Miracle-dz/UniFAR-FTUs huggingface dataset:
Phenotypic variability in human skin mast cells

Mast cells (MCs) are unique constituents of the human body. While inter‐individual differences may influence the ways by which MCs operate in their skin habitat, they have not been surveyed in a comprehensive manner so far. We therefore set out to quantify skin MC variability in a large cohort of subjects. Pathophysiologically relevant key features were quantified and correlated: transcripts of c‐kit, FcεRIα, FcεRIβ, FcεRIγ, histidine decarboxylase, tryptase, and chymase; surface expression of c‐Kit, FcεRIα; activity of tryptase, and chymase; histamine content and release triggered by FcεRI and Ca2+ ionophore. While there was substantial variability among subjects, it strongly depended on the feature under study (coefficient of variation 33‐386%). Surface expression of FcεRI was positively associated with FcεRIα mRNA content, histamine content with HDC mRNA, and chymase activity with chymase mRNA. Also, MC signature genes were co‐regulated in distinct patterns. Intriguingly, histamine levels were positively linked to tryptase and chymase activity, whereas tryptase and chymase activity appeared to be uncorrelated. FcεRI triggered histamine release was highly variable and was unrelated to FcεRI expression but unexpectedly tightly correlated with histamine release elicited by Ca2+ ionophore. This most comprehensive and systematic work of its kind provides not only detailed insights into inter‐individual variability in MCs, but also uncovers unexpected patterns of co‐regulation among signature attributes of the lineage. Differences in MCs among humans may well underlie clinical responses in settings of allergic reactions and complex skin disorders alike.
The Lion, the Dragon and the Wardrobe Guarding the Doorway to Information and Communications Privacy on the Internet: A Comparative Case Study of Hong Kong and Singapore - Two Differing Asian Approaches

Almost a decade ago, the electronic commerce revolution began, led by such companies as Amazon.com and Ebay.com. These companies have grown into the internet business giants they are today, diversifying in the products they sell, the services they provide and the jurisdictions they conduct business in. However, aside from these rare examples, most medium and small internet-based business enterprises have grown with the dot.com bubble and dissolved when it burst mid-way through the decade. Now, at the 10th Anniversary of Electronic Commerce, after we have seen the dot.com way of doing business launch like a rocket and plunge like a comet, subsequently emerging into a more cautious, but no less potential, avenue of doing business, other challenges now face the industry as a whole to retain and obtain customers. Internet users are becoming increasingly wary of online transactions. The irony is that as internet users become technologically savvy, they also become more aware of the dangers which connectivity entails and this inhibits their online behaviour. Chief among these concerns, and second only to cybercrimes, is the maintenance of privacy in the context of the protection of personal information, particularly from the unsavory elements trawling the cyberworld. For cyber-trade and the e-commerce market to grow, and for the continued efficiency and utility of the internet for G2C and B2C transactions, governments and industries must re-instill the trust and confidence of internet users both in commercial and non-commercial interaction.
Therapeutic implications of melanoma heterogeneity

Over the last decade, the treatment of metastatic melanoma has been revolutionized by the translation of molecular insights into therapeutic benefit for patients. These include advances in immunotherapeutic and small‐molecule approaches aimed at destroying cells with immunogenic antigens or gene mutations. Despite these advances, the limited durability of clinical response and eventual disease progression underscores a need for better understanding of mechanisms underlying tumor development. Current targeted therapies are developed partly based on the rationale that tumors are primarily clonal with respect to mutant oncogene or cell surface antigen target. However, with the advancement of cell isolation and transplantation approaches coupled with deep sequencing and mutation detection techniques, it has become increasingly clear that tumors are polyclonal. As a result, sensitive malignant cells are eradicated by treatment while the remaining tumor cell populations are conferred varying degrees of resistance and survival advantages by harbouring or acquiring certain epigenetic and genetic abnormalities. Tumor heterogeneity thus represents a major obstacle to the successful application of current therapies. Gaining insights into the cellular and molecular aspects of tumor diversity will not only facilitate the development and selection of therapeutic targets but also promote the evolution of precision medicine. In this viewpoint, we will discuss the implications of tumor heterogeneity for the treatment of metastatic melanoma and propose approaches to accelerate the translation of scientific discovery into improved clinical outcomes.
Client-Centered and Family-Centered Care: Refinement of the Concepts

Occupational therapy has emphasized the relationship between the therapist and the client. The occupational therapy guidelines for client-centered practice produced in the 1980s by the Canadian Department of National Health and Welfare and the Canadian Association of Occupational Therapists (Task Force on Guidelines for the Practice of Occupational Therapy, 1983) has had variable use over the years. While occupational therapists believe in the principles of client-centered care, the philosophical concepts have been difficult to fully implement and also seem narrow in light of all the external forces and challenges posed by today's clients and their rights, and the ethics of medicine. Other concepts need to be in place to facilitate the true constructs of client-centered care. A historical overview of the medical perspective and the occupational therapy perspectives on client-centered and family-centered care are reviewed. Lessons learned from the various iterations of client-centered and family-centered c.
Assessment of health-enhancing physical activity at population level

To assess the levels and patterns of health-enhancing physical activity in the population there is a real need for better instruments to be developed. The overall aims of this thesis were to test the International Physical Activity Questionnaire (IPAQ) and to study the level of health-enhancing physical activity in the Swedish adult population using both the IPAQ (a subjective method) and accelerometry (an objective method). To validate the IPAQ, data was collected from a convenience sample of 46 adult men and women. In a second study data was collected from 980 men and women, aged 18 65, randomly chosen from a population register. The IPAQ data was compared against data from an accelerometer and a logbook for concurrent validity, and body composition and aerobic fitness for construct validity. For the population based studies two nationally representative samples of adult men and women were used (N = 1,470 and N = 1,114). The validation studies showed significant correlations between the IPAQ and the accelerometer and logbook, although large intra-individual differences were found. Vigorous intensity activity and time spent in inactivity were systematically overreported with IPAQ. The IPAQ data showed that adults reported a median (25 75 percentile) of 1,699 (693 3,600) MET-minweek. This corresponds to about 60 (24 128) minutes of brisk walking per day. Men reported significantly more activity than women (1,836 vs. 1,554 MET-minweek, P < 0.001). A significant difference in total physical activity was found across age, BMI and self-rated health categories. For men, walking contributed 35 % (11 73 %) of the total physical activity, while for women, walking contributed 45 % (22 92 %). The accelerometer data showed that men were significantly more active on moderate or higher intensity level than women. For total physical activity and time spent in inactivity, neither gender, age nor BMI could explain the variance. More than half (52 %) of the study population reached the “30 minutes per day” recommendation when every minute at moderate or higher intensity was counted. When activity bouts of 10 minutes or longer were considered, the prevalence estimates were only one percent. This is the first time levels and patterns of physical activity have been assessed at population level, using objective methodology. Even though the absolute values between the instruments used differed, they both provided qualitatively consistent pictures. This thesis has shown a new and sobering picture of health-enhancing physical activity at population level. At the same time, the need to better understand the nature and measurement issues of health-enhancing physical activity has been highlighted.
Action spectrum of melanoblast maturation and involvement of the aryl hydrocarbon receptor

The aryl hydrocarbon receptor (AHR) mediates melanocyte activation and skin tanning. We hypothesized that the AHR also mediates melanoblast‐to‐melanocyte maturation. In a cloned cell line, NCCmelb4, derived from mouse neural crest cells, we investigated AHR expression in melanoblasts stimulated by UV irradiation and AHR agonists. We irradiated the cells with UV, ranging from 280 to 380 nm in 10‐nm increments, using a multiwavelength irradiation spectral apparatus. Tyrosinase expression significantly increased with bimodal peaks at 310 and 360 nm. Although melanoblast activation peaked 48 hours after irradiation, the most suitable irradiation interval was 24 hours. AHR expression significantly increased at 360 nm, but not at 310 nm. The AHR agonist, VAF347, and water‐soluble tobacco smoke extract induced melanoblast maturation and AHR activation. The culture supernatant derived from the NS47 fibroblast cell line also induced melanoblast maturation and AHR activation. These findings suggest that UV and environmental stimulation of melanoblast‐to‐melanocyte maturation are enhanced via the AHR pathway.
Síndrome de disfunción múlti-orgánica por virus Dengue 3 en niños de Neiva Huila, Colombia

Antecedentes. El dengue es la principal enfermedad viral transmitida por vectores en el mundo, con un numero creciente de casos en Neiva. La presentacion clinica del choque por fiebre dengue hemorragica (FDH) esta demostrando un compromiso de organos diferentes al endotelio, con una mayor complejidad y gravedad de la enfermedad, probablemente asociado al serotipo circulante. Objetivo. Alertar sobre la aparicion de la disfuncion organica multiple en ninos afectados por dengue. Resultados. Se describe el diagnostico de disfuncion organica multiple en tres ninas; dos ninas de siete meses y una de tres anos. Con una evolucion de cuatro dias de fiebre, ingresaron en estado de choque resistente a la reanimacion con cristaloides y coloides, con taquicardia, arritmias ventriculares, CPK MB de 524 UI/L, AST de 2157 UI/L y ALT de 226 UI/L, coagulopatia de consumo con prolongacion de TTP y TP sin trombocitopenia severa y alteracion metabolica caracterizada por acidemia e hipoglucemia en las tres ninas. Se aplica el puntaje para disfuncion organica multiple con promedio de 23 y evidencia de mayor compromiso cardiaco, hepatico y hematologico. En los tres casos se demostro la presencia de dengue 3 mediante RT-PCR. Discusion. Se compara con reportes similares encontrados en la literatura y se hace una correlacion fisiopatologica breve. Conclusion. Se debe empezar a pensar en la presentacion de formas de la fiebre dengue hemorragica que comprometen otros organos, ampliando la definicion de severidad por dengue como en los casos descritos, que faciliten un enfoque e intervencion oportuna.
Two‐photon microscopy for intracutaneous imaging of stem cell activity in mice

The adult skin is a typical example of a highly regenerative tissue. Terminally differentiated keratinocytes are shed from the external layers of the epidermis or extruded from the skin as part of the growing hair shaft on a daily basis. These are effectively replenished through the activity of skin‐resident stem cells. Precise regulation of stem cell activity is critical for normal skin homoeostasis or wound healing and irregular stem cell proliferation or differentiation can lead to skin disease. The scarcity and dynamic nature of stem cells presents a major challenge for elucidating their mechanism of action. To address this, we have recently established a system for visualizing stem cell activity, in real time or long term, in the intact skin of live mice using two‐photon microscopy. The purpose of this review was to provide essential information to researchers who wish to incorporate two‐photon microscopy and live imaging into their experimental toolbox for studying aspects of skin and stem biology in the mouse model. We discuss fundamental principles of the method, instrumentation and basic experimental approaches to interrogate stem cell activity in the interfollicular epidermis and hair follicle.
Association of Mismatch Repair Mutation With Age at Cancer Onset in Lynch Syndrome

Importance Lynch syndrome is caused by dominantly inherited germline mutations that predispose individuals to colorectal, endometrial, ovarian, and other cancers through inactivation of the cellular mismatch repair system. Lynch syndrome–associated cancers are amenable to surveillance strategies that may improve survival. The age at which surveillance should start is disputed. Objective To determine whether mutated gene and type of mutation influence age at onset of Lynch syndrome–associated cancers. Design, Setting, and Participants A retrospective cohort study of individuals with Lynch syndrome–associated colorectal, endometrial, and/or ovarian cancers whose medical records were included in the clinical database of a large quaternary referral center for genomic medicine in the Northwest of England. Exposures Mutated gene (MLH1, MSH2, MSH6, and/or PMS2) and type of mutation (truncating, splicing, or large rearrangement). Main Outcomes and Measures Age at cancer diagnosis. Results A total of 1063 individuals with proven Lynch syndrome were included, 495 male and 568 female (mean age 52 years; age range, 10-93 years [children were included in the database, but no children developed cancer]). There were 546 men and women with colorectal cancer, 162 women with endometrial cancer, and 49 women with ovarian cancer; mean follow-up was 68.2 months. Among MLH1 mutation carriers, mutations in MLH1 were associated with colorectal cancer in 249 (61%) of 409 men and women; endometrial cancer in 53 of 196 (27%) women; and ovarian cancer in 15 (8%) of 196 women. Among MSH2 mutation carriers, mutations in MSH2 (the most prevalent mutations overall) were most commonly associated with female-specific cancers: endometrial cancer in 83 (30%) of 279 women; ovarian cancer in 28 (10%) of 279 women; and colorectal cancer in 239 (50%) 479 men and women. Mutations in MSH6 were less prevalent, and MSH6 mutation carriers presented with colorectal and endometrial cancer at later ages than carriers of mutations in MSH2 or MLH1. When stratified by mutation type, women with truncating MLH1 mutations had later ages of onset of endometrial cancer than those with nontruncating mutations (median difference, 6.6 years; 95% CI, 2.7-10.4; P = .002). Carriers of truncating MLH1 mutations presented with colorectal cancer at later ages than those with other mutations, but the difference was not statistically significant. Conclusions and Relevance Individuals with known Lynch syndrome could be risk stratified by mutated gene and mutation type in tailored surveillance programs. Specifically, individuals with MSH6 mutations could be offered cancer surveillance from a later age. Furthermore, those with truncating MLH1 mutations could begin endometrial cancer surveillance later than those with nontruncating mutations.
Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy

Importance There is a clear need for a molecular subtyping approach in prostate cancer to identify clinically distinct subgroups that benefit from specific therapies. Objectives To identify prostate cancer subtypes based on luminal and basal lineage and to determine associations with clinical outcomes and response to treatment. Design, Setting, and Participants The PAM50 classifier was used to subtype 1567 retrospectively collected (median follow-up, 10 years) and 2215 prospectively collected prostate cancer samples into luminal- and basal-like subtypes. Main Outcomes and Measures Metastasis, biochemical recurrence, overall survival, prostate cancer–specific survival, associations with biological pathways, and clinicopathologic variables were the main outcomes. Results Among the 3782 samples, the PAM50 classifier consistently segregated prostate cancer into 3 subtypes in both the retrospective and prospective cohorts: luminal A (retrospective, 538 [34.3%]; prospective, 737 [33.3%]), luminal B (retrospective, 447 [28.5%]; prospective, 723 [32.6%]), and basal (retrospective, 582 [37.1%]; prospective, 755 [34.1%]). Known luminal lineage markers, such as NKX3.1 and KRT18, were enriched in luminal-like cancers, and the basal lineage CD49f signature was enriched in basal-like cancers, demonstrating the connection between these subtypes and established prostate cancer biology. In the retrospective cohort, luminal B prostate cancers exhibited the poorest clinical prognoses on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors (10-year biochemical recurrence-free survival [bRFS], 29%; distant metastasis-free survival [DMFS], 53%; prostate cancer-specific survival [PCSS], 78%; overall survival [OS], 69%), followed by basal prostate cancers (10-year bRFS, 39%; DMFS, 73%; PCSS, 86%; OS, 80%) and luminal A prostate cancers (10-year bRFS, 41%; DMFS, 73%; PCSS, 89%; OS, 82%). Although both luminal-like subtypes were associated with increased androgen receptor expression and signaling, only luminal B prostate cancers were significantly associated with postoperative response to androgen deprivation therapy (ADT) in a subset analysis in our retrospective cohorts (n = 315) matching patients based on clinicopathologic variables (luminal B 10-year metastasis: treated, 33% vs untreated, 55%; nonluminal B 10-year metastasis: treated, 37% vs untreated, 21%; P = .006 for interaction). Conclusions and Relevance Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.
Collapse of human scalp microbiome network in dandruff and seborrhoeic dermatitis

We investigate the relationship between scalp microbiota and dandruff/seborrhoeic dermatitis (D/SD), an unpleasant scalp disorder common in human populations. Bacterial and fungal community analyses on scalp of 102 Korean were performed by next‐generation sequencing. Overall scalp microbiome composition significantly differed between normal and disease groups, and especially co‐occurrence network of dominant members was breakdown in disease groups. These findings will provide novel insights into shifts of microbial community relevant to D/SD.
Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial

Importance The role of epidermal growth factor receptor (EGFR) inhibition in chemoradiation strategies in the nonoperative treatment of patients with esophageal cancer remains uncertain. Objective To evaluate the benefit of cetuximab added to concurrent chemoradiation therapy for patients undergoing nonoperative treatment of esophageal carcinoma. Design, Setting, and Participants A National Cancer Institute (NCI) sponsored, multicenter, phase 3, randomized clinical trial open to patients with biopsy-proven carcinoma of the esophagus. The study accrued 344 patients from 2008 to 2013. Interventions Patients were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation of 50.4 Gy/1.8 Gy fractions with or without weekly cetuximab (400 mg/m2 on day 1 then 250 mg/m2 weekly). Main Outcomes and Measures Overall survival (OS) was the primary endpoint, with a study designed to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided &agr; = . 025. Results Between June 30, 2008, and February 8, 2013, 344 patients were enrolled. This analysis used all data received at NRG Oncology through April 12, 2015. Sixteen patients were ineligible, resulting in 328 evaluable patients, 159 in the experimental arm and 169 in the control arm. Patients were well matched between the treatment arms for patient and tumor characteristics: 263 (80%) with T3 or T4 disease, 215 (66%) N1, and 62 (19%) with celiac nodal involvement. Incidence of grade 3, 4, or 5 treatment-related adverse events at any time was 71 (46%), 35 (23%), or 6 (4%) in the experimental arm and 83 (50%), 28 (17%), or 2 (1%) in the control arm, respectively. A clinical complete response (cCR) rate of 81 (56%) was observed in the experimental arm vs 92 (58%) in the control arm (Fisher exact test, P = .66). No differences were seen in cCR between treatment arms for either histology (adenocarcinoma or squamous cell). Median follow-up for all patients was 18.6 months. The 24- and 36-month local failure for the experimental arm was 47% (95% CI, 38%-57%) and 49% (95% CI, 40%-59%) vs 49% (95% CI, 41%-58%) and 49% (95% CI, 41%-58%) for the control arm (HR, 0.92; 95% CI, 0.66-1.28; P = .65). The 24- and 36-month OS rates for the experimental arm were 45% (95% CI, 37%-53%) and 34% (95% CI, 26%-41%) vs 44% (95% CI, 36%-51%) and 28% (95% CI, 21%-35%) for the control arm (HR, 0.90; 95% CI, 0.70-1.16; P = .47). Conclusions and Relevance The addition of cetuximab to concurrent chemoradiation did not improve OS. These phase 3 trial results point to little benefit to current EGFR-targeted agents in an unselected patient population, and highlight the need for predictive biomarkers in the treatment of esophageal cancer. Trial Registration clinicaltrials.gov Identifier: NCT00655876