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Monkeypox DNA has been detected in skin lesions, saliva, oropharynx, urine, semen, and stool of patients infected during the 2022 clade IIb outbreak; however, the viral dynamics within these compartments remain unknown. We aimed to characterise the viral load kinetics over time in various parts of the body.This was an observational, prospective, multicentre study of outpatients diagnosed with monkeypox in two hospitals and two sexual health clinics in Spain between June 28, 2022, and Sept 22, 2022. Men and women aged over 18 years were eligible if they reported having symptom onset within the previous 10 days of presentation, and were ineligible if disease was severe enough to be admitted to hospital. Samples were collected from five body locations (skin lesions, oropharynx, rectum, semen or vagina, and a dried blood spot) at six time points up to 57 days after the screening visit. Samples were analysed by quantitative PCR and a subset by cell culture. The primary endpoint was time from symptom onset to viral DNA clearance.Overall, 1663 samples were collected from 77 study participants. 75 (97%) participants were men, the median age was 35·0 years (IQR 29·0-46·0), and 39 (51%) participants were living with HIV. The median time from symptom onset to viral clearance was 25 days (95% CI 23-28) in the skin lesions, 16 days (13-19) in the oropharynx, 16 days (13-23) in the rectum, 13 days in semen (9-18), and 1 day in blood (0-5). The time from symptom onset to viral clearance for 90% of cases was 41 days (95% CI 34-47) in skin lesions and 39 days (27-56) in semen. The median viral load in skin lesions was 7·3 logIn immunocompetent patients with mild monkeypox disease, PCR data alone would suggest a contact isolation period of 3 to 6 weeks but, based on detection of replication-competent virus, this time could be reduced. Based on findings from this cohort of patients, semen testing and prolonged use of condoms after recovery from monkeypox might not be necessary.University Hospital Germans Trias i Pujol and the YoMeCorono.For the Spanish translation of the abstract see Supplementary Materials section.

Unstable thoracolumbar spinal injuries benefit from surgical fixation. However, perioperative complications significantly affect outcomes in surgicallytreated spine patients. We evaluated associations between risk factors and postoperative complications in patients surgically treated for thoracolumbar spine fractures.We conducted a retrospective multicenter study collating data from 21 spine centers across 9 countries on the treatment of AOSpine types B and C injuries of the thoracolumbar spine treated via a posterior approach. Comparative analysis was performed between patients with postoperative complications and those without. Univariate and multivariable analyses were performed.Among 535 patients, at least 1 complication occurred in 43%. The most common surgical complication was surgical-site infection (6.9%), while the most common medical complication was urinary tract infection (13.8%). Among 136 patients with American Spinal Injury Association (ASIA) Impairment Scalelevel A disability, 77.9% experienced at least 1 complication. The rate of complications also rose sharply among patients waiting3 days for surgery (P0.001), peaking at 68.4% among patients waiting ≥30 days. On multivariable analysis, significant predictors of complications were surgery at a governmental hospital (odds ratio = 3.38, 95% confidence interval = 1.73-6.60), having ≥1 comorbid illness (2.44, 1.61-3.70), surgery delayed due to health instability (2.56, 1.50-4.37), and ASIA Impairment Scalelevel A (3.36, 1.78-6.35), while absence of impairment (0.39, 0.22-0.71), ASIAlevel E (0.39, 0.22-0.67) and, unexpectedly, delay caused by operating room unavailability (0.60, 0.36-0.99) were protective.Types B and C thoracolumbar spine injuries are associated with a high risk of postoperative complications, especially common at governmental hospitals, and among patients with comorbidity, health instability, longer delays to surgery, and worse preoperative neurologic status.

Introduction Widespread white matter abnormalities and alterations in glutamate levels have been reported in patients with schizophrenia. We hypothesized that alterations in white matter integrity and glutamate levels in individuals at clinical high risk (CHR) for psychosis are associated with the subsequent development of psychosis. Methods Participants included 33 antipsychotic naive CHR (Female 7/Male 26, Age 19.55 (4.14) years) and 38 healthy controls (Female 10/Male 28, Age 20.92 (3.37) years). Whole brain diffusion tensor imaging for fractional anisotropy (FA) and right frontal white matter proton magnetic resonance spectroscopy for glutamate levels were acquired. CHR participants were clinically followed for 2 years to determine conversion to psychosis. Results CHR participants that transitioned to psychosis (N = 7, 21%) were characterized by significantly lower FA values in the posterior thalamic radiation compared to those who did not transition and healthy controls. In the CHR group that transitioned to psychosis only, positive exploratory correlations between glutamate levels and FA values of the posterior thalamic radiation and the retrolenticular part of the internal capsule and a negative correlation between glutamate levels and the cingulum FA values were found. Conclusion The results of the present study highlight that alterations in white matter structure and glutamate are related with the conversion to psychosis.

The calcineurin pathway is often activated in mycosis fungoides. We aimed to assess the activity and safety of topical pimecrolimus, a calcineurin inhibitor, in patients with early mycosis fungoides.PimTo-MF was a single-arm, multicentre, phase 2 trial done at six medical centres in Spain. Patients (aged ≥18 years) had histologically confirmed early mycosis fungoides (stages IA-IIA) and an Eastern Cooperative Oncology Group performance status of 0-1. Key exclusion criteria included the use of concurrent treatments for mycosis fungoides, including sunbathing, topical or systemic corticosteroids, and other calcineurin inhibitors. Patients applied topical pimecrolimus 1% cream on their skin lesions twice daily for 16 weeks (1 g per 2% of body surface), with subsequent follow-up of 12 months. Dosage modifications were not allowed. To evaluate adherence to the treatment, patients were instructed to return all empty tubes to the hospital (as per drug accountability protocols). The primary endpoint was the overall response ratein the intention-to-treat population. PimTo-MF is registered with EudraCT, 2014-001377-14, and is complete.Between March 1, 2015, and Sept 30, 2016, 39 patients were enrolled. All patients were assessable, with a median age of 51·5 years (IQR 45-62), and the population was predominantly male (24 male [62%], 15 female [38%]). Median follow-up after baseline was 5·7 years (IQR 5·7-6·2). 22 (56%) of 39 patients had an overall response (one complete response, 21 partial responses). Responses were observed across IA (14 [54%] of 26 patients) and IB (eight [73%] of 11 patients) clinical stages, but not IIA. Topical pimecrolimus was well tolerated and no patient required a dose reduction or discontinued treatment because of unacceptable drug-related toxicity. No patients were lost to follow-up or discontinued treatment. 13 (33%) of 39 patients reported adverse events; transitory mild burning or pruritus (grade 1) was the most common, seen in eight (21%) patients. In three (8%) of these patients, the burning or pruritus was considered related to treatment. No grade 4 or 5 adverse events were observed.Pimecrolimus 1% cream seems active and safe in patients with early stage mycosis fungoides. Our findings should be taken with caution until long-term follow-up data are obtained that confirm the safety of this treatment. Further controlled clinical trials are warranted to confirm these results.Instituto de Salud Carlos III and the European Regional Development Fund.For the Spanish translation of the abstract see Supplementary Materials section.

Objective Inhalant users may develop toluene leukoencephalopathy, a devastating neuropsychiatric disorder. We present a case of toluene-induced damage to the corticospinal and the corticonuclear tracts, which presented with involuntary emotional expression disorder. Methods Case study of a 20-year-old man with a 3-year history of frequent solvent abuse was admitted to the Neuropsychiatry Unit of the National Institute of Neurology and Neurosurgery because “he could not speak or walk” but would keep “laughing and crying without reason”. Results Neuropsychiatric examination revealed pathological laughter and crying, facial and speech apraxia, a bilateral pyramidal syndrome, and lack of control of urinary sphincter. Magnetic resonance imaging revealed a highly selective bilateral damage to the pyramidal system and the somatosensory pathway. SPECT imaging showed left fronto-parietal hypoperfusion. Conclusions This document provides support for the understanding of involuntary emotional expression disorders as a differential diagnosis in the clinical practice of psychiatrists, as well as the functional anatomy of these conditions.

This study was approved by the institutional ethical review board (CEIC) of Hospital 12 de Octubre (Madrid, Spain) and institutional review board information is04.625 version September 26th2018 on Act 20/18 dated by November 13th2018. Written informed consent was obtained from all participants. Conflict of Interest StatementJohan Skog has patents for exosome-based technologies and is an employee and shareholder of Bio-techne. J. Aquiles Sanchez is an employee of Bio-techne. Lisa Meyer, Daniel Enderle and Mikkel Noerholm are former employees of Bio-techne. Authors declare no additional conflicts of interes To the editor, cutaneous melanoma in its early stages is a curable disease by surgery of skin lesions. However, intermediate stages display variable outcomes. BRAF V600 mutations are the most frequent alterations in melanoma ocurring in 35-50% of patients ( Luke et al., 2017) and remain informative for guiding first-line treatment election ( Robert et al., 2019). We would like to thank Carmen María García, Sara Sánchez-Redondo, Vanesa Santos and Juan García-Agulló for technical support. This work has been funded by Fundación AECC (LABAE19027PEIN) (H.P.), Grupo Español de Melanoma (H.P.), Fundación BBVA (H.P.), FIS PI-17/00957 (P.L.O-R) and Centro de Excelencia “Severo Ochoa” (CEX2019-000891-S) (S.G-S.). No

Risk calculators for prediction of conversion of Clinical High-Risk (CHR) individuals to syndromal psychosis have recently been developed and have generated considerable clinical use and research interest. Predictor variables in these calculators have been clinical rather than biological, and our goal was to incorporate a neurochemical imaging measure into this framework and assess its impact on prediction. We combined striatal glutamate 1H MRS data with the SIPS symptoms identified by the Columbia Risk Calculator as having the greatest predictive value in order to develop an imaging-based risk calculator for conversion to psychosis. We evaluated the calculator in 19 CHR individuals, 7 (36.84%) of whom converted to syndromal psychosis during the 2-year follow up. The receiver operating characteristic (ROC) curve for the logistic model including only striatal glutamate and visual perceptual abnormalities showed an AUC = 0.869 (95% CI = [0.667, 1.000]) and AUCoa = 0.823, with sensitivity of 0.714, specificity of 0.917, positive predictive value of 0.833, and negative predictive value of 0.846. These results represent modest improvements over each of the individual ROC curves based on either striatal glutamate or visual perceptual abnormalities alone. The preliminary model building and evaluation presented here in a small CHR sample suggests that the approach of incorporating predictive imaging measures into risk classification is not only feasible but offers the potential of enhancing risk assessment.

Diazinon (DZN) is an organophosphate pesticide characterized by inhibiting the enzyme acetylcholinesterase (AChE) (E.C. 3.1.1.7), affecting the nervous system. There is currently enough evidence proving this pesticide also affects the immune response; however, the immunotoxicity mechanisms through which these substances exerts toxic effects remain unclear. For that reason, this work evaluated the effect of diazinon on the intracellular calcium flux, ERK1/2 phosphorylation (pERK1/2), apoptosis, senescence, and mitochondrial membrane potential (ΔΨm) in spleen mononuclear cells (SMNC) of Nile tilapia, a teleost fish of commercial and ecological relevance. The results obtained indicate that diazinon causes significant damage in all evaluated parameters, which play an essential role in intracytoplasmic signaling of immune cells, suggesting these signal pathways could be related with the immunotoxicity mechanism of these type of pesticides.

A new set of four fluorinated aromatic poly(benzamide imide)s was synthesized with the objective of preparing condensation polymers with good processability while maintaining high chemical resistance, thermal stability and good mechanical properties. Their synthesis was carried out using commercially available cycloalkane substituted diamines, 3,5-dinitrbenzoyl chloride and 4,4'-(hexafluoroisopropylidene)diphthalic anhydride (6FDA) as starting materials. The research was focused on the influence of pendant groups and the testing of a computational methodology that could help to predict polymer properties based on their structure and available QSPR models. To this end, extensive tests were performed on these new poly(imide)s including, IR, NMR, X-ray diffraction, UV absorption, thermal stability, mechanical tests, gas permeation and solubility analyses. The results showed that the materials obtained present properties similar to many available commercial poly(imide)s. On the other hand, computational simulations demonstrated that the strategy followed could be useful in reducing the number of compounds to be synthesized and at the same time, maximize the success ratio of finding polymers with certain desired properties.

Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas.In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/mBetween Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group.Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene.Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

Context Cutaneous T-cell lymphomas (CTCLs) are rare non-Hodgkin lymphomas that present in skin and include mycosis fungoides (MF) and Sezary syndrome (SS) subsets. Leukemic involvement is an independent prognostic factor affecting overall and disease-specific survival and increasing the risk of disease progression (Agar 2010, Am Soc J Clin Oncol). CTCL has serious negative effects on patient quality of life (QoL). Therefore, treatment goals include reducing the burden of disease, delaying progression, and improving or preserving QoL. Objective This post hoc analysis of MAVORIC trial data sought to determine whether baseline blood tumor burden affected treatment effects on patient QoL. Design The Phase 3 MAVORIC trial (NCT01728805) compared vorinostat 400 mg daily PO to mogamulizumab 1.0 mg/kg weekly for the first 28-day cycle, then on days 1 and 15 of subsequent cycles. Patient-reported outcome (PRO) analysis of health-related QoL (HRQoL) was performed using the validated Skindex-29 and FACT-G (Functional Assessment of Cancer Therapy-General) instruments. Pruritus was assessed using ItchyQoL and Pruritus Likert scales. All PROs were administered at baseline; Skindex-29 and FACT-G were then administered at every other treatment visit (Cycle 1, 3, 5, …), and ItchyQoL and Pruritus Likert scales were administered every 4 weeks at each cycle. Results Overall, no statistically significant differences between mogamulizumab and vorinostat were seen for patients without blood involvement. Statistically significant differences were seen for patients with blood involvement, with mogamulizumab-treated patients seeing statistically significant improvement in Skindex-29 for treatment Cycles 3–11 in all domains (emotional, functional, symptoms) and in the functional domain of ItchyQoL at most time points. In mogamulizumab-treated patients with blood involvement, the Pruritus Likert Scale score showed a reduction in itch from Cycle 1 and a trend toward reducing levels of itch over 12 cycles. The FACT-G Total Score showed the greatest improvement from baseline for mogamulizumab-treated patients with blood involvement compared to those without blood involvement and all vorinostat-treated patients. Conclusions Mogamulizumab patients with blood involvement saw greater HRQoL improvement than those without blood involvement. Mogamulizumab offers QoL benefit, assessed across a number of PROs, especially to patients with blood involvement (B1 or B2). Supported by Kyowa Kirin, Inc.

Introduction Recent studies have observed that patients with treatment-resistant schizophrenia as well as patients with schizophrenia who do not respond within a medication trial exhibit excess activity of the glutamate system. In this study we sought to replicate the within-trial glutamate abnormality and to investigate the potential for structural differences and treatment-induced changes to improve identification of medication responders and non-responders. Methods We enrolled 48 medication-naive patients in a 4-week trial of risperidone and classified them retrospectively into responders and non-responders using clinical criteria. Proton magnetic resonance spectroscopy and T1-weighted structural MRI were acquired pre- and post-treatment to quantify striatal glutamate levels and several measures of subcortical brain structure. Results Patients were classified as 29 responders and 19 non-responders. Striatal glutamate was higher in the non-responders than responders both pre- and post-treatment (F1,39 = 7.15, p = .01). Volumetric measures showed a significant group x time interaction (t = 5.163, Conclusions Combining anatomic measures with glutamate levels offers the potential to enhance classification of responders and non-responders to antipsychotic medications as well as to provide mechanistic understanding of the interplay between neuroanatomical and neurochemical changes induced by these medications. Ethical statement The study was approved by the Ethics and Scientific committees of the Instituto Nacional de Neurologia y Neurocirugia in Mexico City. All participants over 18 years fully understood and signed the informed consent; in case the patient was under 18 years, informed consent was obtained from both parents. Participants did not receive a stipend.

Higher temperatures and reduced rainfalls that are expected with the advance of climate change can impair the emergence and establishment of tree seedlings in forest ecosystems. These climatic changes can also decrease the availability of soil resources and reduce the performance of seedlings. We evaluated these effects in a temperate forest from Mexico with two native oak species (Quercus crassifolia and Quercus eduardii). As recently emerged oak seedlings are highly sensitive to changing environmental conditions, our field experiment was conducted across the season in which seedling emergence occurs (October–February). In the field, we used open-top chambers to increase temperature and rainout shelters to reduce rainfall, while controls were exposed to the current climate. Experimental plots of both treatments were established beneath the forest canopy because most oaks recruit in understory habitats. In these plots, we sowed acorns of both species in October 2015 and recorded seedling emergence and survival until February 2016, also monitoring temperature, precipitation and contents of water and nitrogen in the soil. On seedlings that survived until the end of the experiment we measured their growth, photosynthetic efficiency and foliar contents of water, carbon and nitrogen. Both the emergence and survival of Q. crassifolia seedlings were lower in climate change plots than in controls, but no differences were found for Q. eduardii. However, seedlings of both species had lower growth rates, photosynthetic efficiencies and contents of water, nitrogen and carbon in climate change simulation plots. These results indicate that climate change can impair tree seedling establishment in oak forest, also suggesting that their development will be constrained by reduced water and nitrogen availability.

Resumen La reciente publicacion de los resultados de ensayos clinicos en los que la diseccion ganglionar no ha demostrado beneficio de supervivencia en pacientes con metastasis en el ganglio centinela plantea la necesidad de modificar el tratamiento del paciente con melanoma. El presente trabajo aporta una actualizacion de la evidencia sobre diferentes aspectos necesarios (vias de progresion metastasica, factores predictores, tratamiento adyuvante, etc.) para la toma de decisiones en el paciente con melanoma y metastasis en el ganglio centinela y plantea un algoritmo de toma de decisiones para este escenario clinico. La evidencia actualmente disponible respalda el abandono de la diseccion ganglionar en aquellos pacientes con metastasis de bajo riesgo en el ganglio centinela (carga tumoral en el ganglio centinela inferior o igual a 1 mm).

Recent publication of the results of clinical trials in which lymph node dissection was not associated with any survival benefit in patients with sentinel node metastasis makes it necessary to reconsider the treatment of patients with melanoma. This article provides an update on the available evidence on the diverse factors (routes of metastatic spread, predictors, adjuvant therapy, etc.) that must be considered when treating patients with sentinel node-positive melanoma. The authors propose a decision-making algorithm for use in this clinical setting. The current evidence no longer supports lymph node dissection in patients with low-risk sentinel node metastasis (sentinel node tumor load ≤ 1 mm).

Background Transcription factor STAT3 has a prominent innate immunity effect on cancer progression. We determined the regulation of STAT3 in the immunophenotype modulation of macrophages from M1 into M2 induced by the cell-culture supernatant of the Prostate-Cancer line PC3. Methods Monocytes-macrophages from healthy donors were cultured in the supernatant of PC3 cells, membrane proteins, and intracytoplasmic and phosphorylated STAT3 were measured using flow cytometry, while cytokines and growth factors were studied using luminescence. Cytotoxicity and nitric oxide were evaluated via colorimetric assays. Results The supernatant of PC3 prostate-tumor cells effectively induced macrophages toward an M2 profile, and the expression of phosphorylated STAT3 in the monocytes-macrophages notably increased, and mainly related to IL-10. In the group of monocytes-macrophages treated with a STAT3 inhibitor, the macrophages were induced toward an M1 phenotype. Conclusions In this study, we showed that the secretion profile of PC3 prostate-cancer cells induces a change in macrophage phenotype from M1 into M2, and that the phenomenon is related to phosphorylation of transcription factor STAT3 and IL-10.

Background Abnormally elevated levels of gamma-aminobutyric acid (GABA) in the medial prefrontal cortex (mPFC) have been reported in antipsychotic-free patients with schizophrenia. Whether such GABA elevations are also present in other brain regions and persist after antipsychotic treatment has not been previously investigated. Methods Twenty-eight antipsychotic-naive patients with first-episode psychosis (FEP) and 18 healthy control subjects completed the study. Following baseline proton magnetic resonance spectroscopy scans targeting the mPFC and a second region, the dorsal caudate, patients with FEP were treated with oral risperidone for 4 weeks at an initial dose of 1 mg/day that was titrated as necessary based on clinical judgment. After the 4-week treatment period, both groups were brought back to undergo outcome magnetic resonance spectroscopy scans, which were identical to the scans conducted at baseline. Results At baseline, higher GABA levels were found both in the mPFC and in the dorsal caudate of patients with FEP compared with healthy control subjects. Following 4 weeks of antipsychotic treatment, GABA levels in patients with FEP decreased relative to baseline in the mPFC, but decreased only at the trend level relative to baseline in the dorsal caudate. For either brain region, GABA levels at 4 weeks or posttreatment did not differ between patients with FEP and healthy control subjects. Conclusions The results of the present study documented elevations of GABA levels both in the mPFC and, for the first time, in the dorsal caudate of antipsychotic-naive patients with FEP, which normalized in both regions following 4 weeks of antipsychotic treatment.

The synthesis of three novel aromatic polyimides (PIs) containing spiro units is described. These PIs are soluble at room temperature in most common organic solvents, facilitating their processability. Additionally, they are highly thermally stable, with thermal decomposition temperatures (Td10%) over 500 °C, and had moderately high Tg values between 230 and 265 °C. Robust self-standing thin films were prepared from these polyimides, via the solution casting method, which were suitable for gas transport measurements. The relatively low permeability and selectivity of these PIs, as compared to Polymers of Intrinsic Microporosity (PIMs) that also contain spirocyclic structures, demonstrate the importance of restricting rotation within the polymer chain, which is a key structural feature of the PIMs.

We present a historic cohort study with 57 patients diagnosed with mycosis fungoides in early stages during the years 1999 to 2002. Our group performed a cDNA microarray on the diagnosis skin biopsies samples with the CNIO (oncologic investigation national center of Spain) Onco-Chip. This chip includes 6386 cancer-related clones. Since the samples were processed in two deferent years the initial set of 57 patients was divided in two groups of 29 and 28 patients due to the heterogeneity of the sample array results. The patients had a medium of 14 years of follow-up and were divided in two groups: progression (development of tumor, nodes, erythroderma, blood involvement or metastasis) and no progression. And we performed volcano pot analysis and GSEA to determine whether there are different genes expressions at diagnosis that determine prognosis. Several pathways were up and down regulated differently in patients progressing. We performed a GSEA analysis with the following results. Pathways related with progression: CXCR4 pathway (p=0.000) Normalized Enrichment Score (NES) 1.91 and FDR 0.027; genes: BCAR1, PXN, PIK3CA, PTK2, PIK3R1, PRKCA, HRAS, RAF1, CXCL12, PIK3C2G, GNB1. Other pathways with p

Time to next treatment (TTNT), a recently established endpoint in clinical trials for primary cutaneous T-cell lymphomas (CTCL), represents a useful indication as a surrogate marker for the durtion of clinical benefit. It is a unique parameter which allows to take into consideration not only the duration of clinical activity of a specific drug regimen but also the patient compliance and tolerability of the treatment schedule. A series of data clearly support the short duration of TTNT in patients with CTCL. The present paper analyses TTNT and time to next systemic treatment (TTNsT) in the PROCLIPI cohort of patients. PROCLIPI registry was established since 2,015 and includes all the new diagnoses of mycosis fungoides/Sezary syndrome (MF/SS) patients in CTCL referral centers worldwide. Untill now, a total of 4,756 treatments were registered among which 2,647 at visit 1. According to the treatment category, 2,364 skin-directed therapies (SDT) were registered (49.7%) and 1,810 systemic (38%), while 482 patients were managed through an expectant policy. TTNT analysis was performed in 2,969 cases who received a further treatment. Median TTNT was 136 days corresponding to 4.5 months for the entire cohort (range from 1 month to 5.7 years. As to TTNsT among 1,743 cases, median values were 169 days (corresponding to 5.6 months (up to 4.3 years). This preliminary analysis confirms the short duration of TTNT and TTNsT in MF/SS patients diagnosed in treated in real life, supporting the importance of identifying clinical and biological markers with predictive value on treatment benefit as well as new treatment approaches aimed to improve disease outcome. on behalf the CLIC Alliance, CLIC Treatment Working Group, EORTC and ISCL collaborative study groups and all the PROCLIPI centers.

The classic Troger's base polymerization of a diamine and dimethoxymethane with trifluoroacetic acid as catalyst generated a Troger's base-type polymer (TBP), which exhibited the absolute insolubility in a variety of organic solvents because of its highly aggregated model. A new porous organic polymer was obtained by a simple Troger's base polymerization reaction between a diamine and formaldehyde in the form of acetal in the presence of trifluoroacetic acid as catalyst. Troger's base-type polymer (TBP) resulted insoluble in a wide range of organic solvents due to its rigid and aromatic structure. TBP was characterized spectroscopically (FT-IR), thermally and morphologically. As result, a thermostable and amorphous polymer bearing pores ranging between 50 and 300 nm and macro-voids of up to 12 μm was obtained. Due to the insolubility of the TBP, it was tested as a metal-free heterogeneous catalyst in the Knoevenagel condensation reaction, showing a high efficiency. For this, the optimal catalyst load, reaction time and reuse of the catalyst were studied using benzaldehyde and malononitrile as substrates. Furthermore, aldehydes with variable chain sizes and ethyl cyanoacetate replacing malononitrile were tested as substrate with a high percent of conversion (97–99%).

Vivipary is the germination of seeds within a fruit before they are shed from the parent plant. Vivipary occurs in a broad range of habitats and species including cacti. The advantages of vivipary in Cactaceae have been poorly studied. Echinocactus platyacanthus is a viviparous endemic and endangered cactus from Mexico. In this study, we determined the vivipary incidence and its benefits in this species. We collected mature fruits of this plant from the fields of two municipalities, Guadalcazar and Vanegas, located in the southern part of the Chihuahuan Desert in San Luis Potosi, Mexico. The seeds in these fruits were classified into three categories: (1) non-viviparous (N-V; from fruits without viviparous seeds), (2) non-viviparous from viviparous plant (N-V-V; from fruits without germinated seeds belonging to a plant with at least one fruit with germinated seeds), and (3) viviparous (V-V, from fruits that contain at least one germinated seed). We evaluated seed germination under three water potential treatments (0, −0.2, and −0.4 MPa). Vivipary incidence was independent of the site. However, we found higher germination of N-V-V and V-V seeds than N-V seeds. Our findings suggest an advantage of viviparous (N-V-V and V-V) phenotypes in germinability, which increases the possibilities of survivorship of wild E. platyacanthus populations and contributes to their natural regeneration in arid environments.

Bovine colostrum contains compounds, which provide passive immune protection from mother to newborn calves. Little is known about cytokine levels and their role in bovine colostrum. Moreover, the capacity of bovine colostrum cells to mount specific immune responses after natural exposure to bovine tuberculosis (bTB) antigens in dairy herds has not been studied, thus far. The purpose of this study was to identify biomarkers for bTB infection measurable in bovine colostrum. The present study reveals that isolated-immune colostrum cells can mount a specific immune response against bTB antigens, by measuring the novo IFN-γ release in cell culture. We found that IFN-γ levels in the responders (Bov+) to bTB antigen were higher than in non-responders (Bov-). On the other hand, proinflammatory cytokines contained in colostrum's whey were tested in Tuberculin Skin Test (TST) reactor (TST+) and non-reactor (TST-) animals to assess their potential role as biomarker. We observed that IFN-γ levels were lower or undetectable, as opposed to IL4 levels were measurable, the TNF-α level was higher in TST- than TST+, while IL-6 levels showed the opposite reaction and with no statistical significance. Moreover, IL-1α mRNA expression levels were higher in colostrum mononuclear cells (CMC) in Bov+ cattle. Collectively, these data suggest that the differential expression of pro and anti-inflammatory cytokines could have relevant value to diagnose bTB in cattle.

Renal cells of the thick ascending limb (TAL) reabsorb NaCl via the apical Na+/K+/2Cl− co-transporter NKCC2. Trafficking of NKCC2 to the apical surface regulates NKCC2-mediated NaCl absorption and blood pressure. The molecular mechanisms by which NKCC2 reaches the apical surface and their role in renal function and maintenance of blood pressure are poorly characterized. Here we report that NKCC2 interacts with the vesicle fusion protein VAMP3, and they co-localize at the TAL apical surface. We observed that silencing VAMP3 in vivo blocks constitutive NKCC2 exocytic delivery, decreasing the amount of NKCC2 at the TAL apical surface. VAMP3 is not required for cAMP-stimulated NKCC2 exocytic delivery. Additionally, genetic deletion of VAMP3 in mice decreased total expression of NKCC2 in the TAL and lowered blood pressure. Consistent with these results, urinary excretion of water and electrolytes was higher in VAMP3 knock-out mice, which produced more diluted urine. We conclude that VAMP3 interacts with NKCC2 and mediates its constitutive exocytic delivery to the apical surface. Additionally, VAMP3 is required for normal NKCC2 expression, renal function, and blood pressure.

Currently, electricity generation and second-generation ethanol production from lignocellulosic feedstocks represent technological alternatives in the bioenergy sector. Nevertheless, the introduction of new production processes denotes a real challenge due to the complexity and diversity of the pathways that can be evaluated. In addition, there are economic and environmental factors that must be considered during the development and consolidation of these new configurations. Accordingly, this paper presents a methodology to perform the exergy and exergo-environmental analysis, and ranking of sugarcane-based biorefineries. The proposed models assessed the Conventional (Route 1), Biochemical (Route 2), and Thermochemical (Route 3) pathways using simulation programs and mathematical tools to simulate the ethanol production and electricity generation. Furthermore, the process integration and different uses for the surplus bagasse were studied, aiming at the optimizing and ranking of routes. The results indicated optimal settings that allowed the routes ranking in terms of the renewability exergy index “λ”. In this context, the biochemical pathway (Route 2) presented the maximum exergy efficiency, therefore the lowest average unitary exergy cost of the evaluated platforms. This system that promoted an increase of 22% and 45% in the ethanol production, when compared to Route 1 and Route 3, respectively. Besides, the thermochemical pathway (Route 3) presented the configuration with the highest power generation rate. Concerning the environmental impact results, it was found that the most sustainable configuration was Route 2, which presented the lowest overall CO2 emissions rates (131.45 gCO2/MJ products).

The era of targeted therapy has introduced a new therapeutic perspective for melanoma patients. Treatment with BRAFV600 inhibitors has improved overall and disease-free survival in metastatic melanoma patients whose tumors harbor BRAFV600 mutations. Although the BRAFV600E mutation appears to have a critical role in tumor initiation, its expression during tumor progression remains controversial. In fact, various authors claim that BRAFV600E heterogeneity is evident in melanoma tumors. Herein, we investigated the pattern of BRAFV600E expression in matched primary and metastatic samples from 140 patients. Using a combination of real-time PCR and immunohistochemical analyses, we demonstrated that BRAFV600E expression is homogeneous in melanoma tumors and hypothesized that the heterogeneity described by others might be attributable to technical issues when molecular methods are used. We also demonstrated the high efficiency of the anti-BRAFV600E VE1 antibody for the detection of BRAFV600E mutations in melanoma tumors.

According to the multifactorial model of cervical cancer (CC) causation, it is now recognized that other modifications, in addition to Human papillomavirus (HPV) infection, are necessary for the development of this neoplasia. Among these, it has been proposed that a dysregulation of the WNT pathway might favor malignant progression of HPV-immortalized keratinocytes. The aim of this study was to identify components of the WNT pathway differentially expressed in CC vs. non-tumorigenic, but immortalized human keratinocytes. Interestingly, WNT7A expression was found strongly downregulated in cell lines and biopsies derived from CC. Restoration of WNT7A in CC-derived cell lines using a lentiviral gene delivery system or after adding a recombinant human protein decreases cell proliferation. Likewise, WNT7A silencing in non-tumorigenic cells markedly accelerates proliferation. Decreased WNT7A expression was due to hypermethylation at particular CpG sites. To our knowledge, this is the first study reporting reduced WNT7A levels in CC-derived cells and that ectopic WNT7A restoration negatively affects cell proliferation and migration.

MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p/5p, miR-21, miR-181a/b, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab/429 cluster, miR-10b, miR-193b, miR-141/200c, and miR-23b/27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p/5p and downregulation of the miR-141/200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients.