Mediastinal Epithelioid Angiosarcoma, New Insights into an Uncommon Diagnosis: A Case Report and Literature Review.

Angiosarcoma is an uncommon malignant mesenchymal neoplasm, accounting for 1-2% of all sarcomas. More than half are cutaneous, with the remainder arising in the deep soft tissue, breast, bone or viscera, particularly the liver, spleen and heart. Mediastinal angiosarcomas are exceedingly uncommon. While epithelioid morphology is sometimes a minor component in conventional angiosarcoma, tumors with a predominance of epithelioid morphologic features are designated as epithelioid angiosarcoma (EAS). This is a report of a 58-year-old woman presenting with severe chest pain, accompanied by worsening dyspnea and dysphagia. Chest computed tomography (CT) revealed a large pericardial effusion and a bulky mediastinal mass. Biopsy revealed a malignant neoplasm with vascular differentiation consistent with high-grade EAS. By immunohistochemistry, epithelioid angiosarcomas express endothelial cell markers, such as CD31, CD34, ERG and FLI-1. A variable proportion express low molecular weight cytokeratin (CK), epithelial membrane antigen (EMA) and CD30. The use of molecular techniques has proven useful in the diagnosis of this rare neoplasm. Targeted next generation sequencing showed aberrations in multiple genes including NRAS, KRAS, MYC and TP53.

The potential of using artificial intelligence to improve skin cancer diagnoses in Hawai'i's multiethnic population.

Skin cancer remains the most commonly diagnosed cancer in the USA with more than 1 million new cases each year. Melanomas account for about 1% of all skin cancers and most skin cancer deaths. Multiethnic individuals whose skin is pigmented underestimate their risk for skin cancers and melanomas and may delay seeking a diagnosis. The use of artificial intelligence may help improve the diagnostic precision of dermatologists/physicians to identify malignant lesions. To validate our artificial intelligence's efficiency in distinguishing between images, we utilized 50 images obtained from our International Skin Imaging Collaboration dataset (n = 25) and pathologically confirmed lesions (n = 25). We compared the ability of our artificial intelligence to visually diagnose these 50 skin cancer lesions with a panel of three dermatologists. The artificial intelligence model better differentiated between melanoma vs. nonmelanoma with an area under the curve of 0.948. The three-panel member dermatologists correctly diagnosed a similar number of images (n = 35) as the artificial intelligence program (n = 34). Fleiss' kappa (ĸ) score for the raters and artificial intelligence indicated fair (0.247) agreement. However, the combined result of the dermatologists panel with the artificial intelligence assessments correctly identified 100% of the images from the test data set. Our artificial intelligence platform was able to utilize visual images to discriminate melanoma from nonmelanoma, using de-identified images. The combined results of the artificial intelligence with those of the dermatologists support the use of artificial intelligence as an efficient lesion assessment strategy to reduce time and expense in diagnoses to reduce delays in treatment.

Evolutionary history of Mycobacterium leprae in the Pacific Islands.

As one of the oldest known human diseases, leprosy or Hansen's disease remains a public health concern around the world with over 200 000 new cases in 2018. Most human leprosy cases are caused by Mycobacterium leprae, but a small number of cases are now known to be caused by Mycobacterium lepromatosis, a sister taxon of M. leprae. The global pattern of genomic variation in M. leprae is not well defined. Particularly, in the Pacific Islands, the origins of leprosy are disputed. Historically, it has been argued that leprosy arrived on the islands during nineteenth century colonialism, but some oral traditions and palaeopathological evidence suggest an older introduction. To address this, as well as investigate patterns of pathogen exchange across the Pacific Islands, we extracted DNA from 39 formalin-fixed paraffin-embedded biopsy blocks dating to 1992-2016. Using whole-genome enrichment and next-generation sequencing, we produced nine M. leprae genomes dating to 1998-2015 and ranging from 4-63× depth of coverage. Phylogenetic analyses indicate that these strains belong to basal lineages within the M. leprae phylogeny, specifically falling in branches 0 and 5. The phylogeographical patterning and evolutionary dating analysis of these strains support a pre-modern introduction of M. leprae into the Pacific Islands. This article is part of the theme issue 'Insights into health and disease from ancient biomolecules'.

Adapting a Skin Cancer Prevention Intervention for Multiethnic Adolescents.

OBJECTIVE: We tested the effectiveness of a school-based skin cancer prevention intervention entitled "SunSafe in the Middle School Years" adapted for multiethnic high school students. METHODS: In Hawai'i, 208 10th graders (51.6% Asian, 30.4% Native Hawaiian/Pacific Islander, 8.4% white, 3.5% Hispanic, 2.7% black) participated. Changes in sun protection knowledge, attitudes, and self-reported behaviors were measured using a standardized 18-item survey. The Systematic Observation of Sun Protection Factors (SOSPF) instrument assessed aggregate sun protection behaviors. RESULTS: At posttest, improvements were found in 13 of 18 survey items (p < .05), and retained in 10 items at 12-months following baseline assessments; sun-protection attitudes and intended tanning behavior did not show improvement. Six observers using SOSPF reliably measured students' sun protection behaviors at school including use of hats, sunglasses, long sleeves, lower body coverage, and shade (ICC > .77). CONCLUSIONS: We uncovered a lack of knowledge about UVR exposure, tanning, and lifetime skin cancer risk among multiethnic high school students. We found that students' tanning attitudes may be influenced by self-perceptions regarding their own complexion, but were willing to modify their sun protection behaviors once informed about skin cancer risk.

Cyclin D1 and p16 Expression in Blue Nevi and Malignant Melanoma.

BACKGROUND: Differentiating benign blue nevi from blue nevus-like melanoma can be diagnostically challenging. We aimed to determine the utility of immunohistochemical staining for p16 and cyclin D1 in distinguishing benign blue nevi and malignant melanoma. MATERIALS AND METHODS: Thirty-two biopsy specimens taken between 2007 and 2015 were obtained from the Department of Pathology at the Queen's Medical Center in Honolulu, HI. These included 9 common blue nevi, 8 cellular blue nevi (2 with atypical features), and 15 malignant melanomas (3 blue nevus-like melanoma). The primary outcome was the difference in p16 and cyclin D1 staining between benign blue nevi and malignant melanoma. Staining of specimens for p16 and cyclin D1 was graded on the strength of staining, and the percent of tumor that stained positive. A specimen was deemed positive if it showed 2+ staining in ≥50% of the tumor. RESULTS: The majority (82%) of blue nevi stained negative for p16. There was not a significant difference between p16 staining in benign blue nevi and melanoma (P=0.06). Eleven (73%) melanomas stained positive for cyclin D1 with a sensitivity of 0.73 and positive predictive value of 1.0. All blue nevi were negative for cyclin D1, making its specificity 1.0 and its negative predictive value 0.8. This difference in cyclin D1 staining in blue nevi and melanoma was significant (P=0.0001). CONCLUSIONS: Cyclin D1 may be useful in differentiating benign blue nevi from melanoma.

Comprehensive care programme for patients with chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: There have been no randomised controlled trials that specifically evaluate the effect of a comprehensive programme with multidisciplinary input on patients who have just been discharged from hospital after treatment of acute exacerbation of COPD (AECOPD). The aim of this study was to assess whether a comprehensive care programme would decrease hospital readmissions and length of hospital stay (LOS) for patients with COPD. METHODS: Patients discharged from hospital after an episode of AECOPD were randomised to an intervention group (IG) or usual care group (UG). The IG received a comprehensive, individualised care plan which included education from a respiratory nurse, physiotherapist support for pulmonary rehabilitation, 3-monthly telephone calls by a respiratory nurse over 1 year, and follow-up at a respiratory clinic with a respiratory specialist once every 3 months for 1 year. The UG were managed according to standard practice. The primary outcome was hospital readmission rate at 12 months. RESULTS: 180 patients were recruited (IG, N=90; UG, N=90; mean±SD age 74.7±8.2 years, 172 (95.6%) men; mean±SD FEV1 45.4±16.6% predicted). At 12 months, the adjusted relative risk of readmission was 0.668 (95% CI 0.449 to 0.995, p=0.047) for the IG compared with the UG. At 12 months, the IG had a shorter LOS (4.59±7.16 vs 8.86±10.24 days, p≤0.001), greater improvement in mean Modified Medical Research Council Dyspnoea Scale (-0.1±0.6 vs 0.2±0.6, p=0.003) and St George's Respiratory Questionnaire score (-6.9±15.3 vs -0.1±13.8, p=0.003) compared with the UG. CONCLUSIONS: A comprehensive COPD programme can reduce hospital readmissions for COPD and LOS, in addition to improving symptoms and quality of life of the patients. TRIAL REGISTRATION NUMBER: NCT 01108835, Results.

Agreement of Different Methods for Tissue Based Detection of HER2 Signal in Invasive Breast Cancer.

Breast cancer is the second leading cause of cancer mortality amongst American women. The HER2 gene encodes a cell surface receptor that affects cell proliferation and has been recognized as a diagnostic factor in treatment selection for invasive breast cancer. Examine accuracy in HER2 detection between manual count, computer assisted, and automated tiling algorithm. 42 randomly selected invasive breast cancer specimens were enumerated by fluorescence in situ hybridization (FISH)for HER2 and CEP17 markers using the Vysis HER2 assay (AbbotLaboratory, North Chicago, IL). Specimens were tested using three methods: Manual, computer assisted nuclei selection (Tissue FISH MetaSystems, Newton, MA), and automated enumeration (MetaSystems, Newton, MA). The greatest bias and widest agreement limits for HER2 and CEP17 were seen in Automatic versus Manual, the gold standard. HER2 values greater than 6 possessed the greatest bias and widest agreement limits. CEP17 comparison showed similar bias and agreement limits for each comparison. Kappa values indicated good agreement for all methods although Tissue FISH and Manual possessed better agreement. Higher agreement at lower HER2 & CEP17 count maybe due to fewer chromosomal aberrations, in which selection of field of views has less variation between methods. Alternatively, increased background signals seen in polyploidy may be responsible for the variations in signal count. Manual and Tissue FISH demonstrated good agreement amongst by both Altman Bland and Cohen's Kappa. While the automatic method has good agreement at lower HER2, the sharp increase in variability at higher HER2 counts illustrates a limitation of the automatic method.

Frailty Screening in the Community Using the FRAIL Scale.

OBJECTIVES: To explore the feasibility of using the FRAIL scale in community screening of older Chinese people aged 65 years and older, followed by clinical validation by comprehensive geriatric assessment of those classified as pre-frail or frail. DESIGN: Two-phase study: screening of people aged 65 years and older by trained volunteers, followed by comprehensive geriatric assessment by multidisciplinary staff for those classified as pre-frail or frail. SETTING: Elderly Centers in the New Territories East Region of Hong Kong SAR China. PARTICIPANTS: A total of 816 members of elderly centers attending by themselves or accompanied by relatives. MEASUREMENTS: For phase 1, questionnaire (including demographic, lifestyle, chronic diseases) and screening tools were administered by trained volunteers. These consist of the FRAIL scale, SARC-F to screen for sarcopenia, and mild cognitive impairment using the abbreviated screening for mild cognitive impairment (Abbreviated Memory Inventory for the Chinese). Blood pressure, body mass index, and grip strength were recorded. For phase 2, comprehensive geriatric assessment include questionnaires assessing lifestyle domain (physical activity, nutritional status using the Mini-Nutritional Assessment-Short Form), the physical domain (number of diseases and number of drugs, activities of daily living and instrumental activities of daily living disabilities, geriatric syndromes, self-rated health, sleep quality), cognitive and psychological domain (Mini-Mental State Examination, Geriatric Depression Scale), and social domain (income, housing, living satisfaction, family support). RESULTS: The prevalence of pre-frailty and frailty were 52.4% and 12.5%, respectively. The prevalence for frailty increasing with age from 5.1% for those aged 65-69 years to 16.8% for those ≥75, being greater in women compared with men (13.9% vs 4.2%). Of those who were pre-frail or frail (n = 529), 42.5% had sarcopenia and 60.7% had mild cognitive impairment. Among those who were frail (n = 102), sarcopenia and mild cognitive impairment were also frequently present: 12.8% had sarcopenia, 14.7% had mild cognitive impairment, 63.7% had both sarcopenia and mild cognitive impairment, and only 8.8% had neither. In phase 2, participants who were classified as pre-frail or frail (n = 529) were invited for further interviews; 255 participants (48.2%) returned. Compared with the pre-frail group, those in the frail group were less physically active, had higher number of chronic diseases, were taking more medications (more were taking sleeping pills), reported more falls, rated their health as poor, had higher prevalence of depressive symptoms and mild cognitive impairment, had higher prevalence of sarcopenia, and a high number of activities of daily living and instrumental activities of daily living disabilities. CONCLUSION: The FRAIL scale may be used as the first step in a step care approach to detecting frailty in the community, allowing targeted intervention to potentially retard decline and future disability.

Recurrent papillary thyroid carcinoma with pleural metastasis diagnosed by effusion cytology: a report of cases with clinicopathologic correlation.

Papillary thyroid carcinoma (PTC) is typically an indolent disease characterized by slow growth and a favorable prognosis. In rare instances, this disease may metastasize to the pleura and manifest as a malignant pleural effusion. We report 3 female patients of Japanese/Okinawan ancestry with a history of PTC who presented with hydrothorax. Cytologic examination in conjunction with immunohistochemical staining enabled a definitive diagnosis of metastatic PTC. Molecular analysis of the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways demonstrated the presence of the v-raf murine sarcoma viral oncogene homolog B (BRAF)(V600E) mutation in 2 of our 3 patients, with the absence of any other clinically significant mutations in all cases. Further investigation is necessary to elucidate the molecular and environmental mechanisms involved in this aggressive manifestation of PTC.

Metastatic lung adenocarcinoma to the kidney diagnosed by urine cytology: a case report.

BACKGROUND: Although lung cancer is the solid tumor which most frequently metastasizes to the kidney, metastatic pulmonary adenocarcinoma detected by urine cytology examination is exceedingly rare. CASE: A 52-year-old woman presented with gross hematuria. Urine cytology revealed numerous crowded, overlapped 3-dimensional clusters with occasional papillary and luminal formations. The tumor nuclei were uniformly enlarged with smooth oval contours, regular nuclear membranes, finely granular chromatin, and prominent nucleoli. Numerous clear, intracytoplasmic vacuoles were noted. Urine fluorescence in situ hybridization (FISH) examination was abnormal. Positive immunohistochemical thyroglobulin transcription factor-1 and Napsin-A staining of a renal calyx biopsy confirmed the diagnosis of metastatic lung cancer. CONCLUSION: Although rare, metastatic lung adenocarcinoma in urine has characteristic cytomorphologic findings which appear distinct from the more commonly encountered urothelial carcinoma. Differentiation from other metastatic malignancies may be more problematic and will likely require immunohistochemical confirmation. Metastatic lung cancer may also cause abnormal urine FISH results and thus may be misdiagnosed as urothelial cancer. Therefore, this ancillary testing modality must be employed with caution in the setting of metastatic disease.

A cutaneous interstitial granulomatous dermatitis-like eruption arising in myelodysplasia with leukemic progression.

Cutaneous manifestations associated with myelodysplastic syndromes (MDS) are uncommon and can occur as specific or nonspecific lesions. Recognizing these cutaneous manifestations is important as they can precede blood or bone marrow transformation to leukemia. Granulomatous reactions have rarely been described as nonspecific lesions of MDS. These rare cases histologically resembled granuloma annulare, sarcoid, and a generalized dermal interstitial granulomatous dermatitis (IGD) which were not associated with leukemic infiltration. The authors report an interesting case of an IGD-like eruption evolving over the course of MDS with eventual progression to systemic leukemia. IGD is an inflammatory reaction that refers to a varied spectrum of histologic patterns and is associated with a variety of systemic illnesses and hypersensitivity reactions, including lymphoma and leukemia. In patients with MDS, surveillance for leukemia is a critical component of their follow-up care. Normally, this surveillance occurs through serial peripheral blood smears and bone marrow studies. IGD-like eruptions are a cutaneous reaction pattern that may serve as an additional clinical indicator of leukemic progression in patients with MDS. Although primarily a reactive pattern, this entity can rarely harbor leukemic blasts.

BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs.

BACKGROUND: BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21. Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms. To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma. METHODS: Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations. We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson χ2 test or two-tailed Fisher's exact test). RESULTS: Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call "melanocytic BAP1-mutated atypical intradermal tumors" (MBAITs). Meta-analysis: 118 individuals from seven unrelated families were selected and divided into a BAP1-mutated cohort and a BAP1-non-mutated cohort. Malignant mesothelioma, uveal melanoma, cutaneous melanoma, and MBAITs prevalence was significantly higher in the BAP1-mutated cohort (p ≤ 0.001). CONCLUSIONS: Germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers. MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers.

Opportunities for reversible inhibitors of monoamine oxidase-A (RIMAs) in the treatment of depression.

Treatment-resistant depression (TRD) may be implicated in 33­57% of depression cases. The currently available effective treatments include electroconvulsive therapy (ECT) or augmentation of serotonin selective reuptake inhibitors (SSRIs) with antipsychotics. ECT and antipsychotics are both associated with safety and tolerability concerns. Depression is hypothesized to result from a dysregulation of monoamine neurotransmitters, although the source of the dysregulation has been unclear. However, recent studies have revealed that an enzyme that degrades the neurotransmitters, known as monamine oxidase-A (MAO-A), may be overactive in patients with depression. Thus, treatments for depression that modulate MAO-A could act upstream relative to current antidepressant treatments. Monoamine oxidase inhibitors (MAOIs) can be highly effective therapeutic agents for depression and some anxiety disorders. Some evidence suggests that MAOIs may act by reversing excessive neurotransmitter depletion within the neuron and the synapse. MAOIs tend to be underutilized in clinical practice, due in part to misinformation and mythology about their dietary and drug interactions. The new class of reversible monoamine oxidase inhibitors (RIMAs) has shown efficacy in depression, with safety and tolerability comparable to SSRIs. This article discusses recent progress in RIMAs toward the treatment of TRD. Dietary and drug interactions of MAOIs will be covered, as well as guidelines for integrating these agents into clinical practice.

Field histology: Point-of-care microscopic technique.

CONTEXT: Standard histology services in geographically remote areas are often not available or have long turn-around time, resulting in delayed diagnosis or inappropriate treatment due to incomplete diagnostic data. The use of rapid tissue processing and a portable microtome technique may offer timely, point-of-care histologic diagnosis to patients in a low resources setting, such as medical missions. OBJECTIVE: To present an alternative to the conventional histologic processing that will permit point-of-care histopathology service. DESIGN: A total of 21 tissue samples from a variety of sites were collected and subjected to a protocol of rapid manual tissue processing, lightweight portable field microtome sectioning, and hematoxylin-eosin staining. The histologic preparations were evaluated for diagnostic quality. The scoring of the preparations was based on completeness and uniformity of the sections, integrity of architectural features, cytologic detail, staining quality, and overall adequacy for diagnosis. RESULTS: Diagnostic quality microscopic slides were obtained from each of the 21 samples that included lesions of the skin, uterus, colon, and breast. The average preparation time, including routine hematoxylin-eosin staining, was 1.5 hours. CONCLUSIONS: We validated a point-of-care field histology technique that will be useful in settings of low resources, such as medical missions. Actual field testing of the procedure with special staining for fungi and acid-fast bacilli is the next step in the validation of the methodology.

Immunohistochemical expression of cyclooxygenage-2 in melanocytic skin lesions.

BACKGROUND: Several reports have shown expression of cyclooxygenase-2 (COX-2) in malignant skin tumors. COX-2 has also recently been reported as a marker of malignant melanoma (MM). OBJECTIVE: Our aim was to investigate whether there is a difference in the immunohistochemical expression of COX-2 between malignant and benign melanocytic lesions of the skin. METHODS: We selected 40 archival cases of MM including 10 cases of superficial spreading melanoma, 10 of lentigo maligna melanoma, 10 of nodular melanoma, and 10 of acral lentiginous melanoma. For comparison, we also selected 35 benign melanocytic lesions, which included 15 nonatypical nevi and 10 atypical nevi. The remaining 10 cases were Spitz nevi. COX-2 immunohistochemical staining was performed, and intensities were assessed quantitatively. RESULTS: The MM group and the benign melanocytic nevi group showed a highly statistically significant difference in the intensity of COX-2 expression (P < 0.0001). Staining intensity in the dermal component of MM cases also showed a tendency to increase with increasing tumor depth. By contrast, the intensity of the dermal component in the melanocytic nevi group decreased with increasing depth as the nevus cells matured from type A to type C cells. No statistical difference was noted between the MM and Spitz nevi cases (P = 0.20). CONCLUSIONS: Malignant melanoma shows stronger immunohistochemical expression of COX-2 than benign melanocytic nevi. Although COX-2 cannot be used alone to differentiate MM from melanocytic nevi, it may serve as an aid in the differential diagnosis of melanocytic skin lesions.

The association of dermatitis herpetiformis and systemic lupus erythematosus.

Dermatitis herpetiformis (DH) is an immune-mediated cutaneous disease occasionally associated with celiac disease, but rarely associated with systemic lupus erythematosus (SLE). The combination of DH and SLE is immunologically mediated and suggests a relationship between the two conditions. We describe a woman with DH and SLE with a novel HLA phenotype.

Optimization of alpha-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site.

We have optimized a novel series of potent p38 MAP kinase inhibitors based on an alpha-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.

Primary cutaneous Richter syndrome: prognostic implications and review of the literature.

The term Richter syndrome (RS) describes the transformation of chronic lymphocytic leukemia into a high-grade lymphoma. RS occurs in 3% to 10% of chronic lymphocytic leukemia cases, and its onset is often characterized by the abrupt development of systemic symptoms (eg, fever in the absence of infection, night sweats, and weight loss), progressive lymphadenopathy, and hepatosplenomegaly. RS frequently arises in the lymph nodes or bone marrow, and rarely presents with extranodal involvement, which includes the gastrointestinal tract, eye, testis, central nervous system, lung, kidney, and skin. We review the literature regarding the clinical course and treatment of RS, present a patient with primary cutaneous RS, and discuss the prognostic implications.

2,5-Diaminopyrimidines and 3,5-disubstituted azapurines as inhibitors of glycogen synthase kinase-3 (GSK-3).

The discovery of two classes of pyrimidine-based inhibitors of GSK-3 is described. Optimization of these series led to inhibitors with IC(50)<10nM and >100-fold selectivity over Aurora A kinase. A proposed binding mode of 21b is presented. One compound (33) of the pyrimidine series showed promising pharmacokinetic parameters.

Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists.

A novel series of imidazopiperidine-tropane CCR5 antagonists is described. The series was optimized for anti-HIV-1 potency using a set of phenotypic viral entry assays. This strategy resulted in the identification of several very potent (IC(50)<10nM) inhibitors of HIV-1 entry. One compound (40) was further profiled and was found to have attractive selectivity, pharmacokinetic, and antiviral properties.