A Painted Ridge Witelson, David Mendel
2019, Letnik:
98
eBook
This book explores a suite of spatially close San (Bushmen) rock painting sites in the Maclear District of South Africa's Eastern Cape Province. As a suite, the sites are remarkable because, despite ...their proximity to each other, they share patterns of similarity and simultaneous difference.
SMYD2 is a lysine methyltransferase that catalyzes the monomethylation of several protein substrates including p53. SMYD2 is overexpressed in a significant percentage of esophageal squamous primary ...carcinomas, and that overexpression correlates with poor patient survival. However, the mechanism(s) by which SMYD2 promotes oncogenesis is not understood. A small molecule probe for SMYD2 would allow for the pharmacological dissection of this biology. In this report, we disclose LLY-507, a cell-active, potent small molecule inhibitor of SMYD2. LLY-507 is >100-fold selective for SMYD2 over a broad range of methyltransferase and non-methyltransferase targets. A 1.63-Å resolution crystal structure of SMYD2 in complex with LLY-507 shows the inhibitor binding in the substrate peptide binding pocket. LLY-507 is active in cells as measured by reduction of SMYD2-induced monomethylation of p53 Lys370 at submicromolar concentrations. We used LLY-507 to further test other potential roles of SMYD2. Mass spectrometry-based proteomics showed that cellular global histone methylation levels were not significantly affected by SMYD2 inhibition with LLY-507, and subcellular fractionation studies indicate that SMYD2 is primarily cytoplasmic, suggesting that SMYD2 targets a very small subset of histones at specific chromatin loci and/or non-histone substrates. Breast and liver cancers were identified through in silico data mining as tumor types that display amplification and/or overexpression of SMYD2. LLY-507 inhibited the proliferation of several esophageal, liver, and breast cancer cell lines in a dose-dependent manner. These findings suggest that LLY-507 serves as a valuable chemical probe to aid in the dissection of SMYD2 function in cancer and other biological processes.
Background: SMYD2 is a methyltransferase whose role in cancer is poorly understood and is lacking cell-active chemical tools.
Results: We describe LLY-507, a small molecule inhibitor of SMYD2.
Conclusion: LLY-507 is potent, selective, cell-active, and binds SMYD2 in a high resolution co-crystal.
Significance: LLY-507 is a first-in-class cell-potent chemical probe that will be valuable in dissecting SMYD2 biology.
Due to the ongoing coronavirus disease 2019 pandemic, virtual interviews are planned for the 2021-2022 residency application cycle. The virtual interview will remain novel to applicants for each ...match cycle until the graduating medical student class has experience from virtual interviews during their medical school admissions. The virtual interview poses unique challenges that are unique from in-person formats. Given the lack of experience of applicants in the 2022 match, practicing interviewing skills prior to the actual date is vital to success. We describe a postgraduate year 1 (PGY1)–run mock interview session for applicants preparing for the 2021-2022 otolaryngology interview cycle and discuss the methodology. Deliberate practice with PGY1 residents who have just recently undergone the virtual interview process can better prepare applicants for their virtual interviews, improve on-camera behaviors, and ameliorate mental health challenges unique to the virtual format.
Dynamic susceptibility contrast (DSC) perfusion weighted imaging (PWI) currently remains the gold standard technique for measuring cerebral perfusion in glioma diagnosis and surveillance. Arterial ...spin labelling (ASL) PWI is a non-invasive alternative that does not require gadolinium contrast administration, although it is yet to be applied in widespread clinical practice. This study aims to assess the utility of measuring signal intensity in ASL PWI in predicting glioma vascularity by measuring maximal tumour signal intensity in patients based on pre-operative imaging and comparing this to maximal vessel density on histopathology.
Pseudocontinuous ASL (pCASL) and DSC images were acquired pre-operatively in 21 patients with high grade gliomas. The maximal signal intensity within the gliomas over a region of interest of 100 mm2 was measured and also normalised to the contralateral cerebral cortex (nTBF-C), and cerebellum (nTBF-Cb). Maximal vessel density per 1 mm2 was determined on histopathology using CD31 and CD34 immunostaining on all participants.
Using ASL, statistically significant correlation was observed between maximal signal intensity (p < 0.05) and nTBF-C (p < 0.05) to maximal vessel density based on histopathology. Although a positive trend was also observed nTBF-Cb, this did not reach statistical significance. Using DSC, no statistically significant correlation was found between signal intensity, nTBF-C and nTBF-Cb. There was no correlation between maximal signal intensity between ASL and DSC. Average vessel density did not correlate with age, sex, previous treatment, or IDH status.
ASL PWI imaging is a reliable marker of evaluating the vascularity of high grade gliomas and may be used as an adjunct to DSC PWI.
Background.
Strategies to reduce anxiety prior to injection procedures are not well understood. The purpose is to determine the effect of a meditation monologue intervention delivered via ...phone/mobile application on pre-injection anxiety levels among patients undergoing a clinical injection. The following hypothesis was tested: patients who listened to a meditation monologue via phone/mobile application prior to clinical injection would experience less anxiety compared to those who did not.
Methods.
A prospective, randomized controlled trial was performed at an orthopedics and sports medicine clinic of a tertiary level medical center in the New England region, USA. Thirty patients scheduled for intra- or peri-articular injections were randomly allocated to intervention (meditation monologue) or placebo (nature sounds) group. Main outcome variables were state and trait anxiety inventory (STAI) scores and blood pressure (BP), heart rate, and respiratory rate.
Results.
There were 16 participants who were allocated to intervention (meditation monologue) while 14 participants were assigned to placebo (nature sounds). There was no interaction effect. However, a main time effect was found. Both state anxiety (STAI-S) and trait anxiety (STAI-T) scores were significantly reduced post-intervention compared to pre-intervention (STAI-S: p = 0.04, STAI-T: p = 0.04). Also, a statistically significant main group effect was detected. The pre- and post- STAI-S score reduction was greater in the intervention group (p = 0.028). Also, a significant diastolic BP increase between pre- and post-intervention was recorded in the intervention group (p = 0.028), but not in the placebo group (p = 0.999).
Conclusion.
Listening to a meditation monologue via phone/mobile application prior to clinical injection can reduce anxiety in adult patients receiving intra- and peri-articular injections. Registration: ClinicalTrials.gov NCT02690194
N-Cbz- and Boc-protected spirocyclic dienes were prepared by dialkylation of cyclopentadiene. These dienes coupled efficiently in a series of iminonitroso Diels−Alder reactions to produce a series of ...new spirocyclic adducts. Hydrogenolysis of these adducts afforded new spirocycles that contain multiple handles for further functionalization. Furthermore, stereocontrolled dihydroxylation and reductive cleavage of the spirocyclic adducts generated versatile scaffolds for the syntheses and derivatization of novel spirocyclic carbocyclic nucleoside analogs.
Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an ...attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7 − 12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
INTRODUCTION:
We previously conducted an initial analysis on the effectiveness of fecal immunochemical test (FIT) screening at our Ambulatory Care Clinic (ACC) for the underserved population during ...the first year of FIT implementation and first year of patient follow up. Although we met our initial goal of FIT completion of >60% (actual 81.8%), the follow up rate for repeat FIT testing was only 18% for patients with an initial negative FIT test (Figure 1). Recognizing these shortcomings, we implemented interventions to improve the follow-up FIT completion rate for those with initial negative testing.
METHODS:
All patients with initial negative FIT testing without a repeat FIT test after 1 year of follow-up were sent a letter notifying them of need for a repeat FIT test, which could be picked up from the front desk of the clinic (Figure 2). After two months, patient compliance was re-assessed and those who had still not completed the FIT test were given individualized phone calls with the same information. FIT completion rates were then assessed 1 month after these phone calls.
RESULTS:
A summary and patient flow diagram is shown (Figure 3). Among the 49 remaining active patients at the start of the intervention period, 9 patients (18%) completed a FIT test within 2 months of receiving the letter. No patients completed a FIT test within one month of receiving a phone call.
CONCLUSION:
1. Neither intervention significantly increased the rate of repeat FIT completion, although our 18% FIT completion at two months after the letter is near the published 23.5% completion rate.
1
2. Significant patient dropout occurred, adding up to 120 patients (71%) during a 6-month window immediately prior to our intervention period. This predominately occurred due to patients becoming inactive at the clinic over lack of follow-up or patients qualifying for insurance through the Virginia Medicaid expansion which started in January 2019. 3. There is clear need to refine our follow-up interventions and consider alternative tools, such as mailing FIT tests, automated text messaging, or incorporating FIT testing into well visits or existing clinic navigation tools. Additionally, the low rates of follow-up in this patient population will need to be monitored closely, as this may be a limiting factor for FIT testing which requires annual screening compared to other screening measures with longer interval screening periods.
Utilizing structure-based techniques and solid-phase synthesis, statine-based tetrapeptide BACE inhibitors were designed and synthesized using a heptapeptide BACE transition-state mimetic, 1, as the ...starting point. Structure-activity relationship studies at the P(3), P(2), and P(2)' positions as well as the N-terminal capping group on scaffold 5 led to the discovery of potent inhibitors 27, 32, and 34 (IC(50) <100 nM). In addition, computational analysis and the X-ray structure of BACE-inhibitor 38 are discussed.
3-(Imidazo1,2-
apyridin-3-yl)-, its aza-analogs, and 3-(pyrazolo1,5-
apyridin-3-yl)-4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl))maleimides are very potent inhibitors of GSK3 (⩽5
nM) ...with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII.
Many 3-aryl-4-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100
nM IC
50), although few show significant selectivity (>100
×) versus CDK2, CDK4, or PKCβII. However, combining 3-(imidazo1,2-
apyridin-3-yl), 3-(pyrazolo1,5-
apyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (⩽5
nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
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