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- ArticleSaxena S, Choudhury S, Mohan KN.MethodsX. 2020;7:101073.Investigation on the effects of disease-associated mutations on neurodevelopment is an essential approach to understand the molecular basis of neurological disorders and can be achieved by generating suitable animal models. However, some of the mutations preclude development of animal models, leaving cell-based models as the only options. Mouse embryonic stem cells (mESCs) are attractive because of the well-established technologies for introducing disease-associated mutations and the feasibility of investigating the abnormalities during different stages of neurogenesis. Importantly, such transgenic mESCs enable large-scale screening and identification of the most promising small molecules and/or drug candidates before undertaking expensive animal studies. Although neuronal differentiation from mESCs is one of the earliest methods to be developed, we observed that the published as well as publicly available methods did not yield neurons consistently. Here, we describe a 16-day differentiation protocol that consistently induced differentiation of mESCs into neurons. This step-wise protocol enables monitoring of the neuronal differentiation process at different stages as well as characterization using the markers for immature and mature neurons by using immunocytochemistry and quantitative real-time PCRs.•Development of a method for differentiating mouse ES cells into neurons.•Differentiating the mouse ES cells into embryoid bodies prior to induction of neuronal differentiation results in better neuron formation.
- ArticleLee M, Hirpara JL, Eu JQ, Sethi G, Wang L, Goh BC, Wong AL.Redox Biol. 2019 07;25:101073.Drug resistance invariably limits the response of oncogene-addicted cancer cells to targeted therapy. The upregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a mechanism of drug resistance in a range of oncogene-addicted cancers. However, the development of inhibitors against STAT3 has been fraught with challenges such as poor delivery or lack of specificity. Clinical experience with small molecule STAT3 inhibitors has seen efficacy signals, but this success has been tempered by drug limiting toxicities from off-target adverse events. It has emerged in recent years that, contrary to the Warburg theory, certain tumor types undergo metabolic reprogramming towards oxidative phosphorylation (OXPHOS) to satisfy their energy production. In particular, certain drug-resistant oncogene-addicted tumors have been found to rely on OXPHOS as a mechanism of survival. Multiple cellular signaling pathways converge on STAT3, hence the localization of STAT3 to the mitochondria may provide the link between oncogene-induced signaling pathways and cancer cell metabolism. In this article, we review the role of STAT3 and OXPHOS as targets of novel therapeutic strategies aimed at restoring drug sensitivity in treatment-resistant oncogene-addicted tumor types. Apart from drugs which have been re-purposed as OXPHOS inhibitors for-anti-cancer therapy (e.g., metformin and phenformin), several novel compounds in the drug-development pipeline have demonstrated promising pre-clinical and clinical activity. However, the clinical development of OXPHOS inhibitors remains in its infancy. The further identification of compounds with acceptable toxicity profiles, alongside the discovery of robust companion biomarkers of OXPHOS inhibition, would represent tangible early steps in transforming the therapeutic landscape of cancer cell metabolism.
- ArticleMerino A, Maakaron J, Bachanova V.Blood Rev. 2023 07;60:101073.Natural Killer (NK) cells yield promise in therapy of hematologic malignancies. The clinical experience with adoptively transferred allogeneic NK cells over past two decades has revealed safety and minimal risk of CRS or ICANS. Unlike T cells which have to be genetically altered to avoid graft vs host disease (GVHD), HLA mismatched NK cells can be infused without GVHD risk. This makes them ideal for the development of off-the-shelf products. In this review we focus on NK biology relevant to the cancer therapy, the trajectory of NK therapeutics for leukemia, lymphoma, and myeloma; and advantages of the NK cell platform. We will also discuss novel methods to enhance NK cell targeting, persistence, and function in the tumor microenvironment. The future of NK cell therapy depends on novel strategies to realize these qualities.
- ArticleGaffney AW, McCormick D, Woolhandler S, Christiani DC, Himmelstein DU.EClinicalMedicine. 2021 Sep;39:101073.BACKGROUND: Because Forced Vital Capacity (FVC) is reduced in Black relative to White Americans of the same age, sex, and height, standard lung function prediction equations assign a lower "normal" range for Black patients. The prognostic implications of this race correction are uncertain.
METHODS: We analyzed 5,294 White and 3,743 Black participants age 20-80 in NHANES III, a nationally-representative US survey conducted 1988-94, which we linked to the National Death Index to assess mortality through December 31, 2015. We calculated the FVC-percent predicted among Black and White participants, first applying NHANES III White prediction equations to all persons, and then using standard race-specific prediction equations. We used Cox proportional hazard models to calculate the association between race and all-cause mortality without and with adjustment for FVC (using each FVC metric), smoking, socioeconomic factors, and comorbidities.
FINDINGS: Black participants' age- and sex-adjusted mortality was greater than White participants (HR 1.46; 95%CI:1.29, 1.65). With adjustment for FVC in liters (mean 3.7 L for Black participants, 4.3 L for White participants) or FVC percent-predicted using White equations for everyone, Black race was no longer independently predictive of higher mortality (HR∼1.0). When FVC-percent predicted was "corrected" for race, Black individuals again showed increased mortality hazard. Deaths attributed to chronic respiratory disease were infrequent for both Black and White individuals.
INTERPRETATION: Lower FVC in Black people is associated with elevated risk of all-cause mortality, challenging the standard assumption about race-based normal limits. Black-White disparities in FVC may reflect deleterious social/environmental exposures, not innate differences.
FUNDING: No funding. - ArticleRong JC, Cui LL, Yang XC, Yi ML, Zhao Q.Mar Genomics. 2023 Dec;72:101073.Novel bacterial resources are valuable for studying bacterial taxonomy, bacterial evolution, and genome mining of novel antibiotics, antitumor agents, and immune modulators. In this study, we de novo sequenced the type strain of a novel bacterial family, Temperatibacteraceae fam. Nov., belonging to class Alphaproteobacteria of phylum Pseudomonadota. The type strain, Temperatibacter marinus NBRC 110045T, is mesophilic and was isolated from surface seawater around Muroto city of Japan at a depth of 0.5 m. Here, the sequenced complete genome of strain NBRC 110045T is composed of a circular chromosome of 3,184,799 bp with a mean G + C content of 43.71%. Genome analysis was applied to reveal the genetic basis of its cellular activities. Cellular regulation and signaling was analyzed to infer the regulatory mechanism of its limited growth temperature range. Genomic features of the novel family Temperatibacteraceae may expand our knowledge on environmental adaptation, genetic evolution and natural product discovery of marine bacteria.
- ArticlePearl PL.Semin Pediatr Neurol. 2023 10;47:101073.AMENABLE TREATABLE SEVERE PEDIATRIC EPILEPSIES: Phillip L. Pearl Seminars in Pediatric Neurology Volume 23, Issue 2, May 2016, Pages 158-166 Vitamin-dependent epilepsies and multiple metabolic epilepsies are amenable to treatment that markedly improves the disease course. Knowledge of these amenably treatable severe pediatric epilepsies allows for early identification, testing, and treatment. These disorders present with various phenotypes, including early onset epileptic encephalopathy (refractory neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalop athy), infantile spasms, or mixed generalized seizure types in infancy, childhood, or even adolescence and adulthood. The disorders are presented as vitamin responsive epilepsies such as pyridoxine, pyridoxal-5-phosphate, folinic acid, and biotin; transportopathies like GLUT-1, cerebral folate deficiency, and biotin thiamine responsive disorder; amino and organic acidopathies including serine synthesis defects, creatine synthesis disorders, molybdenum cofactor deficiency, and cobalamin deficiencies; mitochondrial disorders; urea cycle disorders; neurotransmitter defects; and disorders of glucose homeostasis. In each case, targeted intervention directed toward the underlying metabolic pathophysiology affords for the opportunity to significantly effect the outcome and prognosis of an otherwise severe pediatric epilepsy.
- ArticleFont-Clos F, Zapperi S, La Porta CAM.iScience. 2020 May 22;23(5):101073.The distribution patterns of cancer metastasis depend on a sequence of steps involving adhesion molecules and on mechanical and geometrical effects related to blood circulation, but how much each of these two aspects contributes to the metastatic spread of a specific tumor is still unknown. Here we address this question by simulating cancer cell trajectories in a high-resolution humanoid model of global blood circulation, including stochastic adhesion events, and comparing the results with the location of metastasis recorded in thousands of human autopsies for seven different solid tumors, including lung, prostate, pancreatic and colorectal cancers, showing that on average 40% of the variation in the metastatic distribution can be attributed to blood circulation. Our humanoid model of circulating tumor cells allows us to predict the metastatic spread in specific realistic conditions and can therefore guide precise therapeutic interventions to fight metastasis.
- ArticleOstlund B, Donoghue T, Anaya B, Gunther KE, Karalunas SL, Voytek B, Pérez-Edgar KE.Dev Cogn Neurosci. 2022 04;54:101073.A growing body of literature suggests that the explicit parameterization of neural power spectra is important for the appropriate physiological interpretation of periodic and aperiodic electroencephalogram (EEG) activity. In this paper, we discuss why parameterization is an imperative step for developmental cognitive neuroscientists interested in cognition and behavior across the lifespan, as well as how parameterization can be readily accomplished with an automated spectral parameterization ("specparam") algorithm (Donoghue et al., 2020a). We provide annotated code for power spectral parameterization, via specparam, in Jupyter Notebook and R Studio. We then apply this algorithm to EEG data in childhood (N = 60; Mage = 9.97, SD = 0.95) to illustrate its utility for developmental cognitive neuroscientists. Ultimately, the explicit parameterization of EEG power spectra may help us refine our understanding of how dynamic neural communication contributes to normative and aberrant cognition across the lifespan. Data and annotated analysis code for this manuscript are available on GitHub as a supplement to the open-access specparam toolbox.
- ArticleDong X, Gou Y, Guo M, Zhong J, Li A, Hao A, Zeng W, Haydon RC, Luu HH, Reid RR, He T, Xu Y, Fan J.Genes Dis. 2024 May;11(3):101073.
- ArticleApetrei A, Molin A, Gruchy N, Godin M, Bracquemart C, Resbeut A, Rey G, Nadeau G, Richard N.Bone Rep. 2021 Jun;14:101073.INTRODUCTION: Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) (Inactivating PTH/PTHrP Signaling Disorders type 2, IPPSD2) are two rare autosomal disorders caused by loss-of-function mutations on either maternal or paternal allele, respectively, in the imprinted GNAS gene, which encodes the α subunit of the ubiquitously-expressed stimulatory G protein (Gαs).
CASE PRESENTATION: We investigated a synonymous GNAS variant NM_001077488.2: c.108C>A / p.(Val36=) identified in a family presenting with IPPSD2 phenotype. In silico splicing prediction algorithms were in favor of a deleterious effect of this variant, by creating a new donor splicing site. The GNAS expression studies in blood suggested haploinsufficiency and showed an alternate splice product demonstrating the unmasking of a cryptic site, leading to a 34 base pairs deletion and the creation of a probable unstable RNA.We present the first familial case of IPPSD2 caused by a pathogenic synonymous variant in GNAS gene. - ArticleTaylor RL.Poult Sci. 2021 04;100(4):101073.
- ArticleSummaka M, Zein H, Naim I, Fneish S.Disabil Health J. 2021 07;14(3):101073.BACKGROUND: In February 2020, the Lebanese authorities announced the first Coronavirus 2019 (COVID-19) case. Since then, the cases increased significantly, but information on the public's psychological status and specifically individuals with physical disabilities is still limited.
PURPOSE: The study aims to assess the psychological impact of the COVID-19 outbreak on Lebanese individuals with physical disabilities and study the associated factors.
MATERIALS AND METHODS: This is a cross-sectional study involving 118 individuals with physical disabilities. Each filled out an online survey with three sections: a personal questionnaire, the Arabic versions of the Hopkins Symptom Checklist-25 and the Fear of COVID-19 scale. Data regarding participants' baseline characteristics, fear, anxiety, and depression were collected and analyzed using the Chi-square test and regressions models.
RESULTS: Individuals with physical disabilities exhibited mild fear of COVID-19, with fear being correlated with age, educational level, and employment status. Furthermore, 22.9% of the population was found to be anxious, and 31.5% were depressed. Anxiety was associated with both marital status and employment status. Finally, depression was proved to be influenced by marital status, employment, and educational level.
CONCLUSION: Results extracted showed that individuals with physical disabilities require substantial attention in order to manage their psychological state during pandemics. - ArticleNewton L, Tolman E, Kohli M, Ware JL.Curr Opin Insect Sci. 2023 08;58:101073.Odonata is an order of insects that comprises ∼6500 species. They are among the earliest flying insects, and one of the first diverging lineages in the Pterygota. Odonate evolution has been a topic of research for over 100 years, with studies focusing primarily on their flight behavior, color, vision, and aquatic juvenile lifestyles. Recent genomics studies have provided new interpretations about the evolution of these traits. In this paper, we look at how high-throughput sequence data (i.e. subgenomic and genomic data) have been used to answer long-standing questions in Odonata ranging from evolutionary relationships to vision evolution to flight behavior. Additionally, we evaluate these data at multiple taxonomic levels (i.e. ordinal, familial, generic, and population) and provide comparative analysis of genomes across Odonata, identifying features of these new data. Last, we discuss the next two years of Odonata genomic study, with context about what questions are currently being tackled.
- ArticleAlghamdi B, Al-Kadi M, Alkhayal N, Alhedaithy R, Al Mahdi MJ.Respir Med Case Rep. 2020;30:101073.BACKGROUND: Lobular capillary hemangiomas (LCH) are acquired benign vascular lesions of the skin and mucous membranes mostly affecting the head and neck region. Involvement of the nasal cavity is extremely rare and can manifest as epistaxis and nasal obstruction.
CASE SERIES: In this case series, we present five cases of intranasal LCH. Three cases are of pregnant women that presented with epistaxis and nasal obstruction. The first was surgically treated during her pregnancy with preoperative embolization of the tumor for vascular control, while the other two patients were treated after delivery. The two other cases are of a post trauma pediatric patient, and an elderly lady with multiple co-morbidities, both presenting with recurrent nose bleeds and nasal obstruction. Surgical excision was performed with no complications observed post-operatively.
DISCUSSION: The etiology of LCH is unknown, but certain predisposing factors have been associated with the development of LCH and include pregnancy and trauma. The anterior portion of the nasal septal mucosa and the tip of the inferior turbinate are commonly involved sites. Computed tomography scans and histopathology are used to diagnose LCH. Treatment is surgical excision with or without pre-operative embolization.
CONCLUSION: LCH are rare tumors of the nasal cavity. Treatment of these lesions is surgical with or without preoperative vascular control. - ArticleTaguchi T, Egawa-Takata T, Kunimoto S, Nagano T, Yoshimura M, Haruna K, Shinke G, Ohmura Y, Ito K.Gynecol Oncol Rep. 2022 Dec;44:101073.•A case of concurrent primary ovarian clear cell adenocarcinoma and liver angiosarcoma is detailed herein.•If a liver tumor is found together with ovarian cancer, it is necessary to determine whether this is a primary hepatic malignancy or metastatic liver cancer.•It is important to make a definitive diagnosis by performing a liver biopsy when appropriate.
- ArticleDehbozorgi A, Jandali B, Turner R, Rohr A, Custer B, Young K, Walter C, Clark L, Li Y, Polineni D, Mermis J.Respir Med Res. 2024 Jun;85:101073.BACKGROUND: Peripherally inserted central catheters (PICCs) are the most common route of intravenous (I.V.) access for treatment of cystic fibrosis (CF) pulmonary exacerbations, but repeated PICC placement can result in upper extremity peripheral venous stenosis. Once peripheral stenosis develops, a non-cuffed tunneled central venous catheter (NcTCVC) is an alternative route for IV access. While these are regularly used at some CF centers, the safety and complication rate compared to PICCs in adults with CF has not been reported. This study aims to describe the safety of NcTCVCs in adults with CF.
METHODS: A retrospective cohort study was performed at a CF Foundation accredited institution including adults with CF who received NcTCVCs in interventional radiology from 7/19/2007 to 3/09/2020. Complications analyzed included catheter related deep venous thrombosis (DVT), central line associated blood stream infection (CLABSI), and catheter related central venous stenosis. Complications were considered attributable if they occurred while the catheter was in place or within 30 days of catheter removal.
RESULTS: During the study duration, 386 NcTCVCs were placed in 60 unique patients (55 % female) with a mean of 6.4 catheters per patient. Majority of NcTCVCs placed were 4 French (61.4 %). Average duration of indwelling NcTCVC was 16.2 days. No patients demonstrated catheter attributable symptomatic DVT. The incidence of DVT, CLABSI, and central venous stenosis was 0 (0 %), 4 (1 %), and 1 (0.3 %), respectively.
CONCLUSIONS: Many adults with CF have required insertion of numerous PICCs for the treatment of recurrent pulmonary exacerbations. In those adults that develop PICC-associated peripheral vein stenosis precluding PICC placement, these results indicate NcTCVCs are a safe alternative. - ArticleGe Z, Helmijr JCA, Jansen MPHM, Boor PPC, Noordam L, Peppelenbosch M, Kwekkeboom J, Kraan J, Sprengers D.Transl Oncol. 2021 Jul;14(7):101073.BACKGROUND AND AIMS: Circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) may be used for diagnostic or prognostic purposes in patients with hepatocellular carcinoma (HCC). We aim to determine whether CTCs or ctDNA are suitable to determine oncogenic mutations in HCC patients.
METHODS: Twenty-six mostly advanced HCC patients were enrolled. 30 mL peripheral blood from each patient was obtained. CellSearch system was used for CTC detection. A sequencing panel covering 14 cancer-relevant genes was used to identify oncogenic mutations. TERT promoter C228T and C250T mutations were determined by droplet digital PCR.
RESULTS: CTCs were detected in 27% (7/26) of subjects but at low numbers (median: 2 cells, range: 1-15 cells) and ctDNA in 77% (20/26) of patients. Mutations in ctDNA were identified in several genes: TERT promoter C228T (77%, 20/26), TP53 (23%, 6/26), CTNNB1 (12%, 3/26), PIK3CA (12%, 3/26) and NRAS (4%, 1/26). The TERT C228T mutation was present in all patients with one or more ctDNA mutations, or detectable CTCs. The TERT C228T and TP53 mutations detected in ctDNA were present at higher levels in matched primary HCC tumor tissue. The maximal variant allele frequency (VAF) of ctDNA was linearly correlated with largest tumor size and AFP level (Log10). CtDNA (or TERT C228T) positivity was associated with macrovascular invasion, and positivity of ctDNA (or TERT C228T) or CTCs (≥ 2) correlated with poor patient survival.
CONCLUSIONS: Oncogenic mutations could be detected in ctDNA from advanced HCC patients. CtDNA analysis may serve as a promising liquid biopsy to identify druggable mutations. - ArticleCenni V, Capanni C, Mattioli E, Schena E, Squarzoni S, Bacalini MG, Garagnani P, Salvioli S, Franceschi C, Lattanzi G.Ageing Res Rev. 2020 09;62:101073.Lamin A, a main constituent of the nuclear lamina, is the major splicing product of the LMNA gene, which also encodes lamin C, lamin A delta 10 and lamin C2. Involvement of lamin A in the ageing process became clear after the discovery that a group of progeroid syndromes, currently referred to as progeroid laminopathies, are caused by mutations in LMNA gene. Progeroid laminopathies include Hutchinson-Gilford Progeria, Mandibuloacral Dysplasia, Atypical Progeria and atypical-Werner syndrome, disabling and life-threatening diseases with accelerated ageing, bone resorption, lipodystrophy, skin abnormalities and cardiovascular disorders. Defects in lamin A post-translational maturation occur in progeroid syndromes and accumulated prelamin A affects ageing-related processes, such as mTOR signaling, epigenetic modifications, stress response, inflammation, microRNA activation and mechanosignaling. In this review, we briefly describe the role of these pathways in physiological ageing and go in deep into lamin A-dependent mechanisms that accelerate the ageing process. Finally, we propose that lamin A acts as a sensor of cell intrinsic and environmental stress through transient prelamin A accumulation, which triggers stress response mechanisms. Exacerbation of lamin A sensor activity due to stably elevated prelamin A levels contributes to the onset of a permanent stress response condition, which triggers accelerated ageing.
- ArticleChen JH, Shiu CS.SSM Popul Health. 2022 Jun;18:101073.Racial gaps in vaccine uptake in the United States have been widely reported. Existing studies, however, have not explored how individuals' concerns about COVID-19 vaccines are clustered. In this study, racial and ethnic background is linked to constellations of COVID-19 vaccine concerns during the early phase of vaccines in the United States, using the Household Pulse Survey (N = 60,492). Latent class analysis reveals five distinct classes of vaccine concerns: general skepticism, distrust of science and the government, safety, a desire to wait and see, and vague uncertainty. Compared to Whites, people of color more consistently report vaccine hesitancy due to safety and a desire to wait and see, rather than distrust of science and the government. Whites, however, more consistently report general skepticism and distrust of science and the government. Our findings suggest that distrust of science and government is not central to racial minorities' vaccine hesitancy, but it is so for Whites.
- ArticleGhimire A, Xu L, Liu XQ, Rainey JK.Mater Today Bio. 2024 Jun;26:101073.Spider silks are natural protein-based biomaterials which are renowned for their mechanical properties and hold great promise for applications ranging from high-performance textiles to regenerative medicine. While some spiders can produce several different types of silks, most spider silk types - including pyriform and aciniform silks - are relatively unstudied. Pyriform and aciniform silks have distinct mechanical behavior and physicochemical properties, with materials produced using combinations of these silks currently unexplored. Here, we introduce an engineered chimeric fusion protein consisting of two repeat units of pyriform (Py) silk followed by two repeat units of aciniform (W) silk named Py2W2. This recombinant ∼86.5 kDa protein is amenable to expression and purification from Escherichia coli and exhibits high α-helicity in a fluorinated acid- and alcohol-based solution used to form a dope for wet-spinning. Wet-spinning enables continuous fiber production and post-spin stretching of the wet-spun fibers in air or following submersion in water or ethanol leads to increases in optical anisotropy, consistent with increased molecular alignment along the fiber axis. Mechanical properties of the fibers vary as a function of post-spin stretching condition, with the highest extensibility and strength observed in air-stretched and ethanol-treated fibers, respectively, with mechanics being superior to fibers spun from either constituent protein alone. Notably, the maximum extensibility obtained (∼157 ± 38 %) is of the same magnitude reported for natural flagelliform silks, the class of spider silk most associated with being stretchable. Interestingly, Py2W2 is also water-compatible, unlike its constituent Py2. Fiber-state secondary structure correlates well with the observed mechanical properties, with depleted α-helicity and increased β-sheet content in cases of increased strength. Py2W2 fibers thus provide enhanced materials behavior in terms of their mechanics, tunability, and fiber properties, providing new directions for design and development of biomaterials suitable and tunable for disparate applications.