterozygous and intronic mutations.Targeted RNA-seq-based systemic gene expression assay may help to increase diagnostic yield in inconclusive cases after comprehensive genomic study.
Hadi K, Yao XT, Behr JM, Deshpande A, Xanthopoulakis C, Tian HS, Kudman S, Rosiene J, Darmofal M, DeRose J, Mortensen R, Adney EM, Shaiber A, Gajic Z, Sigouros M, Eng K, Wala JA, Wrzeszczynski KO, Arora K, Shah M, Emde AK, Felice V, Frank MO, Darnell RB, Ghandi M, Huang F, Dewhurst S, Maciejowski J, de Lange T, Setton J, Riaz N, Reis JS, Powell S, Knowles DA, Reznik E, Mishra B, Beroukhim R, Zody MC, Robine N, Oman KM, Sanchez CA, Kuhner MK, Smith LP, Galipeau PC, Paulson TG, Reid BJ, Li XH, Wilkes D, Sboner A, Mosquera JM, Elemento O, Imielinski M
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Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs

CELL 2020 OCT 1; 183(1):197-210.e32
Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis.
Leon-Lara X, Hernandez-Nieto L, Zamora CV, Rodriguez-D'Cid R, Gutierrez MEC, Espinosa-Padilla S, Bustamante J, Puel A, Blancas-Galicia L
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Disseminated Infectious Disease Caused by Histoplasma capsulatum in an Adult Patient as First Manifestation of Inherited IL-12R beta 1 Deficiency

Histoplasma capsulatum is an endemic, dimorphic fungus commonly found in areas such as midwestern USA, Mexico, and South America [1]. In Mexico, the estimated incidence of histoplasmosis has ranged from 0.1 to 0.29 cases per 100,000, and it is most frequent in the central and southeastern parts of the country [1]. Humans may be infected with H. capsulatum via inhaling microconidia and mycelial fragments of the organism [2]. Clinical presentation depends on the host immune status and the extent of exposed inoculum [3]. The majority of individuals exposed to H. capsulatum (> 99%) are typically asymptomatic or have self-limiting infections [3]. Disseminated histoplasmosis is rare occurring mostly in acute rather than chronic forms of histoplasma infections [2]. After acute exposure, the rate of dissemination in infected population is low, in about one in 2000 patients, and have been more frequent in immunosuppressed patients with a tenfold higher risk [2]. The most frequent immunocompromise associated with disseminated histoplasmosis in adults is secondary to the human immunodeficiency virus (HIV) infection [1, 3]. On the other side, there are sporadic cases of primary immunodeficiencies (PID) or inborn errors of immunity associated with disseminated histoplasmosis [4] that characteristically have a beginning in childhood, such as chronic granulomatous disease [5] or Mendelian susceptibility to mycobacterial disease (MSMD) [4], and patients with chronic mucocutaneous disease associated with heterozygous STAT1 mutation, gain-of-function mutation (GOF) [6]. We report a case of an adult otherwise healthy with disseminated histoplasmosis and autosomal recessive (AR) complete IL-12Rβ1 deficiency.
HIV-1 evolution in the cerebrospinal fluid (CSF) and plasma may result in discordant drug resistance mutations (DRMs) in the compartments. Single-genome amplification (SGA) was used to generate partial HIV-1 polymerase genomes in paired CSF and plasma samples from 12 HIV-1-positive participants in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study who were classified as neurocognitively unimpaired or with various degrees of HIV-associated neurocognitive disorders (HAND). Subjects were viremic on combination antiretroviral therapy (cART). HIV-1 DRMs and phylogenetic characteristics were determined using the Stanford HIVdb program and phylogenetic analyses. Individual DRMs were identified more frequently in plasma than in paired CSF (P = 0.0078). Significant differences in the ratios of DRMs in CSF and plasma were found in 3 individuals with HAND (3/7 = 43%). Two HAND subjects (2/7 = 29%) demonstrated one DRM in CSF not identified in paired plasma. Longitudinal analyses (n = 4) revealed significant temporal differences in the ratios of DRMs in the compartments. Statistically significant differences in the frequency of DRMs in the CSF and plasma are readily found in those on nonsuppressive cART. While compartment-based DRM discordance was largely consistent with increased drug-selective pressures in the plasma, overrepresentation of DRMs in the central nervous system (CNS) can occur. Underlying mechanisms of HAND are complex and multifactorial. The clinical impact of DRM discordance on viral persistence and HAND pathogenesis remains unclear and warrants further investigation in larger, longitudinal cohorts. IMPORTANCE Several antiretroviral agents do not efficiently enter the CNS, and independent evolution of HIV-1 viral variants in the CNS and plasma can occur. We used single-genome amplification (SGA) in cross-sectional and longitudinal analyses to uniquely define both the identity and relative proportions of drug resistance mutations (DRMs) on individual HIV-1 polymerase genomes in the cerebrospinal fluid (CSF) and plasma in individuals with incomplete viral suppression and known neurocognitive status. Statistically significant differences in the ratio of DRMs in the CSF and plasma were readily found in those on nonsuppressive cART, and overrepresentation of DRMs in the CNS can occur. Although questions about the clinical significance of DRM discordance remain, in the quest for viral eradication, it is important to recognize that a significant, dynamic, compartment-based DRM ratio imbalance can exist, as it has the potential to go unnoticed in the setting of standard clinical drug resistance testing.
Bin Ramli MN, Lim YS, Koe CT, Demircioglu D, Tng WQ, Gonzales KAU, Tan CP, Szczerbinska I, Liang HQ, Soe EL, Lu ZP, Ariyachet C, Yu KM, Koh SH, Yaw LP, Jumat NHB, Lim JSY, Wright G, Shabbir A, Dan YY, Ng HH, Chan YS
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Human Pluripotent Stem Cell-Derived Organoids as Models of Liver Disease

GASTROENTEROLOGY 2020 OCT; 159(4):1471-1486.e12
BACKGROUND & AIMS: There are few in vitro models for studying the 3-dimensional interactions among different liver cell types during organogenesis or disease development. We aimed to generate hepatic organoids that comprise different parenchymal liver cell types and have structural features of the liver, using human pluripotent stem cells. METHODS: We cultured H1 human embryonic stem cells (WA-01, passage 27-40) and induced pluripotent stem cells (GM23338) with a series of chemically defined and serum-free media to induce formation of posterior foregut cells, which were differentiated in 3 dimensions into hepatic endoderm spheroids and stepwise into hepatoblast spheroids. Hepatoblast spheroids were reseeded in a high-throughput format and induced to form hepatic organoids; development of functional bile canaliculi was imaged live. Levels of albumin and apolipoprotein B were measured in cell culture supernatants using an enzyme-linked immunosorbent assay. Levels of gamma glutamyl transferase and alkaline phosphatase were measured in cholangiocytes. Organoids were incubated with troglitazone for varying periods and bile transport and accumulation were visualized by live-imaging microscopy. Organoids were incubated with oleic and palmitic acid, and formation of lipid droplets was visualized by staining. We compared gene expression profiles of organoids incubated with free fatty acids or without. We also compared gene expression profiles between liver tissue samples from patients with nonalcoholic steatohepatitis (NASH) versus without. We quantified hepatocyte and cholangiocyte populations in organoids using immunostaining and flow cytometry; cholangiocyte proliferation of cholangiocytes was measured. We compared the bile canaliculi network in the organoids incubated with versus without free fatty acids by live imaging. RESULTS: Cells in organoids differentiated into hepatocytes and cholangiocytes, based on the expression of albumin and cytokeratin 7. Hepatocytes were functional, based on secretion of albumin and apolipoprotein B and cytochrome P450 activity; cholangiocytes were functional, based on gamma glutamyl transferase and alkaline phosphatase activity and proliferative responses to secretin. The organoids organized a functional bile canaliculi system, which was disrupted by cholestasis-inducing drugs such as troglitazone. Organoids incubated with free fatty acids had gene expression signatures similar to those of liver tissues from patients with NASH. Incubation of organoids with free fatty acid-enriched media resulted in structural changes associated with nonalcoholic fatty liver disease, such as decay of bile canaliculi network and ductular reactions. CONCLUSIONS: We developed a hepatic organoid platform with human cells that can be used to model complex liver diseases, including NASH.
Horpaopan S, Fann CSJ, Lathrop M, Ott J
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Shared genomic segment analysis with equivalence testing

GENETIC EPIDEMIOLOGY 2020 OCT; 44(7):741-747
An important aspect of disease gene mapping is replication, that is, a putative finding in one group of individuals is confirmed in another set of individuals. As it can happen by chance that individuals share an estimated disease position, we developed a statistical approach to determine thep-value for multiple individuals or families to share a possibly small number of candidate susceptibility variants. Here, we focus on candidate variants for dominant traits that have been obtained by our previously developed heterozygosity analysis, and we are testing the sharing of candidate variants obtained for different individuals. Our approach allows for multiple pathogenic variants in a gene to contribute to disease, and for estimated disease variant positions to be imprecise. Statistically, the method developed here falls into the category of equivalence testing, where the classical null and alternative hypotheses of homogeneity and heterogeneity are reversed. The null hypothesis situation is created by permuting genomic locations of variants for one individual after another. We applied our methodology to the ALSPAC data set of 1,927 whole-genome sequenced individuals, where some individuals carry a pathogenic variant for the BRCA1 gene, but no two individuals carry the same variant. Our shared genomic segment analysis found significant evidence for BRCA1 pathogenic variants within +/- 5 kb of a given DNA variant.
Dunphy MPS, Pressl C, Pillarsetty N, Grkovski M, Modi S, Jhaveri K, Norton L, Beattie BJ, Zanzonico PB, Zatorska D, Taldone T, Ochiana SO, Uddin MM, Burnazi EM, Lyashchenko SK, Hudis CA, Bromberg J, Schoder HM, Fox JJ, Zhang HW, Chiosis G, Lewis JS, Larson SM
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First-in-Human Trial of Epichaperome-Targeted PET in Patients with Cancer

CLINICAL CANCER RESEARCH 2020 OCT 1; 26(19):5178-5187
Purpose: I-124-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-inhuman study of microdose I-124-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging. Experimental Design: Adult patients with cancer (n = 30) received I-124-PU-H71 tracer (201 + 12 MBq, <25 mu g) intravenous bolus followed by PET/CT scans and blood radioassays. Results: I-124-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). I-124-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects. Conclusions: Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using I-124-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.
Schneider C, Shen C, Gopal AA, Douglas T, Forestell B, Kauffman KD, Rogers D, Artusa P, Zhang Q, Jing H, Freeman AF, Barber DL, King IL, Saleh M, Wiseman PW, Su HC, Mandl JN
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Migration-induced cell shattering due to DOCK8 deficiency causes a type 2-biased helper T cell response

Humans with inherited defects inDOCK8expression are prone to allergic, type 2 CD4(+)T cell responses. Mandl and colleagues reveal an important role for cell death in driving such type 2 signals during infection. Mutations that impact immune cell migration and result in immune deficiency illustrate the importance of cell movement in host defense. In humans, loss-of-function mutations inDOCK8, a guanine exchange factor involved in hematopoietic cell migration, lead to immunodeficiency and, paradoxically, allergic disease. Here, we demonstrate that, like humans,Dock8(-/-)mice have a profound type 2 CD4(+)helper T (T(H)2) cell bias upon pulmonary infection withCryptococcus neoformansand other non-T(H)2 stimuli. We found that recruitedDock8(-/-)CX3CR1(+)mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing interleukin (IL)-1 beta that drives granulocyte-macrophage colony-stimulating factor (GM-CSF) production by CD4(+)T cells. Blocking IL-1 beta, GM-CSF or caspase activation eliminated the type-2 skew in mice lackingDock8. Notably, treatment of infected wild-type mice with apoptotic cells significantly increased GM-CSF production and T(H)2 cell differentiation. This reveals an important role for cell death in driving type 2 signals during infection, which may have implications for understanding the etiology of type 2 CD4(+)T cell responses in allergic disease.