Benign proliferating pilar tumor excised with Slow Mohs surgery: A case report.

Proliferating pilar tumors are rare, benign, exophytic neoplasms, which can closely resemble a squamous cell carcinoma. We describe a patient with a large benign exophytic tumor on the scalp that had been slowly growing over 10 years. While this class of benign follicular tumors is rare, the standard of care is typically excision with clear histologic margins. In this case, this large scalp tumor was surgically excised with clear margins/permanent section margin control using "Slow Mohs" technique, with subsequent repair using a skin substitute dressing, followed by a delayed skin graft.

Nuclear waste Educator's workshop: What and how do we teach about nuclear waste?

A workshop was held at the Massachusetts Institute of Technology (MIT) on July 25th and 26th, 2022. The objective was to develop a blueprint for educating next-generation engineers and scientists about nuclear waste management and disposal, which requires knowledge from diverse disciplines, including nuclear, chemical, civil, environmental, and geological science and engineering. The 49 participants included university professors, researchers, industry experts, and government officials from different areas. First, we have developed a list of key fundamental knowledge on waste management and disposal across the nuclear fuel cycle. In addition, we discussed strategies on how to teach students with diverse backgrounds through innovative teaching strategies as well as how to attract students into this area. Through the workshop, we identified the critical needs to (1) develop community resources for nuclear waste education; (2) synthesize historical perspectives, including past contamination and the management of general hazardous waste; (3) emphasize a complete life-cycle perspective, including proper waste management as the key component for energy sustainability; (4) teach students how to communicate about the key facts and risks to technical and non-technical audiences; and (5) accelerate the use of the state-of-art-technologies to attract and retain a young workforce. Furthermore, we aim to build a diverse, inclusive community that supports students in developing their own narratives about nuclear waste, particularly in recognizing that antagonistic views have been important to improving safety and protecting public health and the environment.

Combined cemiplimab and radiotherapy for advanced basal cell carcinoma: A case report.

Advanced basal cell carcinoma may be treated with systemic therapies such as hedgehog pathway inhibitors or programmed cell death protein 1 inhibitors, namely cemiplimab. We report a case of a 70-year-old man with a nodulo-infiltrative advanced basal cell carcinoma over the right posterior neck and scapula. The patient had a partial response to the hedgehog pathway inhibitor, vismodegib. The tumour progressed, and the patient was switched from vismodegib to radiotherapy combined with cemiplimab, which led to a significant reduction in pain, bleeding, and tumour size. A combined treatment approach with radiotherapy and cemiplimab may be beneficial for advanced basal cell carcinoma cases that progress after treatment with hedgehog pathway inhibitors.

EVALUATION OF EXISTING PUBLIC DOSE LIMITS APPLIED TO RECREATIONAL SPACEFLIGHT.

Establishing realistic radiation dose limits with a solid scientific basis is a key component of the 'as low as reasonably achievable' (ALARA) principle. Although existing occupational dose limits have been established for civil astronauts, with the rise in popularity and technological maturation of the 'space tourism' sector, there does not appear to be considerable discussion on the subject of non-occupational astronaut dose limits. The necessity to come to a collective decision on dose limits and radiation safety procedures for recreational spaceflight is urgent and imperative to maintain ALARA goals, as existing federal dose limits to the public cannot be adequately or universally applied to the space tourism sector. Development of an entirely new set of regulations and guidelines should also provide long-term benefits in public perception as evidence of safety commitments from decision makers and the community in protecting passengers from radiological risks balanced with other spaceflight hazards.

Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia.

PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.

Dose Estimation for Extravasation of 177Lu, 99mTc, and 18F.

ABSTRACT: Extravasation is the situation in which a nuclear medicine injection deposits some fraction of its radioactivity into the soft tissue rather than the bloodstream and may result in a large local radiation dose to tissue. An understanding of localized radiation dose from such unexpected events can be an important aspect of clinical radiation protection. The aim of this study was to estimate and assess absorbed radiation dose to localized soft tissue for hypothetical scenarios of radiopharmaceutical extravasation. Specifically, the goal was to understand whether a radiopharmaceutical extravasation could exceed the US Nuclear Regulatory Commission's medical event reporting limit of 0.5 Sv dose equivalent to tissue or levels at which tissue damage would be anticipated (1.0 Sv dose equivalent). We used the GATE Monte Carlo simulation software to calculate self-dose to spherical volumes containing uniformly distributed amounts of common radiopharmaceutical isotopes. Simulated volumes, radioactivity levels, and effective half-lives represented real-world nuclear medicine procedures. Chosen scenarios consisted of 50 mCi and 100 mCi 177Lu within 20 cm3 and 40 cm3 tissue volumes and a 60 min biological clearance half-time (59.6 min effective half-life), 6 mCi and 12 mCi 99mTc within 1 cm3 and 5 cm3 tissue volumes and a 120 min biological clearance half-time (90 min effective half-life), and 3 mCi and 6 mCi 18F within 1 cm3 and 5 cm3 tissue volumes with a 30 min biological clearance half-time (23.6 min effective half-life). We calculated absorbed doses to be between 5.5 Gy and 23.5 Gy for 177Lu, between 0.9 Gy and 12.4 Gy for 99mTc, and between 1.5 Gy and 16.2 Gy for 18F. Radiopharmaceutical extravasations can result in tissue doses that surpass both medical event reporting limits and levels at which deterministic effects are expected. Radiation safety programs should include identification, mitigation, dosimetry, and documentation of significant extravasation events.

Probing the effect of glycosaminoglycan depletion on integrin interactions with collagen I fibrils in the native extracellular matrix environment.

Fibrillar collagen-integrin interactions in the extracellular matrix (ECM) regulate a multitude of cellular processes and cell signalling. Collagen I fibrils serve as the molecular scaffolding for connective tissues throughout the human body and are the most abundant protein building blocks in the ECM. The ECM environment is diverse, made up of several ECM proteins, enzymes, and proteoglycans. In particular, glycosaminoglycans (GAGs), anionic polysaccharides that decorate proteoglycans, become depleted in the ECM with natural aging and their mis-regulation has been linked to cancers and other diseases. The impact of GAG depletion in the ECM environment on collagen I protein interactions and on mechanical properties is not well understood. Here, we integrate ELISA protein binding assays with liquid high-resolution atomic force microscopy (AFM) to assess the effects of GAG depletion on the interaction of collagen I fibrils with the integrin α2I domain using separate rat tails. ELISA binding assays demonstrate that α2I preferentially binds to GAG-depleted collagen I fibrils in comparison to native fibrils. By amplitude modulated AFM in air and in solution, we find that GAG-depleted collagen I fibrils retain structural features of the native fibrils, including their characteristic D-banding pattern, a key structural motif. AFM fast force mapping in solution shows that GAG depletion reduces the stiffness of individual fibrils, lowering the indentation modulus by half compared to native fibrils. Together these results shed new light on how GAGs influence collagen I fibril-integrin interactions and may aid in strategies to treat diseases that result from GAG mis-regulation.

Prospective cohort study on the use of low molecular weight heparin calibrated anti-Xa assay for measurement of direct oral Xa inhibitors in ex vivo patient samples.

Drug-specific anti-Xa chromogenic assays are recommended for measurement of direct anti-Xa inhibitor levels but are not routinely available in many institutions. We performed a prospective study to determine: (1) the relationship between low molecular weight heparin (LMWH) calibrated anti-Xa measurements and apixaban or rivaroxaban levels measured using drug-specific anti-Xa assays and, (2) if a LMWH calibrated anti-Xa assay can be used to detect clinically significant apixaban or rivaroxaban levels. Haematology outpatients on rivaroxaban or apixaban for at least 72 h were recruited for this study. Anti-Xa LMWH assay was performed using the Innovance Heparin Anti-Xa kit/calibrator. Drug-specific levels were determined using STA-Liquid anti-Xa kit/STA-Apixaban or STA-Rivaroxaban calibrators. Serial dilutions with pooled normal plasma were performed for specimens with anti-Xa LMWH activity greater than 1.50 ng/mL to obtain anti-Xa levels within the reportable range (0.10-1.50 ng/mL) and multiplied by the dilution factor to determine actual anti-Xa level. Seventy-five (39 rivaroxaban, 36 apixaban) specimens from 67 patients (mean age 60.3 years; 53.3% males) were available for analysis. Rivaroxaban levels ranged from <25 to 500 ng/mL while apixaban levels ranged from <20 to 236.1 ng/mL. For both rivaroxaban and apixaban, there was linear and good correlation (R2 = 0.96) between direct oral anticoagulants and anti-Xa LMWH levels. Using the correlation equation from our data, a rivaroxaban concentration of 50 ng/mL [International Society on Thrombosis and Haemostasis (ISTH) threshold for consideration of antidotes in bleeding patients] and 30 ng/mL (ISTH threshold for consideration of reversal agents prior to interventions), corresponds to anti-Xa LMWH levels of 0.50 and 0.35 IU/mL, respectively. For apixaban the corresponding anti-Xa LMWH levels were 0.35 and 0.20 IU/mL, respectively. In conclusion, LWWH calibrated anti-Xa assay can be used in emergency situations to screen for clinically significant apixaban or rivaroxaban levels when drug-specific calibrators are not available.

Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase.

All herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies include nucleoside and non-nucleoside inhibitors (NNI) that target the DNA-bound state of herpesvirus polymerase and block replication. Here we report the ternary complex crystal structure of Herpes Simplex Virus 1 DNA polymerase bound to DNA and a 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 Å resolution. PNU bound at the polymerase active site, displacing the template strand and inducing a conformational shift of the fingers domain into an open state. These results demonstrate that PNU inhibits replication by blocking association of dNTP and stalling the enzyme in a catalytically incompetent conformation, ultimately acting as a nucleotide competing inhibitor (NCI). Sequence conservation of the NCI binding pocket further explains broad-spectrum activity while a direct interaction between PNU and residue V823 rationalizes why mutations at this position result in loss of inhibition.

The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer.

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.

In Silico Identification of Potential Phosphorylation in the Cytoplasmic Domain of Epithelial Cell Adhesion Molecule.

The epithelial cell adhesion molecule (EpCAM) is a transmembrane cell adhesion glycoprotein, which primarily contributes to stemness, proliferation, and metastasis properties of tumor cells. Regulated intramembrane proteolysis by ADAM proteases and γ-secretase cleaves EpCAM into an ∼27 kDa soluble extracellular and an ∼4 kDa cytoplasmic domain (EpICD). After the EpICD fragment is released inside the cell, the formation of a nuclear signaling complex with the FHL2 molecule is critical for exerting its regulatory role. Trop-2, a homologous protein of EpCAM, undergoes phosphorylation in its cytoplasmic domain (Trop-IC). The phosphorylation of Trop-2 is reported to be crucial for its function. This led us to ask the fundamental question if EpCAM does undergo similar post-translational modification(PTM) like its homologous protein to carry out its diverse biological function. Here, we identify a putative phosphorylation site at Tyr297 located in the cytoplasmic domain of EpCAM. Molecular dynamic simulation (MDS) of 90 ns was carried out to understand the biological/functional relevance of the putative phosphorylation. It was observed that this phosphorylation stabilizes the α-helical structure of the EpICD. Though Tyr297 does not affect the γ-secretase mediated cleavage of EpCAM, it affects the binding of EpICD to FHL2. Docking analysis revealed that phosphorylation mediated structural stability of EpICD positively impacts its binding affinity with FHL2, which was further validated using 100 ns MDS. Phosphorylated EpICD forms higher numbers of hydrogen bonds, salt bridges, and other non-bonded interactions with FHL2, leading to enhanced interactions. This in silico study reveals a potential PTM in the EpICD, providing the basis for future research in understanding the mechanism behind the diverse biological function of EpCAM.

Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5).

Protein arginine methyltransferase 5 (PRMT5) belongs to a family of enzymes that regulate the posttranslational modification of histones and other proteins via methylation of arginine. Methylation of histones is linked to an increase in transcription and regulates a manifold of functions such as signal transduction and transcriptional regulation. PRMT5 has been shown to be upregulated in the tumor environment of several cancer types, and the inhibition of PRMT5 activity was identified as a potential way to reduce tumor growth. Previously, four different modes of PRMT5 inhibition were known-competing (covalently or non-covalently) with the essential cofactor S-adenosyl methionine (SAM), blocking the substrate binding pocket, or blocking both simultaneously. Herein we describe an unprecedented conformation of PRMT5 in which the formation of an allosteric binding pocket abrogates the enzyme's canonical binding site and present the discovery of potent small molecule allosteric PRMT5 inhibitors.

Low level EPR dosimetry of a commercial sugar.

This work demonstrated the combined utility of empty tube subtraction, over-modulation, native signal subtraction and spectral filtration in low level dosimetry using commercial sugar samples. The native signal component was found to have an effective peak to peak equivalent of 150 mGy. If the zero dose native signal is accurately modeled and subtracted, the detection limit was estimated to be 0.2 Gy although intercept uncertainties were as low as 25 mGy. This was enabled by resultant slope uncertainties as low as 3% with residual variations of approximately 0.1 Gy.

Making sense of parameter estimation and model simulation in bioprocesses.

Most articles that report fitted parameters for kinetic models do not include meaningful statistical information. This study demonstrates the importance of reporting a complete statistical analysis and shows a methodology to perform it, using functionalities implemented in computational tools. As an example, alginate production is studied in a batch stirred-tank fermenter and modeled using the kinetic model proposed by Klimek and Ollis (1980). The model parameters and their 95% confidence intervals are estimated by nonlinear regression. The significance of the parameters value is checked using a hypothesis test. The uncertainty of the parameters is propagated to the output model variables through prediction intervals, showing that the kinetic model of Klimek and Ollis (1980) can simulate with high certainty the dynamic of the alginate production process. Finally, the results obtained in other studies are compared to show how the lack of statistical analysis can hold back a deeper understanding about bioprocesses.

Effect of Insulin and Fasting Regimen on Blood Glucose Concentrations of Diabetic Dogs During Phacoemulsification.

This study aimed to compare four protocols for preanesthetic insulin administration and fasting time with respect to the variation of intraoperative blood glucose (BG) concentrations versus preanesthetic values (baseline). The patient records of dogs undergoing cataract surgery were included. Data on anesthetic protocols, comorbidities, and intraoperative complications (hyper- and hypoglycemia, hypotension, hypothermia, and bradycardia) were analyzed. The insulin/fasting protocols included (A) 12 hr fasting and half insulin dose, (B) 6 hr fasting and half insulin dose, (C) 12 hr fasting and full insulin dose, and (D) 12 hr fasting and no insulin. Forty-eight dogs were included (14 in A, 10 in B, 13 in C, and 11 in D). Protocol D resulted in a significant increase of intraoperative BG concentrations compared with baseline (P = .001), whereas in the remaining groups, the baseline BG did not differ from intraoperative values. There were no statistically significant associations between the treatment group and the occurrence of intraoperative complications or the presence of diagnosed comorbidities. In conclusion, different insulin and fasting regimen protocols may be used for diabetic patients with no apparent benefit or risk from one protocol versus another. The use of insulin before surgery results in lesser increase of BG intraoperatively as compared with preanesthetic values. However, whether this should be interpreted as better perioperative control of glycemia remains debatable.

Validation of a rapid, conservative transuranic alpha activity estimation method in air samples.

In air filter assay for radiological emergency response, radon (222Rn) and thoron (220Rn) progeny are known interferents to transuranic activity estimation. Previous work detailed a conservative, graded approach for TRU alpha activity estimation from air samples void of transuranic activity yet containing varying amounts of radon and thoron progeny. Validation of this method to produce rapid, conservative and defensible transuranic alpha activity estimates was accomplished through introduction of surrogate transuranic activity, 239Pu and 230Th check sources, along with the naturally occurring radioactive progeny from an environmental air filter. Following air collection, the filter was centre hole-punched with the transuranic check source placed underneath the filter during counting. With the surrogate transuranic activity introduced into the measurement, verification of the previously studied methodology for rapid transuranic activity estimation was determined with quantifiable conservative bias. 70 environmental filters with various levels of radon progeny and air sampling duration were collected; 35 examined with the 239Pu check source and 35 studied with the 230Th check source. To characterise the expected transuranic activity introduced to the counting experiment without the environmental interferents of radon and thoron progeny, 30 blank filters were counted using the described experimental setup with each of the respective surrogate sources. Following characterisation of the sources with blank filters, transuranic activity estimation comparison against the 70 environmental filters with natural background radioactive progeny interferents was accomplished. This work contributes to the comprehensive analysis of operational air samples by detailing validation results for a rapid and conservative transuranic alpha activity estimation methodology.

INITIAL TL/OSL/EPR CONSIDERATIONS FOR COMMERCIAL DIATOMACEOUS EARTH IN RETROSPECTIVE DOSIMETRY AND DATING.

Diatomaceous earth is found in various locations around the planet. It is caused by the deposited exoskeleton material formed by the death of large concentrated populations of diatoms. The exoskeleton is effectively pure silicate and as such becomes a prospective material for retrospective dosimetry and dating. This work investigated the thermoluminescence (TL) and optically stimulated luminescence properties of commercially obtained diatomaceous earth. The material was not found to have useful dosimetric properties with conventional TL methodologies but did provide large dose estimates using the Single Aliquot Regeneration technique on some subset samples. These findings for organic silicate did suggest some mechanisms explaining the sensitization process in geological silicate materials utilized in dosimetry and dating. Electron paramagnetic resonance was identified as a potential future method for evaluating this material as it revealed unique signal components not found in igneous or commercially produced silicates.

Efficacy of adjunctive low-dose cariprazine in major depressive disorder: a randomized, double-blind, placebo-controlled trial.

This 19-week, double-blind, placebo-controlled, randomized phase 2 study evaluated the efficacy, safety, and tolerability of adjunctive cariprazine (0.1-0.3 and 1.0-2.0 mg/day) as an antidepressant treatment for adults with treatment-resistant major depressive disorder (MDD) (NCT00854100). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score and the secondary was change in the Clinical Global Impression-Intensity score. Additional efficacy parameters were also assessed. A total of 231 patients were randomized. None of the predefined parameters reached significance for either cariprazine doses, but higher doses yielded numerically greater mean changes in MADRS and Clinical Global Impression-Intensity scores, and MADRS response and remission rates, compared with placebo. No differences were seen on any measures between cariprazine 0.1-0.3 mg/day and placebo. Cariprazine was relatively well tolerated, and common treatment-emergent adverse events (incidence ≥5% and twice the placebo group rate) in both dosage groups included headache, arthralgia, restlessness, fatigue, increased appetite, insomnia, dry mouth, and constipation. In conclusion, both cariprazine doses were relatively well tolerated; although differences were not statistically significant, patients treated with cariprazine 1.0-2.0 mg/day had greater mean decreases in measures of depression symptoms compared with placebo, which is consistent with another adjunctive cariprazine MDD study, and thus warrants further investigation.

Total Ambient Dose Equivalent Buildup Factors for Portland Concrete.

In this work, total ambient dose equivalent buildup factors for Portland concrete slabs are calculated using Monte Carlo n-particle software MCNP6™. Buildup factor calculations could approach intractable solutions in general as they depend on a large number of variables. These include geometry, source energy, and the composition of the shield (which itself can be heterogeneous). In this work, Cf and americium-beryllium sources are considered, as well as monoenergetic incident neutrons in the energy range from 0.025 eV to 14 MeV at multiple incident angles. The shielding material of interest was taken to be standard Portland concrete. The transmitted neutron and gamma-ray ambient dose rate was calculated first and then used for total buildup factor calculations. Perhaps more telling than the calculated theoretical buildup factor, the credible dispersion in expected resultant buildup factors was also calculated by conducting a very rudimentary sensitivity analysis, varying the water content in the first case and then varying the amount of aggregate. An additional aim of this work is to provide a model based on the machine-learning technique called the support vector regression method in the calculation of concrete buildup factors.