Virulent Burkholderia species mimic host actin polymerases to drive actin-based motility.

Burkholderia pseudomallei and B. mallei are bacterial pathogens that cause melioidosis and glanders, whereas their close relative B. thailandensis is non-pathogenic. All use the trimeric autotransporter BimA to facilitate actin-based motility, host cell fusion, and dissemination. Here, we show that BimA orthologs mimic different host actin-polymerizing proteins. B. thailandensis BimA activates the host Arp2/3 complex. In contrast, B. pseudomallei and B. mallei BimA mimic host Ena/VASP actin polymerases in their ability to nucleate, elongate, and bundle filaments by associating with barbed ends, as well as in their use of WH2 motifs and oligomerization for activity. Mechanistic differences among BimA orthologs resulted in distinct actin filament organization and motility parameters, which affected the efficiency of cell fusion during infection. Our results identify bacterial Ena/VASP mimics and reveal that pathogens imitate the full spectrum of host actin-polymerizing pathways, suggesting that mimicry of different polymerization mechanisms influences key parameters of infection.

Faster Crystallization during Coral Skeleton Formation Correlates with Resilience to Ocean Acidification.

The mature skeletons of hard corals, termed stony or scleractinian corals, are made of aragonite (CaCO3). During their formation, particles attaching to the skeleton's growing surface are calcium carbonate, transiently amorphous. Here we show that amorphous particles are observed frequently and reproducibly just outside the skeleton, where a calicoblastic cell layer envelops and deposits the forming skeleton. The observation of particles in these locations, therefore, is consistent with nucleation and growth of particles in intracellular vesicles. The observed extraskeletal particles range in size between 0.2 and 1.0 µm and contain more of the amorphous precursor phases than the skeleton surface or bulk, where they gradually crystallize to aragonite. This observation was repeated in three diverse genera of corals, Acropora sp., Stylophora pistillata─differently sensitive to ocean acidification (OA)─and Turbinaria peltata, demonstrating that intracellular particles are a major source of material during the additive manufacturing of coral skeletons. Thus, particles are formed away from seawater, in a presumed intracellular calcifying fluid (ICF) in closed vesicles and not, as previously assumed, in the extracellular calcifying fluid (ECF), which, unlike ICF, is partly open to seawater. After particle attachment, the growing skeleton surface remains exposed to ECF, and, remarkably, its crystallization rate varies significantly across genera. The skeleton surface layers containing amorphous pixels vary in thickness across genera: ∼2.1 µm in Acropora, 1.1 µm in Stylophora, and 0.9 µm in Turbinaria. Thus, the slow-crystallizing Acropora skeleton surface remains amorphous and soluble longer, including overnight, when the pH in the ECF drops. Increased skeleton surface solubility is consistent with Acropora's vulnerability to OA, whereas the Stylophora skeleton surface layer crystallizes faster, consistent with Stylophora's resilience to OA. Turbinaria, whose response to OA has not yet been tested, is expected to be even more resilient than Stylophora, based on the present data.

Local recurrence of cutaneous mixed tumor (chondroid syringoma) as malignant mixed tumor of the thumb 20 years after initial diagnosis.

Benign cutaneous mixed tumor (chondroid syringoma) is the cutaneous counterpart of the benign mixed tumor (pleomorphic adenoma) of salivary glands, consisting of both epithelial and mesenchymal elements. The incidence of cutaneous mixed tumor is rare, composing <0.01% of all primary skin tumors. Herein, we report a case of malignant mixed tumor which recurred in the right thumb 20 years after the reported initial diagnosis of a benign mixed tumor at this site. Histologically, the lesion consisted of highly atypical and infiltrative cells in cords and ductal structures, with an adjacent focus of residual benign mixed tumor present. Perineural invasion of multiple dermal and subcutaneous nerves was also seen. Immunohistochemical staining was strongly and diffusely positive for CK5/6 and p63, with patchy positive S100 and CK7 staining. Wide excision was performed, with no evidence of recurrence or metastasis 5 years later.

Clear cell atypical fibroxanthoma: a case report and review of the literature.

Atypical fibroxanthoma (AFX) is a group of cutaneous tumors characterized by a population of fusiform, epithelioid and pleomorphic cells. Clinically, AFX is commonly found on the head and neck of older adults as a solitary ulcerated nodule. Clear cell atypical fibroxanthoma is a very rare variant of AFX, with only 13 cases reported to date. The differential diagnoses often include dermal neoplasms composed of clear cells, such as squamous cell carcinoma, basal cell carcinoma, metastatic renal cell carcinoma and balloon cell malignant melanoma. These diagnoses can be ruled out by the typical immunohistochemical profile of clear cell AFX, which is negative for specific epithelial and melanocytic markers. Herein, we describe a rare and unusual case of clear cell AFX arising on the ear of a relatively young adult patient. Histologically, the dermis was completely replaced by an atypical population of vacuolated cells with numerous atypical mitoses. Immunohistochemical stains were negative forpancytokeratin, CK5/6, CK7, and p63 S100 and Melan-A stains. CD10 and CD68 stains were positive, making the findings consistent with the diagnosis of clear cell atypical fibroxanthoma.

Primary Cutaneous Interdigitating Dendritic Cell Sarcoma: A Case Report and Review of the Literature.

Interdigitating dendritic cell sarcoma (IDCS) is a rare tumor of spindle to ovoid cells intermixed with lymphocytes and plasma cells. Primary cutaneous IDCS, with no nodal or other organ involvement is extremely rare, with less than 10 cases reported to date. Herein, the authors describe a case in which a 61-year-old man presented with scattered subcutaneous nodules on his left shoulder and right anterior thigh. A biopsy was performed, and the histopathologic findings revealed prominent, diffuse superficial, and deep dermal infiltration by an atypical epithelioid-shaped tumor forming sheets and cords infiltrating throughout the dermis. Immunohistochemical stains were strongly and diffusely positive for S100, CD45, CD68, and lysozyme, whereas CD21, CD23, CD3, CD20, CD30, CD34, and CD117 were all negative. The histologic and immunohistochemical findings were consistent with an IDCS. A positron emission tomography scan was negative for metastases, leading to the diagnosis of primary cutaneous IDCS. The patient was started on chemotherapy with gemcitabine and docetaxel, and was stable at 4 months follow-up. Our findings contribute to the limited existing literature on primary cutaneous IDCS. This is the first documented case in which chemotherapy with gemcitabine and docetaxel was implemented for treatment, helping to establish an optimal treatment protocol for clinical remission.

Cutaneous PEComas Express CD10: Implications for the Classification of PEComas and the Differential Diagnosis With Metastatic Renal Cell Carcinoma.

Cutaneous perivascular epithelioid cell tumors (PEComas) are peculiar, rare mesenchymal tumors of uncertain lineage. They show a characteristic epithelioid morphology, and they are usually composed of monomorphous clear-to-granular appearing perivascular cells. One of the main differential diagnoses with PEComas is a cutaneous metastasis from renal cell carcinoma (RCC). CD10 has been emphasized to be a crucial marker in the diagnosis of metastasis from RCC. Although visceral PEComas have been studied for CD10 expression, primary cutaneous PEComas have not. Although it could be assumed a priori that cutaneous PEComas would stain as their visceral counterpart, there is increasing evidence that cutaneous PEComas could actually be unrelated to PEComas from other organs. In this report, the author's studied three primary cutaneous PEComas, and included CD10 in our immunohistochemical studies. All three PEComas expressed the marker. They conclude that a CD10 clear-cell dermal tumor is not necessarily equivalent to a metastasis from RCC and that additional stains should be added to rule out PEComa, even if the biopsy or the panel of antibodies is limited.

Improvement of Nail and Scalp Psoriasis Using Apremilast in Patients With Chronic Psoriasis: Phase 2b and 3, 52-Week Randomized, Placebo-Controlled Trial Results.

INTRODUCTION: A significant portion of patients with psoriasis have scalp and nail involvement. It has been reported that 40% to 45% of patients with psoriasis have nail psoriasis, and up to 80% have scalp involvement. Nail and scalp psoriasis have often been found to be difficult to treat, due to the poor penetration and poor compliance of topical medication. Oral and biologic therapies have shown significant efficacy but often with undesirable side effects. Herein, we analyze the efficacy of apremilast, an oral phosphodiesterase-4 (PDE-4) inhibitor, in the treatment of nail and scalp psoriasis at 16-, 32-, and 52 weeks. METHODS: We reviewed the results of the phase IIb and phase III clinical trials for apremilast in treating nail and scalp psoriasis. RESULTS: In ESTEEM 1, patients on apremilast showed a 22.5%, 43.6%, and 60.2% improvement in NAPSI at weeks 16, 32, and 52. 33.3%, 45.2%, and 63% of patients achieved NAPSI-50, respectively. In ESTEEM 2, patients on apremilast showed a 29%, 60%, and 59.7% improvement in NAPSI at weeks 16, 32, and 52, with 44.6%, 55.4%, and 68.6% of patients achieving NAPSI-50. In PSOR-005 at week 16, patients on a dose of 30 mg twice weekly had a 42.9% improvement in NAPSI with 45.5% reaching NAPSI-50. For scalp psoriasis, 46.5%, 37.4%, and 73% of patients achieved an Sc-PGA of 0 or 1 at weeks 16, 32, and 52 in ESTEEM 1. In ESTEEM 2, 40.9%, 32.4%, and 62.5% of patients achieved an Sc-PGA of 0 or 1 at weeks 16, 32, and 52. CONCLUSION: With its limited safety profile of only diarrhea and headache and no additional lab requirements, apremilast may be a safer and more convenient alternative for patients with severe nail and scalp psoriasis.

Psychodermatologic Effects of Atopic Dermatitis and Acne: A Review on Self-Esteem and Identity.

Atopic dermatitis (AD) and acne vulgaris are among the most-prevalent skin diseases in children. Both have been well documented in the literature to have significant negative effects on quality of life. Herein, we discuss the results of a comprehensive literature review aimed at assessing the impact of acne and AD on self-esteem and identity. We highlight clinical tools for their assessment and offer coping strategies for patients and families. Multiple factors including relationships with parents and classmates, sports participation, and the sex of the patient contribute to the development of self-esteem and identity in individuals with AD and acne. Atopic dermatitis was found to have significant behavioral effects on children, ultimately resulting in a lack of opportunity to develop proper coping. AD had a more-prominent role in identity formation and gender roles in girls. Acne vulgaris was found to have a more direct effect on self-esteem, self-confidence and identity, especially in girls. The Cutaneous Body Image Scale is reviewed and offered as an easy and reliable tool to evaluate a patient's mental perception of the appearance of their skin. Coping strategies that may be offered to patients and families include empowerment and cognitive adaptation.

Folliculosebaceous Cystic Hamartoma With Spindle Cell Lipoma-Like Stromal Features.

Folliculosebaceous cystic hamartoma is a distinctive cutaneous hamartoma composed of follicular, sebaceous, and mesenchymal components. The lesions are most commonly found on the face and scalp of young adults, with approximately 30% occurring in the nasal or paranasal regions of the face. The clinical differential diagnoses are extensive and include epidermoid cyst, dermal nevus, soft fibroma, and adnexal tumors including sebaceous neoplasms. Here, the authors present a case of a 24-year-old man who presented for evaluation of an asymptomatic growth on the nose, which had slowly enlarged over 9 years. On examination, there was a 0.6 cm dome-shaped flesh-colored papule on the nasal bridge. The clinical differential included dermatofibroma versus intradermal nevus. A shave biopsy was performed, and histological examination of the sections showed a proliferation of multiple enlarged and irregular-appearing sebaceous glands attached to a cystic follicular structure. The associated dermal mesenchymal component consisted of numerous mature-appearing adipocytes associated with a fibromyxoid stroma, prominent collections of mucin, and bundles of ropey collagen resembling a spindle cell lipoma. This combination of a folliculosebaceous cystic hamartoma with a spindle cell lipoma-like mesenchymal proliferation is unusual and has not been previously reported.

Blastic Plasmacytoid Dendritic Cell Neoplasm in the Pediatric Population: A Case Series and Review of the Literature.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive hematologic malignancy primarily found in adults, often carrying a poor prognosis. There are only 33 reported pediatric cases of BPDCN in the literature. Although standard treatment is not yet established for children, current literature recommends the use of high-risk acute lymphoblastic leukemia (ALL)-type chemotherapy. Recent studies, however, have explored the benefits of combining chemotherapy with stem-cell transplantation. Here, the authors present 2 cases of pediatric BPDCN treated with different modalities. The first case is a 13-year-old girl who presented with a 3-month history of an initially asymptomatic firm nodule on her left shin. The second case is a 15-year-old boy who presented with a 4-month history of an enlarging subcutaneous nodule on the lower leg. Immunohistochemical staining of both patients was positive for markers consistent with BPDCN. The latter patient received ALL-type therapy alone, whereas the former received ALL-type chemotherapy and stem-cell transplantation. Since initial treatment, both patients remain disease-free. These cases contribute to the limited number of pediatric BPDCN cases, thus helping to advance our knowledge toward an optimal treatment protocol for clinical remission.

Emerging systemic therapies for atopic dermatitis: oral small molecules and targeted topical agents.

BACKGROUND: Until recently, treatment of atopic dermatitis has been limited to topical corticosteroids, calcineurin inhibitors, phototherapy, and systemic immunomodulatory agents. With improved understanding of the pathogenesis underlying atopic dermatitis, targeted oral small molecules and topical agents are being developed. OBJECTIVE: Discuss efficacy and safety profiles of emerging oral small molecules and targeted topical agents in phase 2 and 3 clinical trials. METHODS: A systemic literature review was conducted to identify results of randomized, placebo-controlled trials of oral small molecules and topical Janus kinase inhibitors up to March 1 2020 for the treatment of atopic dermatitis. RESULTS: Three novel oral small molecules, abrocitinib, upadacitinib, and baricitinib, demonstrated improvement of clinical severity, pruritus, and quality of life with acceptable safety profiles. Apremilast, a phosphodiesterase inhibitor, was less efficacious with use limited by adverse effects. Two novel topical agents, ruxolitinib and delgocitinib, were effective and well-tolerated. CONCLUSIONS: Targeted therapeutics including oral small molecules and topical agents show promise for the treatment of atopic dermatitis. The use of validated core measures is necessary for future trials in order to adequately compare agents and progress evidence-based medicine.

Emerging systemic therapies for atopic dermatitis: biologics.

BACKGROUND: The mainstay of atopic dermatitis treatment has been largely unchanged over the last few decades. With improved understanding of the immunologic pathways underlying atopic dermatitis in recent years, targeted biologic therapies are being developed. OBJECTIVE: Discuss efficacy and safety profiles of emerging biologics in phase 2 and 3 clinical trials. METHODS: A systemic literature review was conducted to identify results of randomized, placebo-controlled trials of monoclonal antibodies up to March 1, 2020 for the treatment of atopic dermatitis. RESULTS: Targeted biologics appear to have acceptable safety profiles. Dupilumab, lebrikizumab, and nemolizumab demonstrate efficacy as agents producing improvement in clinical severity and pruritus. CONCLUSIONS: The growing class of biologics shows promise in meeting the needs of treatment-resistant atopic dermatitis. The use of validated core measurements is necessary for future trials in order to adequately compare agents and progress evidence-based medicine.

Small Molecule Potentiation of Gram-Positive Selective Antibiotics against Acinetobacter baumannii.

In 2016, the World Health Organization deemed antibiotic resistance one of the biggest threats to global health, food security, and development. The need for new methods to combat infections caused by antibiotic resistant pathogens will require a variety of approaches to identifying effective new therapeutic strategies. One approach is the identification of small molecule adjuvants that potentiate the activity of antibiotics of demonstrated utility, whose efficacy is abated by resistance, both acquired and intrinsic. To this end, we have identified compounds that enhance the efficacy of antibiotics normally ineffective against Gram-negative pathogens because of the outer membrane permeability barrier. We identified two adjuvant compounds that dramatically enhance sensitivity of Acinetobacter baumannii to macrolide and glycopeptide antibiotics, with reductions in minimum inhibitory concentrations as high as 256-fold, and we observed activity across a variety of clinical isolates. Mode of action studies indicate that these adjuvants likely work by modulating lipopolysaccharide synthesis or assembly. The adjuvants were active in vivo in a Galleria mellonella infection model, indicating potential for use in mammalian infections.

Analogue synthesis reveals decoupling of antibiofilm and ß-lactam potentiation activities of a lead 2-aminoimidazole adjuvant against Mycobacterium smegmatis.

Biofilm formation is one of the many mechanisms bacteria utilize to survive antibiotic treatment. It has been demonstrated that when Mycobacterium tuberculosis exists in a biofilm in vitro, it expresses phenotypic resistance to antimicrobial drugs. As the in vivo survival of M. tuberculosis following drug treatment is potentially linked to a biofilm-like expression of drug tolerance, it is hypothesized that biofilm dispersion should increase antibiotic susceptibility and reduce the duration of the current antibiotic treatment regimen. Previously, we have identified a 2-aminoimidazole (2-AI) compound capable of dispersing and inhibiting M. tuberculosis and M. smegmatis biofilms in vitro. Additionally, this compound potentiated the activity of carbenicillin against M. tuberculosis and, to a lesser degree, M. smegmatis. Here, we describe a SAR study on this compound evaluating each derivative for biofilm dispersion and ß-lactam potentiation capabilities against M. smegmatis. This study identified a compound that improved upon the biofilm dispersion capabilities of the lead compound. Interestingly, a different compound was identified with an increased ability to potentiate a subset of ß-lactam antibiotics. These compounds indicate that biofilm dispersion and potentiation capabilities may not be associated.

An open label pilot study of supraerythemogenic excimer laser in combination with clobetasol spray and calcitriol ointment for the treatment of generalized plaque psoriasis.

A common therapeutic modality for psoriasis includes the combination of phototherapy with topical treatments. The recent development of targeted phototherapy with the excimer laser and spray formulations for topical treatments has increased the efficacy and convenience of these combinational therapies. Herein, we aim to assess the efficacy of a novel combination of therapies using the 308 nm excimer laser, clobetasol propionate spray and calcitriol ointment for the treatment of moderate to severe generalized psoriasis. In this 12-week study, patients with moderate to severe psoriasis received twice weekly treatments with a 308-nm excimer laser combined with clobetasol proprionate twice daily for a month followed by calcitriol ointment twice daily for the next month. Of the 30 patients enrolled, 83% of patients (25/30) achieved PASI-75 [65-94%, 95% confidence interval (CI)] at week 12. For PGA, there was an estimated decrease of 3.6 points (3.1-4.1, 95% CI, p < 0.0005) by week 12. In conclusion, the combination of excimer laser with alternating clobetasol and calcitriol application has shown to be a promising combination of therapies for the treatment of moderate to severe generalized psoriasis. Further evaluation may be conducted with a larger study inclusive of control groups and head-to-head comparisons against topical steroid and UVB therapy as monotherapies.

The psychosocial impact of acne, vitiligo, and psoriasis: a review.

INTRODUCTION: Chronic skin conditions have been well reported to affect a patient's quality of life on multiple dimensions, including the psychosocial domain. Psychosocial is defined as the interrelation of social factors with an individual's thoughts and behavior. The assessment of the psychosocial impact of skin disease on a patient can help direct the dermatologists' treatment goals. To evaluate the psychosocial impact of skin disease, we conducted a review of the literature on three skin conditions with onsets at various stages of life: acne, vitiligo, and psoriasis. METHODS: A PubMed search was conducted in March 2015 using the terms "psychosocial" AND "acne", "psychosocial" AND "vitiligo", and "psychosocial" AND "psoriasis". The results were limited to articles published in English in the past 5 years studying patients of all ages. Results and their references were evaluated for relevance according to their discussion of psychosocial qualities in their patients and the validity of psychosocial assessments. The search for acne yielded 51 results, and eleven were found to be relevant; vitiligo yielded 30 results with ten found to be relevant; and psoriasis yielded 70 results with seven found to be relevant. RESULTS: According to the articles evaluated, 19.2% of adolescent patients with acne were affected in their personal and social lives. Social phobia was present in 45% of patients with acne compared to 18% of control subjects. Race and sex played a role in self-consciousness and social perceptions of the disease. Vitiligo negatively affected marriage potential and caused relationship problems in >50% of patients. Psoriasis negatively affected multiple domains of life, including work, relationships, and social activities. Anxiety and depression affected not only psoriasis patients but also their cohabitants; up to 88% of cohabitants had an impaired quality of life. CONCLUSION: Though all three skin conditions resulted in an increase in anxiety and depression among their patient populations, the psychosocial focus varied slightly for each disease. Overall, acne, vitiligo, and psoriasis can have negative psychosocial impact in different stages of life development.

Genomic imprinting in psoriasis and atopic dermatitis: A review.

Genomic imprinting is a genetic process where only one allele of a particular gene is expressed in a parent-of-origin dependent manner. Epigenetic changes in the DNA, such as methylation or acetylation of histones, are primarily thought to be responsible for silencing of the imprinted allele. Recently, global CpG methylation changes have been identified in psoriatic skin in comparison to normal skin, particularly near genes known to be upregulated in psoriasis such as KYNU, OAS2, and SERPINB3. Furthermore, imprinting has been associated with multi-chromosomal human disease, including diabetes and multiple sclerosis. This paper is the first to review the clinical and genetic evidence that exists in the literature for the association between imprinting and general skin disorders, including atopic dermatitis and psoriatic disease. Atopy was found to have evidence of imprinting on chromosomes 6, 11, 14, and 13. The ß subunit of the IgE receptor on chromosome 11q12-13 may be imprinted. Psoriatic disease may be related to imprinting effects on chromosome 6 for psoriasis and 16 for psoriatic arthritis.

Loss of the p53/p63 target PERP is an early event in oral carcinogenesis and correlates with higher rate of local relapse.

BACKGROUND: PERP is a p53/p63-regulated gene encoding a desmosomal protein that plays a critical role in cell-cell adhesion and tumor suppression. STUDY DESIGN: We evaluated PERP expression in different grades of oral dysplasia (34 cases) and at different stages of invasive squamous cell carcinoma (SCC), and correlated the latter with clinical outcome. A tissue microarray consisting of nondysplastic mucosa, carcinoma in situ, SCC, and nodal metastases from 33 patients with human papilloma virus-negative SCC was stained for PERP and E-cadherin. RESULTS: Complete loss of PERP expression was associated with worse local control in patients with SCC. The 5-year local control rate was 91% for patients with partial PERP loss versus 31% for those with complete loss (P = .01). CONCLUSIONS: This is the first study to show that loss of PERP expression correlates with the transition to SCC and with increased local relapse in patients with oral cavity SCC.