High Transcriptional Activity and Clinical Correlations in Eosinophils of Patients with Late-Onset Asthma.

Background: The immunological features of eosinophils in early-onset asthma (EOA) differ from those in late-onset asthma (LOA). Clinical trials of anti-interleukin-5 (IL-5) treatment for severe eosinophilic asthma showed a better response for LOA patients than EOA patients. We wonder if the transcriptional activity of activated eosinophils was different in EOA and LOA. Methods: Eosinophils obtained from well-controlled EOA and LOA patients and normal subjects were compared in terms of the mRNA expression of activation-related genes and specific markers related to cell functions in eosinophils activated by IL-5 or IL-17. The correlation between mRNA expression and clinical features and lung function was further analyzed. Results: The transcriptional expression of most genes was higher in activated eosinophils from LOA patients than in those from EOA patients and normal subjects. After IL-17 stimulation, the expression of certain genes was higher in atopic EOA patients than in non-atopic EOA patients. Similar observation was noted in obese EOA patients. After IL-5 stimulation, the transcriptional expression of most genes in eosinophils from LOA patients was negatively correlated with indicators of lung function. These correlations were less pronounced in EOA patients: After IL-17 stimulation, some genes in EOA patients were negatively correlated with post-bronchodilator changes in lung function. Conclusion: This study describes differences in the transcriptional active patterns of eosinophils and their correlation to atopy and obesity by age of onset. High transcriptional activity in activated eosinophils and a negative correlation to lung function indicate the importance of eosinophils in the pathogenesis of LOA.

Xanthogranulomatous reaction to trametinib for metastatic malignant melanoma.

Trametinib, a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated great promise in treating metastatic melanoma associated with BRAF V600E and V600K mutations; however, it also is highly associated with cutaneous adverse events (AEs). As both BRAF and MEK inhibitors become increasingly used to treat malignant melanoma, it is important to better characterize these AEs so that we can manage them. Herein, we present a case of a 66-year-old man who developed erythematous scaly papules on the face and bilateral upper extremities after beginning therapy with trametinib. The severity of the reaction worsened on trametinib monotherapy compared to combination therapy with a BRAF inhibitor. Biopsy revealed a xanthogranulomatous reaction.

Ripple-Pattern Sebaceous Trichoblastoma.

A 28-year-old man of Middle-Eastern descent presented with a raised, pearly, slightly pigmented lesion on the right nasal ala. The lesion had been present for approximately 4 months. An excisional biopsy was taken, and the lesion measured 1.0 cm × 0.9 cm in dimension. The cut surface revealed a firm, white to tan nodule located within the dermis. The patient had no other significant medical history. After the initial excision, the lesion did not recur.

Syringocystadenocarcinoma Papilliferum: A Rare Malignant Sweat Gland Tumor.

A 73-year-old Hispanic woman presented to the clinic with an erythematous, friable 3.0 cm × 2.7 cm × 0.7 cm mass located on the posterior vertex of the scalp (Figure 1). The lesion had been present since birth but had recently begun to bleed intermittently, prompting evaluation. A biopsy was obtained, revealing a tumor with irregular, complex papillomatous invaginations lined by a two-layered epithelium. Atypical and crowded columnar cells lined the luminal aspect, while cuboidal cells lined the epithelium adjacent to the stroma (Figure 2). Decapitation secretion was noted in several areas on the luminal surface.

Histologic changes associated with talaporfin sodium-mediated photodynamic therapy in rat skin.

BACKGROUND AND OBJECTIVE: Alternative treatments are needed to achieve consistent and more complete port wine stain (PWS) removal, especially in darker skin types; photodynamic therapy (PDT) is a promising alternative treatment. To this end, we previously reported on Talaporfin Sodium (TS)-mediated PDT. It is essential to understand treatment tissue effects to design a protocol that will achieve selective vascular injury without ulceration and scarring. The objective of this work is to assess skin changes associated with TS-mediated PDT with clinically relevant treatment parameters. STUDY DESIGN/MATERIALS AND METHODS: We performed TS (0.75 mg/kg)-mediated PDT (664 nm) on Sprague Dawley rats. Radiant exposures were varied between 15 and 100 J/cm2 . We took skin biopsies from subjects at 9 hours following PDT. We assessed the degree and depth of vascular and surrounding tissue injury using histology and immunohistochemical staining. RESULTS: TS-mediated PDT at 0.75 mg/kg combined with 15 and 25 J/cm2 light doses resulted in vascular injury with minimal epidermal damage. At light dose of 50 J/cm2 , epidermal damage was noted with vascular injury. At light doses >50 J/cm2 , both vascular and surrounding tissue injury were observed in the forms of vasculitis, extravasated red blood cells, and coagulative necrosis. Extensive coagulative necrosis involving deeper adnexal structures was observed for 75 and 100 J/cm2 light doses. Observed depth of injury increased with increasing radiant exposure, although this relationship was not linear. CONCLUSION: TS-mediated PDT can cause selective vascular injury; however, at higher light doses, significant extra-vascular injury was observed. This information can be used to contribute to design of safe protocols to be used for treatment of cutaneous vascular lesions. Lasers Surg. Med. 49:767-772, 2017. © 2017 Wiley Periodicals, Inc.

Sleep time and pattern of adult individuals in primary care in an Asian urbanized community: A cross-sectional study.

Sleep norms vary between individuals, being affected by personal, communal, and socioeconomic factors. Individuals with sleep time which deviate from the population norm are at risks of adverse mental, cardiovascular, and metabolic health. Sleep-related issues are common agenda for consultation in primary care. This study aimed to determine the sleep time, pattern, and behavior of multiethnic Asian individuals who attended public primary care clinics in an urban metropolitan city-state.Standardized questionnaires were assistant-administered to adult Asian individuals who visited 2 local public primary care clinics in north-eastern and southern regions of Singapore. The questionnaire included questions on demographic characteristics, self-reported sleep time, patterns, and behavior and those originated from the American National Sleep Foundation Sleep Diary. The data were collated, audited, rectified, and anonymized before being analyzed by the biostatistician. Individuals with 7 h sleep time or longer were deemed getting adequate sleep. Chi-squared or Fisher exact test was used to test the association between the demographic and behavioral variables and sleep time. Next, regression analysis was performed to identify key factors associated with their sleep time.A total of 350 individuals were recruited, with higher proportion of those of Chinese ethnicity reporting adequate sleep. Almost half (48.1%) of those who slept <7 h on weekdays tended to sleep ≥7 h on weekends. More individuals who reported no difficulty falling asleep, had regular sleep hours and awakening time, tended to sleep adequately. Those who slept with children, studied, read leisurely, used computer or laptops in their bedrooms, drank caffeinated beverages or smoked had inadequate sleep. Those who perceived sufficient sleep and considered 8 h as adequate sleep time had weekday and weekend sleep adequacy.Sleep time varied according to ethnicity, employment status, personal behavior, and perception of sleep sufficiency. Awareness of sleep time and pattern allows the local physicians to contextualize the discussion of sleep adequacy with their patients during consultation, which is a prerequisite to resolve their sleep-related issues.

Immune biomarkers are more accurate in prediction of survival in ulcerated than in non-ulcerated primary melanomas.

INTRODUCTION: Ulcerated melanomas may have a unique biology and microenvironment. We test whether markers of immune infiltration correlate with clinical outcome in ulcerated compared to non-ulcerated primary melanoma tumors. METHODS: Sixty-two stage II-III cutaneous melanomas, 32 ulcerated and 30 non-ulcerated, were analyzed for tumor-infiltrating lymphocytes (TILs). Immunohistochemistry (IHC) was performed for CD2, a marker previously shown to correlate with overall survival (OS) and recurrence-free survival (RFS) in this patient population. IHC using antibody, VE1, to BRAF V600E was also performed on a subset of 41 tumors to assess the relationship of BRAF mutation to immune markers. RESULTS: We found, using Cox regression models, that the presence of TILs was associated with improved OS (p = 0.034) and RFS (p = 0.002) in ulcerated melanoma tumors, but not in non-ulcerated melanoma (p = 0.632, 0.416). CD2 expression also was correlated with improved OS (p = 0.021) and RFS (p = 0.001) in ulcerated melanoma, but no relationship was seen in non-ulcerated melanoma (p = 0.427, 0.682). In this small population, BRAF status did not correlate with TILs or CD2+ count. CONCLUSION: Our data show that immune markers including TILs and CD2 count correlate more closely with survival in ulcerated melanomas than that in non-ulcerated melanomas. We propose that immune biomarkers may be particularly relevant to ulcerated, as compared to non-ulcerated, melanomas and that this merits study in larger populations.

Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma.

Histone variants are emerging as key regulatory molecules in cancer. We report a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the transcriptional output of E2F target genes in melanoma cells. These genes are highly expressed and display a distinct signature of H2A.Z occupancy. We identify BRD2 as an H2A.Z-interacting protein, levels of which are also elevated in melanoma. We further demonstrate that H2A.Z.2-regulated genes are bound by BRD2 and E2F1 in an H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targeted therapies. Collectively, our findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma, holding translational potential for novel therapeutic strategies.

Acute onset of a vesiculopustular rash in an ICU patient.

A 63 year-old woman with hyperthyroidism was admitted to the Medical Intensive Care Unit for ARDS following damage to her lungs from propylthiouracil. She was placed on 250 mg SSKI PO TID as an alternative therapy until thyroidectomy could be performed. Four days after admission, she abruptly developed an acneiform rash on her face, shown to be iododerma. The eruption rapidly resolved after discontinuation of the SSKI.

Fulminant hepatic failure attributed to ackee fruit ingestion in a patient with sickle cell trait.

We report a case of fulminant liver failure resulting in emergent liver transplantation following 3 weeks of nausea, vomiting, and malaise from Jamaican Vomiting Sickness. Jamaican Vomiting Sickness is caused by ingestion of the unripe arils of the Ackee fruit, its seeds and husks. It is characterized by acute gastrointestinal illness and hypoglycemia. In severe cases, central nervous system depression can occur. In previous studies, histologic sections taken from patients with Jamaican Vomiting Sickness have shown hepatotoxicity similar to that seen in Reye syndrome and/or acetaminophen toxicity. We highlight macroscopic and microscopic changes in the liver secondary to hepatoxicity of Ackee fruit versus those caused by a previously unknown sickle cell trait. We discuss the clinical variables and the synergistic hepatotoxic effect of Ackee fruit and ischemic injury from sickled red blood cells, causing massive hepatic necrosis in this patient.

Four-dimensional intensity-modulated radiotherapy planning for dynamic multileaf collimator tracking radiotherapy.

PURPOSE: To develop a four-dimensional intensity-modulated radiotherapy (IMRT) planning method for dynamic multileaf collimator (DMLC)-based tumor tracking that takes respiratory motion into consideration. METHODS AND MATERIALS: Using the concept of optimal deformation, a series of apertures are placed at different phases in the same segment to ensure maximally similar dose contributions at various anatomic points. We used a direct aperture optimization method to find a set of segments that achieved an optimal dose distribution for aperture shapes at the reference phase and achieved corresponding optimal deformations at other phases that took respiratory motion into consideration. In our four-dimensional direct aperture optimization (4D-DAO) method, a simulated annealing algorithm and a conjugate gradients algorithm were used to optimize the shape of the segments and the monitor units, respectively. We then compared the optimization results for three-dimensional conformal radiotherapy and 4D-DAO based on a set of simulated respiration 4D computed tomography (4DCT) data and a set of real 4DCT data. RESULTS: Dosimetric analysis indicated that, compared with the 3DCRT method, the dose distribution is significantly improved when the optimal deformation tracking technique is used, even when the maximum velocity limit of the DMLC leaves is set. CONCLUSIONS: The proposed 4D-IMRT planning method can find a set of segments and the corresponding leaf movements, which can trace the tumor motion and thus protect more normal tissue from radiation.

A particle swarm optimization algorithm for beam angle selection in intensity-modulated radiotherapy planning.

Automatic beam angle selection is an important but challenging problem for intensity-modulated radiation therapy (IMRT) planning. Though many efforts have been made, it is still not very satisfactory in clinical IMRT practice because of overextensive computation of the inverse problem. In this paper, a new technique named BASPSO (Beam Angle Selection with a Particle Swarm Optimization algorithm) is presented to improve the efficiency of the beam angle optimization problem. Originally developed as a tool for simulating social behaviour, the particle swarm optimization (PSO) algorithm is a relatively new population-based evolutionary optimization technique first introduced by Kennedy and Eberhart in 1995. In the proposed BASPSO, the beam angles are optimized using PSO by treating each beam configuration as a particle (individual), and the beam intensity maps for each beam configuration are optimized using the conjugate gradient (CG) algorithm. These two optimization processes are implemented iteratively. The performance of each individual is evaluated by a fitness value calculated with a physical objective function. A population of these individuals is evolved by cooperation and competition among the individuals themselves through generations. The optimization results of a simulated case with known optimal beam angles and two clinical cases (a prostate case and a head-and-neck case) show that PSO is valid and efficient and can speed up the beam angle optimization process. Furthermore, the performance comparisons based on the preliminary results indicate that, as a whole, the PSO-based algorithm seems to outperform, or at least compete with, the GA-based algorithm in computation time and robustness. In conclusion, the reported work suggested that the introduced PSO algorithm could act as a new promising solution to the beam angle optimization problem and potentially other optimization problems in IMRT, though further studies need to be investigated.

Automatic beam angle selection in IMRT planning using genetic algorithm.

The selection of suitable beam angles in external beam radiotherapy is at present generally based upon the experience of the human planner. The requirement to automatically select beam angles is particularly highlighted in intensity-modulated radiation therapy (IMRT), in which a smaller number of modulated beams is hoped to be used, in comparison with conformal radiotherapy. It has been proved by many researchers that the selection of suitable beam angles is most valuable for a plan with a small number of beams (< or = 5). In this paper an efficient method is presented to investigate how to improve the dose distributions by selecting suitable coplanar beam angles. In our automatic beam angle selection (ABAS) algorithm, the optimal coplanar beam angles correspond to the lowest objective function value of the dose distributions calculated using the intensity-modulated maps of this group of candidate beams. Due to the complexity of the problem and the large search space involved, the selection of beam angles and the optimization of intensity maps are treated as two separate processes and implemented iteratively. A genetic algorithm (GA) incorporated with an immunity operation is used to select suitable beam angles, and a conjugate gradient (CG) method is used to quickly optimize intensity maps for each selected beam combination based on a dose-based objective function. A pencil-beam-based three-dimensional (3D) full scatter convolution (FSC) algorithm is employed for the dose calculation. Two simulated cases with obvious optimal beam angles are used to verify the validity of the presented technique, and a more complicated case simulating a prostate tumour and two clinical cases are employed to test the efficiency of ABAS. The results show that ABAS is valid and efficient and can improve the dose distributions within a clinically acceptable computation time.

Genetic algorithm based deliverable segments optimization for static intensity-modulated radiotherapy.

The static delivery technique (also called step-and-shoot technique) has been widely used in intensity-modulated radiotherapy (IMRT) because of the simple delivery and easy quality assurance. Conventional static IMRT consists of two steps: first to calculate the intensity-modulated beam profiles using an inverse planning algorithm, and then to translate these profiles into a series of uniform segments using a leaf-sequencing tool. In order to simplify the procedure and shorten the treatment time of the static mode, an efficient technique, called genetic algorithm based deliverable segments optimization (GADSO), is developed in our work, which combines these two steps into one. Taking the pre-defined beams and the total number of segments per treatment as input, the number of segments for each beam, the segment shapes and weights are determined automatically. A group of interim modulated beam profiles quickly calculated using a conjugate gradient (CG) method are used to determine the segment number for each beam and to initialize segment shapes. A modified genetic algorithm based on a two-dimensional binary coding scheme is used to optimize the segment shapes, and a CG method is used to optimize the segment weights. The physical characters of a multileaf collimator, such as the leaves interdigitation limitation and leaves maximum over-travel distance, are incorporated into the optimization. The algorithm is applied to some examples and the results demonstrate that GADSO is able to produce highly conformal dose distributions using 20-30 deliverable segments per treatment within a clinically acceptable computation time.