Stromal cell-derived factor-1 (CXCL12) activates integrins by direct binding to an allosteric ligand-binding site (site 2) of integrins without CXCR4.

Leukocyte arrest on the endothelial cell surface during leukocyte extravasation is induced by rapid integrin activation by chemokines. We recently reported that fractalkine induces integrin activation without its receptor CX3CR1 through binding to the allosteric site (site 2) of integrins. Peptides from site 2 bound to fractalkine and suppressed integrin activation by fractalkine. We hypothesized that this is not limited to membrane-bound fractalkine. We studied whether stromal cell-derived factor-1 (SDF1), another chemokine that plays a critical role in leukocyte arrest, activates integrins through binding to site 2. We describe here that (1) SDF1 activated soluble integrin αvß3 in cell-free conditions, suggesting that SDF1 can activate αvß3 without CXCR4; (2) site 2 peptide bound to SDF1, suggesting that SDF1 binds to site 2; (3) SDF1 activated integrins αvß3, α4ß1, and α5ß1 on CHO cells (CXCR4-negative) and site 2 peptide suppressed the activation; (4) A CXCR4 antagonist AMD3100 did not affect the site 2-mediated integrin activation by SDF1; (5) Cell-surface integrins were fully activated in 1 min (much faster than activation of soluble αvß3) and the activation lasted at least for 1 h. We propose that the binding of SDF1 to cell-surface proteoglycan facilitates the allosteric activation process; (6) Mutations in the predicted site 2-binding site in SDF1 suppressed integrin activation. These results suggest that SDF1 (e.g. presented on proteoglycans) can rapidly activate integrins in an allosteric manner by binding to site 2 in the absence of CXCR4. The allosteric integrin activation by SDF1 is a novel target for drug discovery.

The residency interview is still paramount: results of a retrospective cohort study on concordance of dermatology residency applicant evaluators and influence of the applicant interview.

Application to dermatology residency is a highly competitive process. Although factors associated with successfully matching have been studied, less is known regarding the ability of admissions committees to screen applicants in a uniform manner or the importance of the interview in ranking applicants. Our goal was to retrospectively measure our admission committee evaluators' concordance regarding residency application credentials and interview performance, and ultimately the effects on final applicant ranking.

Dermatology Medical Education: A Multicenter Survey Study of the Undergraduate Perspective of the Dermatology Clinical Clerkship.

BACKGROUND/AIMS: Limited data are available regarding the undergraduate dermatology clinical clerkship curriculum in the United States. Our primaryaim is to assess medical students' perspectives of the dermatology clinical clerkship. METHODS: A multicenter survey study was conducted, which included four California dermatology academic programs. A 17-item questionnaire was designed to investigate medical student perception with regard tothe overall educational value of the various teaching aspects of the dermatology clinical clerkship. RESULTS: A total of 152 medical student surveys were completed. Over half of the medical students felt proficient in diagnosing the most commondermatologic conditions. Eighty-seven percent of medical students were very satisfied with the dermatology clerkship. Ninety-one percent of students felt the length of the clerkship was appropriate. CONCLUSIONS: The vast majority of medical students reported a high level of proficiency in the treatment and diagnosis of common skin disorders. In contrast, our findings suggest that medical students may not begaining sufficient hands-on experience in conducting certain dermatologic procedures following the dermatology clerkship. Overall, medical studentperception of the dermatology clinical clerkship was mostly positive.

360-degree Evaluations on Physician Performance as an Effective Tool for Interprofessional Teams: A critical analysis of physician self-assessment as compared to nursing staff and patient evaluations of providers.

ImportanceThe dynamics of the medical care team, including interactions between physicians and nursing staff, has a large role to play in patient care, patient satisfaction, and future possible reimbursement determination. In order to implement changes to improve this dynamic within the medical team, it is imperative that appropriate assessments are completed to determine baseline satisfaction of our patients and nursing staff in addition to provider self-assessment.ObjectiveWe aimed to investigate patient and nursing staff satisfaction with regards to provider quality of care in an outpatient academic dermatology clinic setting. We also sought out to determine provider insight in regards to satisfaction of patient and nursing staff.MethodsOur nursing staff, patients, and providers completed a questionnaire. We then compared nursing satisfaction data and patient satisfaction data with provider self-assessment to determine provider self-awareness.ResultsA total of 23 provider and nurse surveys and 562 patient satisfaction surveys were completed. Paired comparison and descriptive statistics were utilized to compare patient satisfaction, nursing satisfaction, and provider self-assessments.ConclusionsOverall, the results of the surveys demonstrated that the nursing staff and patients had high satisfaction in their interactions with the dermatology physicians. The physicians had appropriate insight into how they were perceived by the nursing staff and patients. Attending physicians as compared to resident physicians and male physicians as compared to female physicians tended to underrate themselves.

Cutaneous and mucosal lichen planus: a comprehensive review of clinical subtypes, risk factors, diagnosis, and prognosis.

Lichen planus (LP) is a chronic inflammatory disorder that most often affects middle-aged adults. LP can involve the skin or mucous membranes including the oral, vulvovaginal, esophageal, laryngeal, and conjunctival mucosa. It has different variants based on the morphology of the lesions and the site of involvement. The literature suggests that certain presentations of the disease such as esophageal or ophthalmological involvement are underdiagnosed. The burden of the disease is higher in some variants including hypertrophic LP and erosive oral LP, which may have a more chronic pattern. LP can significantly affect the quality of life of patients as well. Drugs or contact allergens can cause lichenoid reactions as the main differential diagnosis of LP. LP is a T-cell mediated immunologic disease but the responsible antigen remains unidentified. In this paper, we review the history, epidemiology, and clinical subtypes of LP. We also review the histopathologic aspects of the disease, differential diagnoses, immunopathogenesis, and the clinical and genetic correlations.

Cross-talk between integrin α6ß4 and insulin-like growth factor-1 receptor (IGF1R) through direct α6ß4 binding to IGF1 and subsequent α6ß4-IGF1-IGF1R ternary complex formation in anchorage-independent conditions.

Integrin αvß3 plays a role in insulin-like growth factor-1 (IGF1) signaling (integrin-IGF1 receptor (IGF1R) cross-talk). The specifics of the cross-talk are, however, unclear. In a current model, "ligand occupancy" of αvß3 (i.e. the binding of extracellular matrix proteins) enhances signaling induced by IGF1 binding to IGF1R. We recently reported that IGF1 directly binds to αvß3 and induces αvß3-IGF1-IGF1R ternary complex formation. Consistently, the integrin binding-defective IGF1 mutant (R36E/R37E) is defective in inducing ternary complex formation and IGF signaling, but it still binds to IGF1R. Like αvß3, integrin α6ß4 is overexpressed in many cancers and is implicated in cancer progression. Here, we discovered that α6ß4 directly bound to IGF1, but not to R36E/R37E. Grafting the ß4 sequence WPNSDP (residues 167-172), which corresponds to the specificity loop of ß3, to integrin ß1 markedly enhanced IGF1 binding to ß1, suggesting that the WPNSDP sequence is involved in IGF1 recognition. WT IGF1 induced α6ß4-IGF1-IGF1R ternary complex formation, whereas R36E/R37E did not. When cells were attached to matrix, exogenous IGF1 or α6ß4 expression had little or no effect on intracellular signaling. When cell-matrix adhesion was reduced (in poly(2-hydroxyethyl methacrylate-coated plates), IGF1 induced intracellular signaling and enhanced cell survival in an α6ß4-dependent manner. Also IGF1 enhanced colony formation in soft agar in an α6ß4-dependent manner. These results suggest that IGF binding to α6ß4 plays a major role in IGF signaling in anchorage-independent conditions, which mimic the in vivo environment, and is a novel therapeutic target.

Direct binding of the EGF-like domain of neuregulin-1 to integrins ({alpha}v{beta}3 and {alpha}6{beta}4) is involved in neuregulin-1/ErbB signaling.

Integrin-growth factor receptor cross-talk plays a role in growth factor signaling, but the specifics are unclear. In a current model, integrins and growth factor receptors independently bind to their ligands (extracellular matrix and growth factors, respectively). We discovered that neuregulin-1 (NRG1), either as an isolated EGF-like domain or as a native multi-domain form, binds to integrins αvß3 (with a K(D) of 1.36 × 10(-7) m) and α6ß4. Docking simulation predicted that three Lys residues at positions 180, 184, and 186 of the EGF-like domain are involved in integrin binding. Mutating these residues to Glu individually or in combination markedly suppressed integrin binding and ErbB3 phosphorylation. Mutating all three Lys residues to Glu (the 3KE mutation) did not affect the ability of NRG1 to bind to ErbB3 but markedly reduced the ability of NRG1 to induce ErbB3 phosphorylation and AKT and Erk1/2 activation in MCF-7 and T47D human breast cancer cells. This suggests that direct integrin binding to NRG1 is critical for NRG1/ErbB signaling. Notably, stimulation of cells with WT NRG1 induced co-precipitation of ErbB3 with α6ß4 and with αvß3 to a much lower extent. This suggests that WT NRG1 induces integrin-NRG1-ErbB3 ternary complex formation. In contrast, the 3KE mutant was much less effective in inducing ternary complex formation than WT NRG1, suggesting that this process depends on the ability of NRG1 to bind to integrins. These results suggest that direct NRG1-integrin interaction mediates integrin-ErbB cross-talk and that α6ß4 plays a major role in NRG-ErbB signaling in these cancer cells.

Loss of Blm enhances basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Ptch1+/- mice.

Basal cell carcinomas (BCCs) have relative genomic stability and relatively benign clinical behavior but whether these two are related causally is unknown. To investigate the effects of introducing genomic instability into murine BCCs, we have compared ionizing radiation-induced tumorigenesis in Ptch1(+/-) mice versus that in Ptch1(+/-) mice carrying mutant Blm alleles. We found that BCCs in Ptch1(+/-) Blm(tm3Brd/tm3Brd) mice had a trend toward greater genomic instability as measured by array comprehensive genomic hybridization and that these mice developed significantly more microscopic BCCs than did Ptch1(+/-) Blm(+/tm3Brd) or Ptch1(+/-) Blm(+/+) mice. The mutant Blm alleles also markedly enhanced the formation of rhabdomyosarcomas (RMSs), another cancer to which Ptch1(+/)(-) mice and PTCH1(+/)(-) (basal cell nevus syndrome) patients are susceptible. Highly recurrent but different copy number changes were associated with the two tumor types and included losses of chromosomes 4 and 10 in all BCCs and gain of chromosome 10 in 80% of RMSs. Loss of chromosome 11 and 13, including the Trp53 and Ptch1 loci, respectively, occurred frequently in BCCs, suggesting tissue-specific selection for genes or pathways that collaborate with Ptch deficiency in tumorigenesis. Despite the quantitative differences, there was no dramatic qualititative difference in the BCC or RMS tumors associated with the mutant Blm genotype.

Exploration of Mistreatment and Burnout Among Resident Physicians: a Cross-Specialty Observational Study.

PURPOSE: Resident physician mistreatment and burnout are widespread issues in medical training, but the association between the two remains unclear. This study examines the prevalence and types of mistreatment among resident physicians in core specialties and its association with burnout syndrome as well as feelings of depression/anxiety. METHODS: A cross-sectional, survey-based observational study of medical residents was conducted at the University of California, Davis Medical Center in 2014. Current residents (PGY2 or higher) in the internal medicine, family medicine, obstetrics/gynecology, surgery, and pediatrics programs completed anonymous questionnaires addressing topics such as workplace mistreatment, feelings of depression/anxiety, and stress management. Burnout was measured using the Maslach Burnout Inventory. RESULTS: Forty-four out of 105 residents (41.9%) witnessed mistreatment of their co-residents while 26 residents (24.8%) disclosed personal accounts of mistreatment. Seventy-one percent of residents met the criteria for burnout. Residents who had been personally mistreated were almost eight times more likely to report burnout (OR 7.6, 95% CI = 1.7-34.4) and almost four times more likely to report symptoms of anxiety and depression (OR 3.8, 95% CI = 1.6-9.1). Public belittlement or humiliation was the most common type of mistreatment. CONCLUSION: Encountering mistreatment was associated with higher rates of burnout, as well as depression/anxiety. While it is uncertain if mistreatment in the workplace has a causative impact on burnout syndrome, the findings reveal the need to address work-related environmental factors that may contribute to both resident physician mistreatment and burnout.

A neglected issue in interpretation of results of randomized controlled trials: informative censoring.

The presence of informative censoring is a commonly neglected issue that can lead to inaccurate results in randomized controlled trials. It is mandatory to perform an intention to treat analysis to minimize this source of error.

Epidemiological, clinical, laboratory findings, and outcomes of disseminated tuberculosis in Tehran, Iran.

BACKGROUND: Disseminated tuberculosis (TB) accounts for 1 to 3% of all TB cases. This retrospective study reviews the clinical, radiological, laboratory findings and outcome in patients with disseminated tuberculosis in an endemic area. METHODS: Medical records were reviewed for patients with disseminated TB admitted to two tertiary centers in Tehran, Iran between 1999 and 2006. RESULTS: Fifty patients were found to have disseminated TB. A miliary pattern was documented in the chest x-ray of 34 patients. Hematologic abnormalities including anemia, leukopenia, and thrombocytopenia were frequently observed. Death occurred in nine of the cases. The mortality rate was significantly higher in diabetic patients, injection drug users, and patients with hematologic abnormalities; however, steroid usage and human immunodeficiency virus infection were not significantly associated with a higher mortality rate. Clinical improvement occurred in 41 patients following treatment. CONCLUSION: Disseminated TB could have different manifestations. Hematologic abnormalities are common and are considered poor prognostic signs in these patients.

Ultraviolet Radiation Inhibits Mammary Carcinogenesis in an ER-Negative Murine Model by a Mechanism Independent of Vitamin D3.

Three decades ago, the Garlands postulated that vitamin D3 produced in the skin by ultraviolet radiation (UVR)-induced conversion of 7-dehydrocholesterol to pre-D3 has anticancer effects, thus triggering more than 9,500 publications on D3 and cancer. Here, we report that UVR treatment of transgenic mice of the well-established C3(1)/SV40 Tag mammary cancer model significantly inhibits both autochthonous carcinogenesis and allograft tumor growth, but in contrast neither dietary nor topical D3 influences mammary carcinogenesis in this specific mouse model. Furthermore, UVR's inhibitory effects occur irrespective of whether or not the treatment increases circulating D3 in the mice. The inhibitory effect of UVR on autochthonous tumors occurs at or before the stage of ductal carcinoma in situ. Our studies indicate clearly that UVR can exert D3-independent anticancer effects in C3(1)/SV40 Tag mice. Therefore, supplemental D3 may not mimic all possible beneficial effects of UVR, and uncovering non-D3-mediated mechanisms of UVR tumor inhibition may lead to novel strategies for cancer prevention. Cancer Prev Res; 11(7); 383-92. ©2018 AACR.

Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus.

BACKGROUND: Lichen planus is a common chronic inflammatory mucocutaneous disease, affecting 0.1% to 4% of the general population. There is no published randomized active control clinical trial on pimecrolimus for the treatment of oral lichen planus (OLP). OBJECTIVE: The purpose of this study was to compare the efficacy and safety of pimecrolimus 1% cream with triamcinolone acetonide 0.1% paste in treating OLP. METHODS: In this investigator-blinded parallel-group randomized clinical trial, 40 patients were randomly assigned in two equal groups to receive either pimecrolimus 1% cream or triamcinolone acetonide 0.1% paste 4 times daily for a total of 2 months and followed up for another 2 months. The patients were assessed for painful symptoms measured by visual analog scale, the Oral Health Impact Profile score, and objective clinical score. Nonparametric tests were used to assess the main outcomes. Intention-to-treat analysis was used. RESULTS: Eighteen patients in pimecrolimus group and 17 patients in triamcinolone group finished the 4-month trial course. Both pimecrolimus and triamcinolone groups showed significant improvement in all measured efficacy end points throughout the visits. There was no significant difference between changes from baseline median values of pimecrolimus and triamcinolone groups after treatment termination in terms of visual analog scale score (-9.8 +/- 11.3 vs -8.4 +/- 18.3, P = .70), Oral Health Impact Profile score (-1.5 +/- 2.6 vs -1.6 +/- 2.1, P = .38), and clinical score (-0.7 +/- 0.6 vs -0.8 +/- 0.7, P = .86), respectively. Two patients in pimecrolimus group experienced prominent but transient burning sensation whereas none of the patients in triamcinolone group had any prominent adverse event (P = .24). LIMITATIONS: Blood levels in pimecrolimus group were not measured and carcinogenicity of pimecrolimus, especially in its long-term use for OLP, is yet to be determined. CONCLUSION: This study showed that patients with OLP may benefit from both topical pimecrolimus and triamcinolone acetonide therapy with minimal side effects. Further studies should be conducted to assess the maintenance effects and long-term safety of both drugs (Cochrane skin group identifier: CSG TrialNo. 22).

Think globally, act locally: expert opinions from Asia on the diagnosis and treatment of pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV) is the most common blistering disease in Iran and many other Asian countries with a relatively high incidence and involvement of both skin and mucous membranes in majority of the patients. AIMS: To assess the opinions of Asian experts on the diagnosis and management of PV. SETTINGS AND DESIGN: It was a questionnaire-based mailed/e-mailed survey. MATERIALS AND METHODS: The questionnaire was sent to 29 dermatologists from different countries of Asia who treat autoimmune blistering disorders, with at least 5 years' experience in this field and who visit at least five new PV patients annually. Questions included duration of experience, number of patients treated and diagnostic and treatment approaches for PV. STATISTICAL ANALYSIS USED: Percentage prevalence; some data are reported as mean +/- SD. RESULTS: All of the 29 physicians participated in the survey; among them, 79.3% visit their patients within 6 months after the onset of symptoms. Diagnosis of PV is confirmed by histologic and direct immunofluorescence examinations by 65.5% of physicians. All of them initiate the treatment with corticosteroids (48.3% with a dose of at least 2 mg/kg/day prednisolone) and 89.7% add adjuvant immunosuppressors at the same time. Of the adjuvant agents used, azathioprine is used by 82.8% of physicians. CONCLUSIONS: Different trends in diagnostic techniques and treatment options for PV among the experienced authorities emphasize the urgent need for large-scale controlled trials in order to reach consensus standards in this field. In addition, regional and worldwide consensus meetings to consider all regional and genetic similarities and differences are highly recommended.

Contact stomatitis.

Contact stomatitis occurs in up to 10% of the population. Mechanical or chemical irritation, ill-fitting dentures, and dental fillings can induce irritant contact stomatitis. Type I hypersensitivity and type IV hypersensitivity to dental products and foods are frequently responsible for the allergic types of contact stomatitis. We review the causal agents of contact stomatitis, the differential diagnoses, diagnostic testing, and potential treatment.

Practical pearls for oral procedures.

We provide an overview of clinically relevant principles of oral surgical procedures required in the workup and management of oral mucosal diseases. An understanding of the fundamental concepts of how to perform safely and effectively minor oral procedures is important to the practicing dermatologist and can minimize the need for patient referrals. This chapter reviews the principles of minor oral procedures, including incisional, excisional, and punch biopsies, as well as minor salivary gland excision. Pre- and postoperative patient care is also discussed.

Clinical features of Behçet's disease: A retrospective chart review of 26 patients.

BACKGROUND: Behçet's disease (BD) is a multi-organ inflammatory disorder with mucocutaneous, ocular, neurological, musculoskeletal, gastrointestinal, and pulmonary manifestations. The aim of this study was to determine the clinical features of BD in a cohort of patients diagnosed at the University of California, Davis, United States. METHODS: The medical records of 59 patients with an ICD9-code of BD were retrospectively reviewed. The International Criteria for BD was used to identify patients with a point score ≥5. The clinical manifestations of BD were investigated over a 10-year period in this cohort. RESULTS: Twenty-six patients (20 women, six men; female:male ratio = 3.3:1.0) had a point score ≥5 based on the International Criteria. The average age of onset of BD was 29.25 ± 14.25 years. Oral ulcers (100%), genital ulcers (84.6%), articular involvement (69.2%), ocular involvement (65.3%), and skin lesions (50.0%) were the most prevalent manifestations of BD in this cohort. CONCLUSION: Oral ulcers were the most common presenting and lifetime sign of BD. In our cohort, oral and genital ulcers were hallmarks of BD, independent of patient demographics. Thus, patients with these signs require close surveillance for other manifestations of the disease.

Effect of a Pre-Treatment Educational Video in Improving Patient Satisfaction with 5-Fluorouracil Treatment for Actinic Keratoses: A Randomized Controlled Trial.

INTRODUCTION: Patient treatment satisfaction and adherence may be affected by the initial understanding of outcomes in the treatment of actinic keratoses with 5-fluorouracil 5% cream (5-FU). Pre-treatment educational videos may optimize this understanding. The objective of this study was to determine whether prospective patient viewing of an educational video delineating treatment effects and expectations improves patient satisfaction and treatment completion rates for the treatment of actinic keratoses with 5-FU. METHODS: Forty-four participants were recruited to the UC Davis Dermatology outpatient clinic. Each participant was randomized to the video (group A) or control group (group B), and topical 5-FU cream treatment was conducted for 2 weeks in both groups. RESULTS: A follow-up questionnaire was performed to assess patient satisfaction and adherence to the treatment regimen. The results of these questions were analyzed using the Mann-Whitney test. One item on the questionnaire asked the patient to rate their overall level of satisfaction on a score of 0-100. The results of this question were analyzed using the unpaired t test. The results of the statistical analysis show no significant difference between the patient group that viewed the video and the patient group that did not view the video. CONCLUSIONS: We speculate that this study may establish a foundation for subsequent studies that may affect the broader medical community and promote development of educational videos.

Mucosal lichen planus: an evidence-based treatment update.

BACKGROUND: Mucosal lichen planus (MLP) is a chronic mucosal disorder that often poses a therapeutic challenge to dermatologists, dentists, and gynecologists. To relieve patients' pain and discomfort, improve their quality of life, and achieve clinical improvement, various therapeutic approaches can be considered for this disease. Based on the current literature it is difficult to define any particular treatment as the main therapeutic modality. OBJECTIVE: We aimed to systematically review the current literature for the effectiveness of available treatment modalities for MLP. METHODS: All of the randomized controlled trials and systematic reviews of MLP were collected by searching Pubmed, EMBASE, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, and China National Knowledge Infrastructure. Meta-analysis was performed, if possible. RESULTS: Topical betamethasone valerate, clobetasol-17-propionate, and fluocinonide are effective in the treatment of oral lichen planus (OLP) when compared with placebo. Calcineurin inhibitors and topical retinoids are also beneficial treatment options. LIMITATIONS: The review does not include therapies with a lower level of evidence. CONCLUSION: Topical corticosteroids are the mainstay of therapy for OLP. High-quality evidence is lacking for the treatment of lichen planus.