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Introduction:The limit of the method of calculating organ doses using voxelised phantoms with a Monte Carlo simulation code is that dose calculation errors in the boundaries of the organs are especially relevant for thin, small or complex geometries. In this report, we describe a tool that helps overcome this problem, accurately calculating organ doses by applying the “parallel geometry” utility feature of Geant4 through the GAMOS framework.

FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1–5. However, the role and the molecular mechanisms by which FAT1mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1activates a CAMK2–CD44–SRC axis that promotes YAP1 nuclear translocation and ZEB1expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.

A large number of studies have been focused on investigating serum biomarkers associated with risk or diagnosis of type-2 diabetes mellitus. In the last decade, promising studies have shown that circulating levels of adipokines could be used as a relevant biomarker for diabetes mellitus progression as well as therapeutic future targets. Here, we discuss the possible use of recently described adipokines, including apelin, omentin-1, resistin, FGF-21, neuregulin-4 and visfatin, as early biomarkers for diabetes. In addition, we also include recent findings of other well known adipokines such as leptin and adiponectin. In conclusion, further studies are needed to clarify the pathophysiological significance and clinical value of these biological factors as potential biomarkers in type-2 diabetes and related dysfunctions.

Thrombotic disorders are characterized by an increase in the probability of the formation of unnecessary thrombi that might be due to the activation of the coagulation cascade or the circulating platelets. Platelets or thrombocytes play an essential role in hemostasis but abnormal platelet function leads to the development of a number of cardiovascular complications, including thrombotic disorders. Under pathological conditions, platelets are associated with the development of different thrombotic disorders, including atherosclerosis, arterial thrombosis and stroke, deep venous thrombosis and pulmonary embolism; therefore, platelets are the target of a number of anti-thrombotic strategies. Flavonoids, a large group of polyphenols ubiquitously expressed in fruits and vegetables that have attracted considerable attention because of their benefits in human health, including the reduction of the risk of cardiovascular disease. Flavonoids have been reported to reduce platelet activity by attenuating agonist-induced GPIIb/IIIa receptor activation, mobilization of intracellular free Ca2+, granule exocytosis, as well as activation of different signaling molecules such as mitogen- activated protein kinases or phospholipases. This review summarizes the current studies concerning the modulation of platelet activation by flavonoids, giving especial attention to those events associated to thrombotic disorders.

IMPORTANCE: Forehead reconstruction after Mohs surgery has become a challenge for dermatology surgeons, and achieving an excellent cosmetic and functional result is imperative in this location. OBJECTIVE: To highlight the utility of a frontalis myocutaneous transposition flap (FMTF) for forehead reconstruction after Mohs surgery. DESIGN, SETTING, AND PARTICIPANTS: Surgical technique case series including 12 patients with large forehead defects recruited between January 2010 and June 2017 at the Dermatology Department of the University Clinic of Navarra, Spain. All patients underwent Mohs micrographic surgery for skin cancer (5 basal cell carcinomas, 4 melanomas, 2 squamous cell carcinomas, and 1 adnexal tumor) located on the forehead (8 paramedian, 2 midline, and 2 lateral subunits) resulting in defects ranging from 9 to 28 cm2 in size. INTERVENTION: Mohs micrographic surgery followed by FMTF. Taking into account the defect’s size and location, a lateral lobulated flap is designed with an inferior pedicle and incision lines are made vertically to the hairline containing part of the frontalis muscle or its fascia. The flap swings into the primary defect and direct closure of the donor site is achieved. Additional corrections for removing skin folds or a guitar-string suture can be made. MAIN OUTCOMES AND MEASURES: Absence of acute complications and achievement of high aesthetic and functional goals in postoperative follow-up. RESULTS: Satisfactory cosmetic and functional results were achieved for all 12 patients (7 men and 5 women; mean age, 62.7 years [range, 47-86 years]) and there were no postoperative complications. All the myocutaneous flaps survived without any acute complications, such as episodes of local bleeding, infection, flap margin necrosis, or congestion. Postoperative follow-up ranged from 6 months to 3 years. No patient needed scar revision. Six patients presented with paresthesia in areas of the forehead and scalp. Sensory recovery tended to improve over time, and paresthesia gradually decreased, disappearing in 5 of 6 cases after 12 months. In 3 patients there was a minimal hair transposition that required laser treatment. CONCLUSIONS AND RELEVANCE: The FMTF provides a simple method for 1-stage reconstruction of large forehead defects as an alternative to classic advancement flaps.

ABSTRACTThis study evaluated the effect of dietary supplementation with Amaranthus dubiuson carcass characteristics and meat quality of fattening rabbits. One hundred and six New Zealand White rabbits, weaned at 35 d of age, were assigned to three experimental diets including 0%, 16% and 32% of A. dubius(A0, A16 and A32), and were fed ad libitumuntil their slaughter at 87 d of age. Drip loss percentage (A0: 2.47, A16: 3.83 and A32: 3.61%; P < .05), dissectible fact percentage (A0: 3.02, A16: 3.63 and A32: 3.77%; P < .05) and thoracic cage percentage (A0: 12.97, A16: 13.68 and A32: 13.68%; P < .05) increased with diets including A. dubius. Contrarily, hind part percentage (A0: 40.00, A16: 38.95 and A32: 38.89%; P < .05) and compactness of the carcass decreased (A0: 2.38, A16: 2.42 and A32: 2.48; P < .01). The inclusion of A. dubiusin the diets increased protein (A0: 21.52, A16: 23.76 and A32: 24.27%; P < .05) and fat contents (A0: 3.33, A16: 4.16 and A32: 5.39%; P < .05), while moisture of meat decreased proportionally (A0: 74.23, A16: 70.99 and A32: 67.70%; P < .05). These findings suggest that A. dubiuscan be considered as an alternative raw material for rabbit feeding in tropical and subtropical regions where it is widespread.

Hemostasis is an intrinsic property of the vascular system that prevents blood loss during accidental disruption of the vessel wall. Late mechanisms of hemostasis comprise vessel repair and wound healing. In contrast, the early mechanism of hemostasis comprises the quick formation of a blood cell plug, also known as thrombus, whose function is to seal the region of the vessel near the compromised surface or area. Despite the simplicity of the concept, the molecular mechanisms underlying early hemostasis are highly complex. The local rheological properties of the blood flow, the vascular region and the nature of the injury determine the mechanism of thrombogenesis. Components of the plasma, blood cells such as platelets and vascular endothelial cells are involved in thrombosis. This review focuses on platelet-vascular wall interactions during thrombosis and hemostasis and provides an overview of the main underlying molecular mechanisms.

OBJECTIVE To determine the prevalence of pulmonary arterial hypertension in asymptomatic patients with 2 types of extensive slow-flow vascular malformations: extensive venous malformations or Klippel-Trénaunay syndrome (KTS). DESIGN Case-control. SETTING Multidisciplinary center for vascular anomalies. PATIENTS A consecutive sample of 32 patients with slow-flow vascular malformations of at least 15% of the body surface was identified retrospectively and matched by age and sex with 32 healthy controls. INTERVENTIONS Standard 2-dimensional transthoracic Doppler echocardiography. Venous samples were obtained the same day that echocardiography was performed. MAIN OUTCOME MEASURES Pulmonary artery systolic pressure (PASP) was determined. Levels of D-dimer, fibrinogen, and von Willebrand factor (vWF) in plasma were measured. RESULTS Patients had a mean (SD) PASP that was significantly higher than that of healthy controls (42.16 [8.49] mm Hg in patients vs 27.69 [6.54] mm Hg in healthy controls; P &lt; .001). No significant differences in PASP were found between patients with KTS and patients with venous malformations (P = .80). We observed significant differences in the mean (SD) levels of vWF between patients and healthy controls (124.41% [52.28%] in patients vs 92.69% [28.92%] in controls; P = .01) and also in levels of D-dimer (1032.99 [1367.0] ng/mL in patients vs 102.97 [29.39] ng/mL in healthy controls; P &lt; .001). There was a moderate positive correlation between levels of vWF and levels of PASP (r = 0.42; P = .001) and a high positive correlation between D-dimer and PASP (r = 0.52; P &lt; .001) CONCLUSIONS The presence of pulmonary arterial hypertension in patients with extensive slow-flow vascular malformations is not an isolated feature but is relatively frequent. Levels of D-dimer correlate with PASP in these patientsArch Dermatol.2010;146(12):1347-1352--

BACKGROUND Sclerotherapy with polidocanol microfoam injection under duplex guidance is a new treatment for venous malformations associated with Klippel-Trenaunay syndrome. Multidetector-row computed tomography (MDCT) venography is extremely helpful in the assessment of disease extension and the planning of therapy. OBSERVATION In this particular case, MDCT venography demonstrated the origin, course, and relationship to adjacent anatomical structures of aberrant vessels that configure the superficial venous system with an anatomically normal and patent deep venous system. At the end of the treatment, which consisted of 8 sessions of microfoam sclerotherapy within 12 months, a considerable reduction in the number and size of the percutaneously treated aberrant veins was observed. The obvious clinical improvement was objectively demonstrated with MDCT venography, which showed clear reduction in the number and size of treated veins. Further clinical investigation performed because of isolated migraine episodes related to the sclerotherapy session revealed that the patient had a patent foramen ovale. A transcranial Doppler examination during the procedure showed middle cerebral artery bubbles, which indicated right-to-left shunt. No cerebral damage was observed in a subsequent diffusion-weighted magnetic resonance examination. CONCLUSIONS Microfoam sclerotherapy is an effective treatment option in patients with Klippel-Trenaunay syndrome. MDCT venography allows diagnosis of the disease, planning of therapy, and assessment of response to treatment. Although foam-induced microembolism is a common phenomenon during sclerotherapy, in this report we demonstrate that polidocanol microfoam prepared with a low-nitrogen gas mixture is safe in a patient with a patent foramen ovale.Arch Dermatol. 2009;145(10):1147-1151--

Reactive oxygen species can induce several biological processes by stimulating signal transduction components such as cytosolic free calcium concentration. The physiological significance of the role of biological oxidants in the regulation of calcium signalling pathway as well as the mechanisms of the oxidantstimulation of signal transduction are discussed in this review.

Store-operated Ca2+entry (SOCE) is a major mechanism for Ca2+influx in platelets and other cells. De novo conformational coupling between elements in the plasma membrane and Ca2+stores, where the actin cytoskeleton plays an important regulatory role, has been proposed as the most likely mechanism to activate SOCE in platelets. Here we have examined for the first time changes in platelet F-actin levels on a subsecond time scale. Using stopped-flow fluorimetry and a quenched-flow approach, we provide evidence for the involvement of cofilin in actin filament reorganization and SOCE in platelets. Thrombin (0.1 U/mL) evoked an initial decrease in F-actin that commenced within 0.1 second and reached a minimum 0.9 second after stimulation, prior to the activation of SOCE. F-actin then increased, exceeding basal levels approximately 2.5 seconds after stimulation. Thrombin also induced cofilin dephosphorylation and activation, which paralleled the changes observed in F-actin, and rapid Btk activation. Inhibition of cofilin dephosphorylation by LFM-A13 resulted in the loss of net actin depolymerization and an increased delay in SOCE initiation. These results suggest that cofilin is important for the rapid actin remodeling necessary for the activation of SOCE in platelets through de novo conformational coupling.

Store-operated Ca2+ entry (SOCE) is a major mechanism for Ca2+ influx in platelets and other cells. De novo conformational coupling between elements in the plasma membrane and Ca2+ stores, where the actin cytoskeleton plays an important regulatory role, has been proposed as the most likely mechanism to activate SOCE in platelets. Here we have examined for the first time changes in platelet F-actin levels on a subsecond time scale. Using stopped-flow fluorimetry and a quenched-flow approach, we provide evidence for the involvement of cofilin in actin filament reorganization and SOCE in platelets. Thrombin (0.1 U/mL) evoked an initial decrease in F-actin that commenced within 0.1 second and reached a minimum 0.9 second after stimulation, prior to the activation of SOCE. F-actin then increased, exceeding basal levels approximately 2.5 seconds after stimulation. Thrombin also induced cofilin dephosphorylation and activation, which paralleled the changes observed in F-actin, and rapid Btk activation. Inhibition of cofilin dephosphorylation by LFM-A13 resulted in the loss of net actin depolymerization and an increased delay in SOCE initiation. These results suggest that cofilin is important for the rapid actin remodeling necessary for the activation of SOCE in platelets through de novo conformational coupling.

Galega officinalis L. is a leguminous perennial herb that presents a demonstrated lac-togenic effect. However, it is toxic to the ewe if it is eaten in substantial amounts, due to the presence of some alkaloids. The objective of this work was i) to optimise its management on Mediterranean-type climate regions, and ii) to determine if controlled amounts of G. officinalis could increase milk yield in “Churra” ewes, without toxicity problems. The high level of specificity of the infective rhizobia makes it necessary to inoculate plants with selected strains, prior to the cultivation of G. officinalis. The optimum stand was 160 000 plants ha-1 obtained after broadcast autumn sowing, which in Mediterranean-type climatic conditions increased yield in the first cutting year. Optimum cutting height was between 6 and 10 cm above ground level. The maximum yield was 13 t dry matter ha-1 in the first year, and 10 in the second year which allowed five cuttings per year before flowering. This avoids an increase in alkaloids at flowering. To increase the yield during the second year, delaying of the last cutting to avoid autumn regrowth is proposed. This cut would be left as green manure. Preliminary results on increasing milk yield indicated that a controlled daily dose of 2 g dry matter kg-1 (body weight) from the first month after lambing until the third milk recording 60 days later, led to a 16.90% increase in total milk yield and a 10.86% increase when the milk yield is readjusted to a lactation length of 120 days.

Store-mediated Ca2+ entry (SMCE) is one of the main pathways for Ca2+ influx in non-excitable cells. Recent studies favour a secretion-like coupling mechanism to explain SMCE, where Ca2+ entry is mediated by an interaction of the endoplasmic reticulum (ER) with the plasma membrane (PM) and is modulated by the actin cytoskeleton. To explore this possibility further we have now investigated the role of the actin cytoskeleton in the activation and maintenance of SMCE in pancreatic acinar cells, a more specialized secretory cell type which might be an ideal cellular model to investigate further the properties of the secretion-like coupling model. In these cells, the cytoskeletal disrupters cytochalasin D and latrunculin A inhibited both the activation and maintenance of SMCE. In addition, stabilization of a cortical actin barrier by jasplakinolide prevented the activation, but not the maintenance, of SMCE, suggesting that, as for secretion, the actin cytoskeleton plays a double role in SMCE as a negative modulator of the interaction between the ER and PM, but is also required for this mechanism, since the cytoskeleton disrupters impaired Ca2+ entry. Finally, depletion of the intracellular Ca2+ stores induces cytoskeletal association and activation of pp60src, which is independent on Ca2+ entry. pp60src activation requires the integrity of the actin cytoskeleton and participates in the initial phase of the activation of SMCE in pancreatic acinar cells.

Vascular endothelial growth factor (VEGF), the most potent angiogenic factor identified to date, is associated with growth and metastasis of solid tumours, including melanoma. It has been shown in vitro that melanoma cells produce raised concentrations of VEGF. We examined the VEGF concentrations in plasma of 20 patients with primary melanoma, local recurrence and metastatic melanoma. We also studied the inhibiting effect of one antioxidant, N-acetylcysteine, on VEGF production in three human melanoma cell lines. We found elevated levels of VEGF (median 205pg ml; 95 percent confidence interval, 80–414) in metastatic melanoma, with respect to primary and locally recurrent melanoma (75pg/ml; 95 percent confidence interval, 35–130). The health control patients had levels of 25pg/ml (95 percent confidence interval, 10–35). Human melanoma cell lines secreted VEGF in basal conditions (550–963±125pg/ml) and N-acetylcysteine (0.5–20mM) significantly decreased the VEGF production in a dose-dependent manner. VEGF concentrations were found to be raised in patients with primary melanoma, local recurrence, and above all, metastatic melanoma (P=0.008). N-acetylcysteine inhibits VEGF production in three human melanoma cell lines. This antioxidant might have therapeutic applications in metastatic melanoma in combination with other cytotoxic drugs.

The influence of two surfactants, sodium taurocholate (STC) and polysorbate 80 (P80), on the bioavailability of albendazole (ABZ), orally administered to rats, has been studied. To assess the effect of the surfactants, they were administered at critical micellar and supramicellar concentrations, 5 and 10 mM for STC and 0.0022 and 0.22% for P80, along with a subclinical dose of 5 mg kg−1of ABZ. Doses of 5 and 10.6 mg kg−1ABZ were also administered as controls. The results show an increase in the sulphoxide AUC values: 55% in the STC 5 mM and 88% in the STC 10 mM and P80 0.0022% treatments when compared to the control ABZ 5 mg kg−1dose. MRT values also show longer‐lasting plasma albendazole sulphoxide concentration following these three treatments, particularly for the P80 0.0022% treatment. While there was no change in the apparent rate of formation of ABZSO, the amount of ABZSO formed was increased significantly by the addition of surfactants (STC 10 mM and P80 0.0022%). © 1998 John Wiley & Sons, Ltd.

The influence of two surfactants, sodium taurocholate (STC) and polysorbate 80 (P80), on the bioavailability of albendazole (ABZ), orally administered to rats, has been studied. To assess the effect of the surfactants, they were administered at critical micellar and supramicellar concentrations, 5 and 10 mM for STC and 0.0022 and 0.22% for P80, along with a subclinical dose of 5 mg kg⁻¹ of ABZ. Doses of 5 and 10.6 mg kg⁻¹ ABZ were also administered as controls. The results show an increase in the sulphoxide AUC values: 55% in the STC 5 mM and 88% in the STC 10 mM and P80 0.0022% treatments when compared to the control ABZ 5 mg kg⁻¹ dose. MRT values also show longer-lasting plasma albendazole sulphoxide concentration following these three treatments, particularly for the P80 0.0022% treatment. While there was no change in the apparent rate of formation of ABZSO, the amount of ABZSO formed was increased significantly by the addition of surfactants (STC 10 mM and P80 0.0022%). © 1998 John Wiley & Sons, Ltd.

REPORT OF A CASE A 78-year-old man presented with a 6-month history of perianal pruritus. His history was noncontributory. His father died of colon carcinoma. Previously, at another hospital, the diagnosis of eczema with possible fungal infection was suggested, and he was treated with topical corticosteroids and antifungals without significant improvement. The patient noted an indurated, damp, painless, and mildly pruritic lesion in the perianal area several weeks earlier.There was an erythematous, slightly elevated, exudative, well-defined plaque with irregular borders (diameter, 4 cm), located in the intergluteal fold near the anus. Around that lesion a symmetrical, erythematous, and slightly desquamative plaque was apparent (Figure 1). Culture was positive for Candida albicans. Topical treatment with an imidazole was begun to limit the extension of the larger lesion. A biopsy specimen of the exudative plaque was stained with hematoxylineosin and is shown in Figure 2.What is your diagnosis?Figure 1.