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.

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.

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.

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.

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.

Infantile hemangioma in a v2 distribution: treatment with nadolol.

Infantile hemangiomas are common benign tumours of infancy affecting up to 10% of children. They are typically not present at birth but undergo a rapid proliferation stage and then plateau in growth before resolving spontaneously. Recently, beta-blockers have been favoured over systemic corticosteroids for treatment of disfiguring or life-threatening infantile hemangiomas. We present a case of an 11-week-old female with a 7 week history of an evolving hemangioma along a facial V2 distribution. Physical exam revealed a well-defined bright red plaque over the right zygoma and lower eyelid. MRI, echocardiograph, and liver ultrasound were normal. Patient was treated with nadolol and had a rapid and substantial regression of the hemangioma. Nadolol is an effective treatment option for disfiguring facial infantile hemangioma. The use of beta-blockers as treatment offers clues into the pathogenesis of infantile hemangioma, which is not yet completely understood.

Skin cancer (Basal cell carcinoma, squamous cell carcinoma, and malignant melanoma): new cases, treatment practice, and health care costs in new brunswick, Canada, 2002-2010.

BACKGROUND: In Canada, there is no formal process for registering nonmelanoma skin cancer (NMSC); thus, the epidemiology, treatment practices, and associated health costs are not well known. OBJECTIVES: To investigate trends in new cases of skin cancer, treatment practices, and health care costs in New Brunswick, Canada. METHODS: Data were extracted from the Provincial Cancer Registry and New Brunswick administrative health databases for 2002-2010. RESULTS: New cases: Basal Cell Carcinoma (BCC) was the most common skin cancer diagnosed, and incidence rates significantly increased between 1992 and 2010.Treatment practice: Dermatologists managed the majority (45%) of the overall skin cancer treatments.Health care costs: NMSC accounted for ∼80% of the health care costs for skin cancer and was dominated by BCC. CONCLUSIONS: Development of best practice treatment guidelines for NMSC in New Brunswick would improve future health care efficiencies, and standard protocols for registering new cases of NMSC in Canada would strengthen surveillance and reporting capacity.

Evaluation of the innovance d-dimer assay for the diagnosis of disseminated intravascular coagulopathy in different clinical settings.

Disseminated intravascular coagulopathy (DIC) is a serious disease with fatal consequences. We prospectively analyzed Innovance d-dimer immunoturbidimetric assay in 68 patients diagnosed with DIC on the background of malignancy (22), severe infection (20), or multitrauma (26) at a single institution between January 2010 and January 2011. Median age was 61 years (range 20-89). All patients were assessed according to the International Society of Thrombosis and Haemostasis (ISTH) DIC score. Applying a threshold of Innovance d-dimer of 10 mg/L fibrinogen equivalent unit (normal <0.5) was correlated with the highest sensitivity in malignancy (86%) and trauma/surgery (80%) compared to 54% in infection. The specificity remained high at 97% in infection, 81% in trauma and 77% in malignancy with a negative predictive value of 97% in trauma and malignancy, and 88% in infection. Our data suggest that Innovance d-dimer is a useful and simple tool that enhances the ISTH DIC diagnostic criteria. Further studies to confirm these findings are warranted.

Structural understanding of the glutathione-dependent reduction mechanism of glutathionyl-hydroquinone reductases.

Glutathionyl-hydroquinone reductases (GS- HQRs) are a newly identified group of glutathione transferases, and they are widely distributed in bacteria, halobacteria, fungi, and plants. GS-HQRs catalyze glutathione (GSH)-dependent reduction of glutathionyl-hydroquinones (GS-hydroquinones) to hydroquinones. GS-hydroquinones can be spontaneously formed from benzoquinones reacting with reduced GSH via Michael addition, and GS-HQRs convert the conjugates to hydroquinones. In this report we have determined the structures of two bacterial GS-HQRs, PcpF of Sphingobium chlorophenolicum and YqjG of Escherichia coli. The two structures and the previously reported structure of a fungal GS-HQR shared many features and displayed complete conservation for all the critical residues. Furthermore, we obtained the binary complex structures with GS-menadione, which in its reduced form, GS-menadiol, is a substrate. The structure revealed a large H-site that could accommodate various substituted hydroquinones and a hydrogen network of three Tyr residues that could provide the proton for reductive deglutathionylation. Mutation of the Tyr residues and the position of two GSH molecules confirmed the proposed mechanism of GS-HQRs. The conservation of GS-HQRs across bacteria, halobacteria, fungi, and plants potentiates the physiological role of these enzymes in quinone metabolism.

Utility of an interferon-gamma release assay for latent tuberculosis diagnosis in a case of bullous pemphigoid.

BACKGROUND: With increasing use of immunosuppressive therapy, including tumor necrosis factor alpha inhibitors, there is concern about infectious complications, including reactivation of latent Mycobacterium tuberculosis infection. Routine testing prior to administration of systemic immunosuppression includes the tuberculin skin test, which lacks sensitivity and specificity and may be difficult to interpret in the presence of extensive cutaneous disease. Treatment of individuals with latent tuberculosis infection is recommended when immunosuppressive medications are to be employed. OBSERVATIONS: We report a case in which a diagnosis of latent tuberculosis infection in a patient with extensive bullous pemphigoid was clarified by the use of an interferon-gamma release assay after equivocal tuberculin skin test results. CONCLUSION: Interferon-gamma release assays are useful adjuncts to the tuberculin skin test in the diagnosis of latent tuberculosis infection in the setting of extensive cutaneous disease.

Incidence of nonmelanoma skin cancer in New Brunswick, Canada, 1992 to 2001.

BACKGROUND: Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), collectively referred to as nonmelanoma skin cancer (NMSC), cause significant morbidity and generate a substantial cost to the health care system. Canadian data on the incidence of NMSC are lacking. OBJECTIVE: To study the incidence and characteristics of NMSC in New Brunswick, Canada (population 729,498 people in 2001), by using the Provincial Cancer Registry. METHOD: Data were obtained from 1992 to 2001 from the New Brunswick Provincial Cancer Registry, to which reporting of all cancers is mandatory. Multiple tumors of a given histologic type are recorded only once in the registry per individual per lifetime. A descriptive analysis of incidence rates of BCC and invasive SCC of the skin was performed in relation to gender, age, and anatomic location. The main outcome measures were the age- and sex-specific incidence rates of BCC and SCC. Age standardization was performed using the Canadian, US, and world standard populations. RESULTS: When adjusted to the world standard population, the age-standardized incidence rates (ASIRs) per 100,000 population for BCC from 1992 through 2001 were 87 for males and 68 for females. For invasive SCC, the ASIRs per 100,000 population were 34 for males and 16 for females. There was an increasing incidence trend for both BCC and invasive SCC over the 10-year study period, with minimal change in the incidence of SCC in women. The overall ratio of BCC to invasive SCC in the population was 2.8 to 1. The approximate lifetime probabilities of developing BCC and invasive SCC were 13% and 5%, respectively. CONCLUSIONS: The incidence of NMSC in the province of New Brunswick is similar to that reported from 1973 through 1987 in the province of British Columbia, higher than those reported in most parts of Europe, and lower than all published rates in the United States and Australia. Owing to the inability of the registry to account for tumor multiplicity, the actual annual number of all NMSC lesions in this population is likely much higher.

Engineered antibody Fc variants with enhanced effector function.

Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fcgamma receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fcgamma receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.

Automated volumetry at CT colonography: a phantom study.

RATIONALE AND OBJECTIVES: To assess the performance of a computer-aided detection (CAD) algorithm for measuring polyp-like structures on CT colonography (CTC) images of a phantom. MATERIALS AND METHODS: We constructed a Plexiglas phantom to which we affixed a series of idealized Plexiglas polyp-like objects, including spheres and hemispheres. We imaged the phantom in a four-channel detector CT scanner at a 1.3 mm slice thickness with a reconstruction interval of 0.6 mm, using combinations of 100 mAs, 30 mAs, horizontal and vertical orientation. For each set of CT images, the interior surface of the phantom was segmented. The CAD algorithm was applied to the resulting surface to identify the polypoid regions of interest and to calculate their volume and maximum linear dimension. Calculated values were then compared with actual values to yield percent error in each measurement. RESULTS: The mean error in volume for the subgroups of spheres and hemispheres was 3% and 5% respectively. Mean error in linear dimension was approximately 2% for both shape subgroups. All CAD-calculated values were closely correlated with their respective actual values. Parameter selection did not significantly affect the accuracy of the calculated measurements. CONCLUSIONS: Our CAD software accurately measured the greatest linear dimension and the volume of each of the polyp-like structures in our phantom. Results were largely independent of phantom orientation and the CT exposure factors.

Refractory erosive oral lichen planus associated with hepatitis C: response to topical tacrolimus ointment.

BACKGROUND: Erosive lichen planus is a painful and disabling disease that is frequently resistant to topical and systemic therapies. Current therapies are considered palliative rather than curative as many patients relapse after discontinuing treatment. An association has been reported between some cases of oral lichen planus (OLP) and chronic hepatitis C infection. OBJECTIVE: We report on a 51-year-old hepatitis C-positive man with corticosteroid refractory erosive lichen planus of the lip who had a rapid resolution of his lesions following a two-week course of topical 0.1% tacrolimus ointment. The patient remains symptom-free at one year post-treatment. CONCLUSION: This case supports the safety and efficacy of topical tacrolimus in patients with steroid-refractory OLP associated with chronic hepatitis C.

Pyoderma gangrenosum with a contiguous erosion of the distal ulna.

BACKGROUND: Pyoderma gangrenosum (PG) has been described in association with sterile neutrophilic infiltration of several organ systems, including the skeleton. The most frequent cause of bony disease in PG has been chronic, recurrent, multifocal osteomyelitis, a sterile inflammatory disease of children and young adults mimicking infectious osteomyelitis. Bony erosions have been only rarely described in direct contiguity to a PG ulcer. OBJECTIVE: We report a 53-year-old woman with recurrent PG who developed an erosion of the distal ulna adjacent to a PG ulcer. The patient responded to high-dose prednisone, and a repeat radiograph of the wrist four months later was normal. CONCLUSION: This case demonstrates another example of cortical osteolysis directly adjacent to a PG ulcer in which the bony changes may be neutrophil-induced.

Stigma directed toward chronic illness is resistant to change through education and exposure.

In the mid-1980s, research reported that people living with HIV were viewed differently on measures of competence, dependence, morbidity, depression, and moral worth from those living with other chronic illnesses. 443 students were surveyed to evaluate present attitudes in comparison to this earlier research. The usefulness of imaginal exposure, i.e., imagining a loved one living with HIV, in reducing stigma toward people with HIV was also investigated. Analysis indicated no difference in the rating of AIDS and cancer patients on measures of competence, depression, and morbidity and patients with heart disease, the latter being rated significantly less competent and more depressed than AIDS or cancer patients. AIDS patients were rated significantly less dependent than cancer and heart disease patients. While these results suggest that stigma associated with an HIV/AIDS diagnosis, in general, may have decreased over the years, ratings of moral worth were still lower for AIDS patients than for patients with cancer and heart disease. Robustness of this specific aspect of stigma may be associated with sexual prejudice. Also, an imagined loved one who lives with HIV was rated significantly more favorably on all 5 composite scales than a generic person living with HIV, suggesting the usefulness of exposure as an intervention for attitude change. Limitations of the research are discussed.

Preliminary measurements of surface removable NORM activity in the WIPP underground.

The results of correlating surface removable activity to that measured on a fixed air sampler is reported. It was found from over 40 smears taken during a two week period that surface removable activity from Naturally Occurring Radioactive Material (NORM) can be predicted to be within a factor of 2 or 3 using either a fixed air sampler measurement or even another smear measurement from a specified surface. The method is being used to take credit for background surface removable activity in similar fashion to a background count for any other radiation detector. The utility of this technique is also discussed from an operational health physics perspective for the Waste Isolation Pilot Plant.