Association Between Natural Hair Color, Race, and Alopecia.

INTRODUCTION: Limited epidemiologic data has suggested direct associations between hair pigment, race, and incidence of alopecia areata (AA). Here, we examine the relationship between natural hair color, race, and the lifetime risk alopecia. METHODS: In this case-control study, we included UK Biobank patients of all races and self-reported hair color with diagnoses of AA, androgenetic alopecia (AGA), or scarring alopecia (SA). Multivariable logistic regression was used to detect differences in lifetime risk. RESULTS: Findings reveal a significantly increased risk of AA among individuals with black hair compared to dark brown hair (OR 1.71 [95% CI 1.22-2.38], p < 0.001). Those with red or blonde hair showed a decreased risk of AA (0.74 [0.56-0.97]; 0.62 [0.41-0.95], p < 0.05). No racial differences in AA prevalence were observed among individuals with black hair. CONCLUSIONS: Darker hair colors may be associated with a higher risk of AA, lighter hair colors with a lower risk, and differences in hair color could contribute to previously noted racial variations in AA incidence, potentially influencing dermatologists' perspectives on the disease's epidemiology.

Correction: Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

[This corrects the article DOI: 10.1371/journal.pone.0140310.].

Primary cutaneous EBV+ extranodal NK/T-cell lymphoma of gamma/delta T-cell lineage in the posttransplantation setting.

Posttransplantation primary cutaneous T-cell lymphomas (PT-CTCL) are a rare complication of sustained immunosuppression in the posttransplant setting. When present, PT-CTCLs are typically EBV- and exhibit features of mycosis fungoides/Sézary syndrome or CD30+ lymphoproliferative disorders. We present a case of a 75-year-old individual who developed skin lesions 30 years after liver transplantation. Pathologic evaluation of the skin biopsy revealed involvement by a clonal, EBV+ T-cell population of gamma/delta lineage with no evidence of systemic disease. Comprehensive genomic profiling was performed, confirming focal one-copy loss of 6q23.3, altogether consistent with the extremely rare and unusual diagnosis of primary cutaneous EBV+ extranodal NK/T-cell lymphoma of gamma/delta T-cell lineage in the posttransplantation setting.

A phase I trial of vaccination with lethally irradiated lymphoma cells admixed with granulocyte-macrophage colony-stimulating factor secreting K562 cells for the treatment of follicular lymphoma.

Several vaccine strategies have been tested for the treatment of follicular lymphoma; however, none have proven successful. In a phase I dose-escalation protocol, we developed a vaccine consisting of lethally irradiated whole lymphoma cells admixed with K562 cells that constitutively secreted granulocyte-macrophage colony-stimulating factor (GM-K562)(ClinicalTrials.gov identifier: NCT00487305). Patients with grade 1, 2, or 3 A follicular lymphoma were divided into 2 study tiers based on prior treatment and received a maximum of 6 vaccines. Vaccines contained dose levels of 5 × 106 or 1 × 107 GM-K562 cells admixed with autologous tumor cells at doses ranging from 1 × 105 to 5 × 107.Correlative studies did not demonstrate a significant immune response as assessed by delayed-type hypersensitivity reactions, B and T cell subsets, and natural killer cell subsets. Future vaccine studies should focus on identifying lymphoma-specific immunogenic proteins and modifying the vaccine immune adjuvant.

Hepatocyte vitamin D receptor functions as a nutrient sensor that regulates energy storage and tissue growth in zebrafish.

Vitamin D receptor (VDR) has been implicated in fatty liver pathogenesis, but its role in the regulation of organismal energy usage remains unclear. Here, we illuminate the evolutionary function of VDR by demonstrating that zebrafish Vdr coordinates hepatic and organismal energy homeostasis through antagonistic regulation of nutrient storage and tissue growth. Hepatocyte-specific Vdr impairment increases hepatic lipid storage, partially through acsl4a induction, while simultaneously diminishing fatty acid oxidation and liver growth. Importantly, Vdr impairment exacerbates the starvation-induced hepatic storage of systemic fatty acids, indicating that loss of Vdr signaling elicits hepatocellular energy deficiency. Strikingly, hepatocyte Vdr impairment diminishes diet-induced systemic growth while increasing hepatic and visceral fat in adult fish, revealing that hepatic Vdr signaling is required for complete adaptation to food availability. These data establish hepatocyte Vdr as a regulator of organismal energy expenditure and define an evolutionary function for VDR as a transcriptional effector of environmental nutrient supply.

Development and Preliminary Evaluation of A Soft Tissue Microtia Simulator.

Surgical simulation has been used extensively for learning microtia reconstruction and has almost exclusively involved framework creation. However, soft tissue reconstruction in microtia is equally challenging and would benefit from a simulation platform. This study aimed to describe the development and preliminary evaluation of a high-fidelity soft tissue microtia simulator. Three-dimensional modeling software, fused deposition 3-dimensional printing, adhesive techniques, silicones, and polyurethane rubbers were utilized to create a right lobular-type microtia simulator that comprises skin, subcutaneous tissue, and cartilage. Two expert microtia surgeons performed a microtia reconstruction on the simulator and evaluated its value and realism using a Likert-type questionnaire. The surgeons utilized a previously developed synthetic framework and successfully performed the critical steps of the soft tissue reconstruction, including marking, incising, dissection, removal of the cartilage remnant, drain insertion, insertion of the framework, closing of the skin, and demonstration of the soft tissue conforming over the framework using suction. A preliminary assessment of the simulator demonstrated that the simulator is anatomically accurate, realistic, and highly valuable as a training tool. A high-fidelity soft tissue microtia simulator was successfully developed and tested. The simulator provides a valuable training platform for learning a critical component of microtia reconstruction.

Nevi and Melanoma.

Cutaneous melanoma is an aggressive form of skin cancer derived from skin melanocytes and is associated with significant morbidity and mortality. A significant fraction of melanomas are associated with precursor lesions, benign clonal proliferations of melanocytes called nevi. Nevi can be either congenital or acquired later in life. Identical oncogenic driver mutations are found in benign nevi and melanoma. While much progress has been made in our understanding of nevus formation and the molecular steps required for transformation of nevi into melanoma, the clinical diagnosis of benign versus malignant lesions remains challenging.

Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: a phase 1b/2a trial.

PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 .

Protein Expression via Transient Transfection of Mammalian Cells in a WAVE Bioreactor.

Large culture volumes are often required when expression constructs are particularly low-yielding or when end uses require significant amounts of material. In these cases, a single homogeneous culture is usually more convenient, in terms of both consistency of expression and labor/resource requirements, than multiple parallel cultures. Using a WAVE Bioreactor culture, volumes as high as 500L may be achieved in a single vessel. Here, we describe the transfection of Expi293F cells in a disposable 50L Cellbag on a WAVE Bioreactor platform to produce recombinant protein. The methods described herein may be adapted, with suitable optimizations, for other suspension-adapted mammalian cell lines.

Corilagin relieves atherosclerosis via the toll-like receptor 4 signaling pathway in vascular smooth muscle cells.

INTRODUCTION: Corilagin possesses a diverse range of pharmacologic bioactivities. However, the specific protective effects and mechanisms of action of corilagin in the context of atherosclerosis remain unclear. In this study, we investigated the impact of corilagin on the toll-like receptor (TLR)4 signaling pathway in a mouse vascular smooth muscle cell line (MOVAS) stimulated by oxidized low-density lipoprotein (ox-LDL). Additionally, we examined the effects of corilagin in Sprague-Dawley rats experiencing atherosclerosis. METHODS: The cytotoxicity of corilagin was assessed using the CCK8 assay. MOVAS cells, pre-incubated with ox-LDL, underwent treatment with varying concentrations of corilagin. TLR4 expression was modulated by either downregulation through small interfering (si)RNA or upregulation via lentivirus transfection. Molecular expression within the TLR4 signaling pathway was analyzed using real-time polymerase chain reaction (PCR) and Western blotting. The proliferation capacity of MOVAS cells was determined through cell counting. In a rat model, atherosclerosis was induced in femoral arteries using an improved guidewire injury method, and TLR4 expression in plaque areas was assessed using immunofluorescence. Pathological changes were examined through hematoxylin and eosin staining, as well as Oil-Red-O staining. RESULTS: Corilagin demonstrated inhibitory effects on the TLR4 signaling pathway in MOVAS cells pre-stimulated with ox-LDL, consequently impeding the proliferative impact of ox-LDL. The modulation of TLR4 expression, either through downregulation or upregulation, similarly influenced the expression of downstream molecules. In an in vivo context, corilagin exhibited the ability to suppress TLR4 and MyD88 expression in the plaque lesion areas of rat femoral arteries, thereby alleviating the formation of atherosclerotic plaques. CONCLUSION: Corilagin can inhibit the TLR4 signaling pathway in VSMCs, possibly by downregulating TLR4 expression and, consequently, relieving atherosclerosis.

Metabolism-driven in vitro/in vivo disconnect of an oral ERɑ VHL-PROTAC.

Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.

Therapeutic potential of natural products in schistosomiasis-associated liver fibrosis.

Schistosomiasis is a parasitic disease that endangers human health and social development. The granulomatous reaction of Schistosoma eggs in the liver is the main cause of hepatosplenomegaly and fibrotic lesions. Anti liver fibrosis therapy is crucial for patients with chronic schistosomiasis. Although Praziquantel is the only clinical drug used, it is limited in insecticide treatment and has a long-term large-scale use, which is forcing the search for cost-effective alternatives. Previous research has demonstrated that plant metabolites and extracts have effective therapeutic effects on liver fibrosis associated with schistosomiasis. This paper summarizes the mechanisms of action of metabolites and some plant extracts in alleviating schistosomiasis-associated liver fibrosis. The analysis was conducted using databases such as PubMed, Google Scholar, and China National Knowledge Infrastructure (CNKI) databases. Some plant metabolites and extracts ameliorate liver fibrosis by targeting multiple signaling pathways, including reducing inflammatory infiltration, oxidative stress, inhibiting alternate macrophage activation, suppressing hepatic stellate cell activation, and reducing worm egg load. Natural products improve liver fibrosis associated with schistosomiasis, but further research is needed to elucidate the effectiveness of natural products in treating liver fibrosis caused by schistosomiasis, as there is no reported data from clinical trials in the literature.

Evaluation of a high-fidelity cleft alveolar bone graft simulator.

INTRODUCTION: Cleft alveolar bone graft surgery is technically challenging to perform as well as difficult to learn and teach. A high-fidelity cleft alveolar bone graft simulator was previously developed. However, further evaluation of the simulator is necessary to assess its efficacy. METHODS: Two cleft simulation workshops were conducted in which participants were led through a simulated cleft alveolar bone graft. The first simulation workshop involved six plastic surgery trainees. The second workshop involved 43 practicing cleft surgeons. The participants were provided with a Likert-type questionnaire assessing the simulators' features, realism, and value as a training tool. The change in self-reported confidence was assessed by providing each participant with a pre- and post-simulation confidence questionnaire. RESULTS: There was overall agreement in the realism of the simulators' features (average score of 4.67 and 3.80 out of 5 for the trainees and surgeons, respectively). There was overall agreement to strong agreement in the simulators value as a training tool (average score of 5 and 4.43 out of 5 for the trainees and surgeons, respectively). The self-reported confidence increased for all questionnaire items for both the trainees and surgeons. This was significant (p < 0.05) for five out of eight and all questionnaire items for the trainees and surgeons, respectively. The magnitude of the confidence increase was generally greater for less experienced participants. CONCLUSION: The cleft alveolar bone graft simulator was found to be realistic and valuable as a training platform. Use of the simulator improved self-reported confidence in cleft alveolar bone graft surgery.

Corilagin alleviates atherosclerosis by inhibiting NLRP3 inflammasome activation via the Olfr2 signaling pathway in vitro and in vivo.

Introduction: Atherosclerosis, a leading cause of global cardiovascular mortality, is characterized by chronic inflammation. Central to this process is the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, which significantly influences atherosclerotic progression. Recent research has identified that the olfactory receptor 2 (Olfr2) in vascular macrophages is instrumental in driving atherosclerosis through NLRP3- dependent IL-1 production. Methods: To investigate the effects of Corilagin, noted for its anti-inflammatory attributes, on atherosclerotic development and the Olfr2 signaling pathway, our study employed an atherosclerosis model in ApoE-/- mice, fed a high-fat, high-cholesterol diet, alongside cellular models in Ana-1 cells and mouse bone marrow-derived macrophages, stimulated with lipopolysaccharides and oxidized low-density lipoprotein. Results: The vivo and vitro experiments indicated that Corilagin could effectively reduce serum lipid levels, alleviate aortic pathological changes, and decrease intimal lipid deposition. Additionally, as results showed, Corilagin was able to cut down expressions of molecules associated with the Olfr2 signaling pathway. Discussion: Our findings indicated that Corilagin effectively inhibited NLRP3 inflammasome activation, consequently diminishing inflammation, macrophage polarization, and pyroptosis in the mouse aorta and cellular models via the Olfr2 pathway. This suggests a novel therapeutic mechanism of Corilagin in the treatment of atherosclerosis.

Current Status of Malaria Control and Elimination in Africa: Epidemiology, Diagnosis, Treatment, Progress and Challenges.

The African continent carries the greatest malaria burden in the world. Falciparum malaria especially has long been the leading cause of death in Africa. Climate, economic factors, geographical location, human intervention and unstable security are factors influencing malaria transmission. Due to repeated infections and early interventions, the proportion of clinically atypical malaria or asymptomatic plasmodium carriers has increased significantly, which easily lead to misdiagnosis and missed diagnosis. African countries have made certain progress in malaria control and elimination, including rapid diagnosis of malaria, promotion of mosquito nets and insecticides, intermittent prophylactic treatment in high-risk groups, artemisinin based combination therapies, and the development of vaccines. Between 2000 and 2022, there has been a 40% decrease in malaria incidence and a 60% reduction in mortality rate in the WHO African Region. However, many challenges are emerging in the fight against malaria in Africa, such as climate change, poverty, substandard health services and coverage, increased outdoor transmission and the emergence of new vectors, and the growing threat of resistance to antimalarial drugs and insecticides. Joint prevention and treatment, identifying molecular determinants of resistance, new drug development, expanding seasonal malaria chemo-prevention intervention population, and promoting the vaccination of RTS, S/AS01 and R21/Matrix-M may help to solve the dilemma. China's experience in eliminating malaria is conducive to Africa's malaria prevention and control, and China-Africa cooperation needs to be constantly deepened and advanced. Our review aims to help the global public develop a comprehensive understanding of malaria in Africa, thereby contributing to malaria control and elimination.

State of the art: The Unilateral Cleft lip and Nose Deformity and Anatomic Subunit Approximation.

The anatomic subunit approximation approach to unilateral cleft lip repair was developed over 20 years ago. While the underlying principles of the repair are unchanged, its description has been simplified, additional landmarks and creases have been added, and objective analysis of perioperative changes have provided better clarity regarding goals and desired alterations. We review recent insights regarding the deformity; describe the repair in a simplified manner; and link a stepwise approach to foundation-based primary rhinoplasty as a part of the avenue to creating nasolabial balance and harmony.

L'approximation de la sous-unité anatomique pour réparer la fissure palatine unilatérale a été mise au point il y a plus de 20 ans. Les principes fondamentaux de la réparation n'ont pas changé, mais la description est simplifiée et des repères et des plis ont été ajoutés, sans compter qu'une analyse objective de la malformation et des changements chirurgicaux ont permis de mieux comprendre les objectifs ainsi que les modifications souhaitées. Les auteurs analysent la malformation dans le contexte de récentes études objectives, décrivent la réparation selon des concepts contemporains et relient une approche graduelle à la rhinoplastie primaire fondamentale dans le cadre de la trajectoire visant à créer une harmonie et un équilibre nasolabiaux.

Examining online international health professions education: a mixed methods review of barriers, facilitators, and early outcomes☠.

BACKGROUND: Access to quality healthcare education across the world is disproportionate. This study explores the potential for Cardiovascular Perfusion education to be delivered online to reach international students. METHODS: Exploratory mixed methods were used to identify the barriers, facilitators, and early outcomes of online international health professions education. RESULTS: Qualitative analysis yielded four primary and nine subthemes. Multiple interventions were implemented in the planning of a novel online international Extracorporeal Science (ECS) program based on these themes. Quantitative data from the first semester of the new ECS program was collected along with data from the traditional entry-level program and historic data from previous entry-level cohorts. No significant correlations or differences were found between students. Student satisfaction surveys were determined to be equivalent for each group. Mixed data analysis revealed exceptional student satisfaction in areas where qualitative feedback was incorporated into the program design. CONCLUSIONS: Online international education may be a viable option in the health professions. Barriers and facilitators to this mode of education were identified and utilized in designing one such program. Early outcomes from the novel ECS program reveal that student performance and satisfaction are equivalent to those of a traditional in-person training program.

Are Higher Body Mass Index and Worse Metabolic Parameters Associated with More Aggressive Differentiated Thyroid Cancer? A Retrospective Cohort Study.

Obesity is a risk factor for differentiated thyroid cancer (DTC), but the association with DTC aggressiveness is controversial. To evaluate the association between preoperative body mass index (BMI)/other metabolic parameters and DTC aggressiveness in our surgical cohort, we retrospectively evaluated patients following thyroid surgery who were diagnosed with DTC between December 2013 and January 2021. Baseline characteristics, histopathological features, treatment modalities, and follow-up data were studied. We conducted logistic regression to analyze the association between BMI/other metabolic parameters and adverse DTC features. The final study cohort included 211 patients (79.6% women; mean age± standard deviation 48.7 ± 15.9 years): 66 (31.3%) with normal weight, 81 (38.4%) with overweight, and 64 (30.3%) with obesity. The median follow-up was 51 months (range 7-93). Complete versus partial thyroidectomy was more common among patients living with overweight or obesity than in normal weight patients (79.7% versus 61.7%, p = 0.017, respectively). Logistic regression demonstrated that higher BMI was associated with mildly increased risk for lymph nodes metastases (odds ratio [OR] 1.077, 95% CI: 1.013-1.145), and higher triglycerides/high-density lipoprotein-cholesterol (TG/HDL-C) ratio was associated with aggressive histological variants of DTC (OR 1.269, 95% CI 1.001-1.61). To conclude, specific adverse clinical and histopathological DTC features were indeed associated with higher BMI and higher TG/HDL-C ratio.

Indirect genetic effects should make group size more evolvable than expected.

Group size is an important trait for many ecological and evolutionary processes. However, it is not a trait possessed by individuals but by social groups, and as many genomes contribute to group size understanding its genetic underpinnings and so predicting its evolution is a conceptual challenge. Here I suggest how group size can be modelled as a joint phenotype of multiple individuals, and so how models for evolution accounting for indirect genetic effects are essential for understanding the genetic variance of group size. This approach makes it clear that (a) group size should have a larger genetic variance than initially expected as indirect genetic effects always contribute exactly as much as direct genetic effects and (b) the response to selection of group size should be faster than expected based on direct genetic variance alone as the correlation between direct and indirect effects is always at the maximum positive limit of 1. Group size should therefore show relatively rapid evolved increases and decreases, the consequences of which and evidence for I discuss.