Regulation of the MYC oncogene remains unclear. Using 10058-F4, a compound that inhibits MYC-MAX transcription factor, MYC protein and gene expression were down-regulated in Namalwa cells, a Burkitt ...lymphoma. Compound 10058-F4 decreased MYC mRNA (45%), MYC protein (50%), and cell growth (32%). MYC-MAX transcription factor was disrupted 24 h after treatment, resulting in transcriptional inhibition of target genes. Because microRNAs (miRNA) disrupt mRNA translation, let-7a, let-7b, and mir-98 were selected using bioinformatics for targeting MYC. Inhibition of MYC-MAX transcription factor with 10058-F4 increased levels of members of the let-7 family. In inhibited cells at 24 h, let-7a, let-7b, and mir-98 were induced 4.9-, 1.3-, and 2.4-fold, respectively, whereas mir-17-5p decreased 0.23-fold. These results were duplicated using microRNA multianalyte suspension array technology. Regulation of MYC mRNA by let-7a was confirmed by transfections with pre-let-7a. Overexpression of let-7a (190%) decreased Myc mRNA (70%) and protein (75%). Down-regulation of Myc protein and mRNA using siRNA MYC also elevated let-7a miRNA and decreased Myc gene expression. Inverse coordinate regulation of let-7a and mir-17-5p versus Myc mRNA by 10058-F4, pre-let-7a, or siRNA MYC suggested that both miRNAs are Myc-regulated. This supports previous results in lung and colon cancer where decreased levels of the let-7 family resulted in increased tumorigenicity. Here, pre-let-7a transfections led to down-regulation of expression of MYC and its target genes and antiproliferation in lymphoma cells. These findings with let-7a add to the complexity of MYC regulation and suggest that dysregulation of these miRNAs participates in the genesis and maintenance of the lymphoma phenotype in Burkitt lymphoma cells and other MYC-dysregulated cancers.
Cognitive disengagement syndrome (CDS), formerly termed sluggish cognitive tempo, is a set of symptoms characterized by excessive daydreaming, mental confusion, and slowed behavior/thinking. CDS is ...distinct from symptoms of attention-deficit/hyperactivity disorder (ADHD) and other psychopathologies and uniquely associated with functional impairment. However, despite significant progress in developing and evaluating rating scale measures of CDS, no clinical interview of CDS exists with established psychometric properties that can facilitate a multimethod approach assessing CDS. Accordingly, the present study evaluated the psychometric properties of the semistructured Cognitive Disengagement Syndrome–Clinical Interview (CDS-CI). The CDS-CI and the ADHD inattention (ADHD-IN) and hyperactive-impulsivity (ADHD-HI) modules from the Kiddie Schedule of Affective Disorders and Schizophrenia for School-Age Children (K-SADS) were administered to a sample of early adolescents ( N = 341, ages 10–12 years) and their caregivers. Adolescents and caregivers also completed rating scale measures of CDS and ADHD symptoms. The CDS-CI demonstrated high internal consistency and interrater reliability. CDS-CI scores showed excellent same-source discriminant validity from K-SADS, ADHD-IN, and ADHD-HI scores and encouraging convergent and discriminant validity with rating scale measures, especially for caregivers. Above and beyond K-SADS, ADHD-IN, and ADHD-HI scores, higher parent and adolescent CDS-CI scores were both significantly associated with greater functional impairment. A threshold of ≥ 6 out of 15 symptoms was selected as an initial threshold for determining clinically elevated CDS using the CDS-CI. Findings provide psychometric support for the CDS-CI as a tool in the multimethod assessment of CDS. (PsycInfo Database Record (c) 2024 APA, all rights reserved) (Source: journal abstract)
In recent years, it has become apparent that the gaseous pollutant, hydrogen sulphide (H2S) can be synthesised in the body and has a multitude of biological actions. This review summarizes some of ...the actions of this 'gasotransmitter' in influencing the smooth muscle that is responsible for controlling muscular activity of hollow organs. In the vasculature, while H2S can cause vasoconstriction by complex interactions with other biologically important gases, such as nitric oxide, the prevailing response is vasorelaxation. While most vasorelaxation responses occur by a direct action of H2S on smooth muscle cells, it has recently been proposed to be an endothelium-derived hyperpolarizing factor. H2S also promotes relaxation in other smooth muscle preparations including bronchioles, the bladder, gastrointestinal tract and myometrium, opening up the opportunity of exploiting the pharmacology of H2S in the treatment of conditions where smooth muscle tone is excessive. The original concept, that H2S caused smooth muscle relaxation by activating ATP-sensitive K(+) channels, has been supplemented with observations that H2S can also modify the activity of other potassium channels, intracellular pH, phosphodiesterase activity and transient receptor potential channels on sensory nerves. While the enzymes responsible for generating endogenous H2S are widely expressed in smooth muscle preparations, it is much less clear what the physiological role of H2S is in determining smooth muscle contractility. Clarification of this requires the development of potent and selective inhibitors of H2S-generating enzymes.
Evaluate and compare the retinal microvasculature in the superficial capillary plexus (SCP) in Alzheimer's disease (AD), mild cognitive impairment (MCI), and cognitively intact controls using OCT ...angiography. OCT parameters were also compared.
Cross-sectional study.
Seventy eyes from 39 AD participants, 72 eyes from 37 MCI participants, and 254 eyes from 133 control participants were enrolled.
Participants were imaged using Zeiss Cirrus HD-5000 with AngioPlex (Carl Zeiss Meditec, Dublin, CA) and underwent cognitive evaluation with Mini-Mental State Examination.
Vessel density (VD) and perfusion density (PD) in the SCP within the Early Treatment Diabetic Retinopathy Study 6-mm circle, 3-mm circle, and 3-mm ring were compared between groups. Foveal avascular zone (FAZ) area, central subfield thickness (CST), macular ganglion cell-inner plexiform layer (GC-IPL) thickness, and peripapillary retinal nerve fiber layer (RNFL) thickness were also compared.
Alzheimer's participants showed significantly decreased SCP VD and PD in the 3-mm ring (P = 0.001 and P = 0.002, respectively) and 3-mm circle (P = 0.003 and P = 0.004, respectively) and decreased SCP VD in the 6-mm circle (P = 0.047) compared with MCI and significantly decreased SCP VD and PD in the 3-mm ring (P = 0.008 and P = 0.004, respectively) and 3-mm circle (P = 0.015 and P = 0.009, respectively) and SCP PD in the 6-mm circle (P = 0.033) when compared with cognitively intact controls. There was no difference in SCP VD or PD between MCI and controls (P > 0.05). FAZ area and CST did not differ significantly between groups (P > 0.05). Alzheimer's participants showed significantly decreased GC-IPL thickness over the inferior (P = 0.032) and inferonasal (P = 0.025) sectors compared with MCI and significantly decreased GC-IPL thickness over the entire (P = 0.012), superonasal (P = 0.041), inferior (P = 0.004), and inferonasal (P = 0.006) sectors compared to controls. MCI participants showed significantly decreased temporal RNFL thickness (P = 0.04) compared with controls.
Alzheimer's participants showed significantly reduced macular VD, PD, and GC-IPL thickness compared with MCI and controls. Changes in the retinal microvasculature may mirror small vessel cerebrovascular changes in AD.
The past 50 years have witnessed profound changes in the specialty of pediatric surgery in North America. There has been a marked increase in the number of both pediatric surgical training programs ...and practicing pediatric general and thoracic surgeons. Despite this trend, the population of children in the United States and the birth rate have recently remained relatively flat. Some pediatric surgeons have become “super specialists”, concentrating their practices in oncology or colorectal surgery. This has the potential to result in a dilution of experience for both pediatric surgical trainees and practicing pediatric surgeons, thus limiting their ability to acquire and maintain expertise, respectively. Coincident with this, there has been a relative paradigm shift in recognition that “quality of life” is based more on maintaining a creative balance in lifestyle and is not “all about work”. There has been a parallel growth in the number of practicing pediatric general and thoracic surgeons in urban settings, but we have not appreciated as much growth in rural and underserved areas, where access to pediatric surgical care remains limited and fewer pediatric general and thoracic surgeons practice. This is a complex issue, as some underserved areas are economically depressed and geographically sparse, but others are just underserved with adult providers taking care of children in settings that are often under resourced for pediatric surgical care. This problem may extend beyond the boundaries of pediatric general and thoracic surgery to other specialties. As the premier association representing all pediatric surgeons in the United States, the American Pediatric Surgical Association (APSA) has concluded that the quality of pediatric surgical care will likely decline should the status quo be allowed to continue. Therefore, APSA has initiated a Right Child/Right Surgeon initiative to consider these issues and propose some potential solutions. What follows is a brief statement of intent.
Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent ...studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP.
Objective:
Researchers have speculated that the COVID-19 pandemic may expand the academic performance gap experienced by at-risk students. We examined learning experiences during the 2020 to 2021 ...school year and the impact the pandemic has had on high school student grade point average (GPA), including predictors of change in GPA from 2019–2020 to 2020–2021.
Method:
Participants were 238 adolescents (55.5% male), 49.6% with attention-deficit/hyperactivity disorder (ADHD), in the United States. Adolescents reported on their GPAs via online surveys.
Results:
GPA significantly decreased on average from 2019–2020 to 2020–2021 school year. ADHD status and biological sex significantly moderated change—students with ADHD and male students reported decreased GPA, whereas students without ADHD and female students’ GPA did not change. Low income and Black/Latinx students had lower GPAs in both school years.
Conclusion:
It is imperative that additional supports be provided for at-risk students to help them catch up on missed learning during the pandemic.
Primary malignant liver tumors are rare but all require surgical resection as part of therapy with curative intent. A minority of patients have resectable tumors at diagnosis. Chemotherapy has a ...therapeutic role in hepatoblastoma but only one‐third of patients have resectable disease at diagnosis. Two children with hepatoblastoma and suboptimal responses to initial chemotherapy received therapy with transarterial radioembolization utilizing yttrium‐90 (TARE‐Y90) and had significant response leading to resection and remission. The role of TARE‐Y90 needs to be studied further to define its use in primary pediatric liver neoplasms.
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