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Mitochondria from different types of cancer show bioenergetics and dysfunction that favor cell proliferation. The mechanistic understanding of estrogen in cervical cancer is poorly understood. Therefore, the objective of this study was to determine how 17β‑estradiol (E2) affects mitochondrial function and the Warburg effect in SiHa, HeLa and C33A cervical cancer cells. Mitochondrial compromise was evaluated measuring changes in the membrane permeability by immunofluorescence, calcium concentration, redox status, iron and ferritin reserves. Glucose consumption and lactic acid assays were used to detect the metabolic activity. Results were confirmed at molecular level by analysis of the differential gene expression using RNA sequencing. E2 modified the mitochondrial permeability and produced an alteration in the calcium signaling pathway. In HeLa and SiHa, there was a significant decrease in nitric oxide levels and lipid peroxidation, and an increase in glucose consumption and lactic acid levels when stimulated with E2. Intracellular iron or ferritin reserves were not affected by the E2 treatment. Genes differentially modulated by E2 were involved in the mitochondrial electron transport chain, oxidative phosphorylation system, glycolysis, pentose phosphate pathway and the regulation of metabolic signaling pathways. Herein, we provide evidence for a primary effect of estrogen on mitochondrial function and the Warburg effect, favoring the metabolic adaptation of the cervical cancer cell lines and their survival.

Akodon oenos, a nominal form with type locality in northern Mendoza province, Argentina, has an intricate taxonomic history. Recently, it was considered a junior synonym of Akodon spegazzinii on the basis of morphological similarities of one individual captured in southern Mendoza with specimens belonging to the type series of A. oenos, plus the genetic similarity of that single specimen with representatives of A. spegazzinii. We compared specimens of the Akodon boliviensis species group recently captured in Mendoza with the type series of A. oenos and series of A. spegazzinii from northwestern Argentina. We conducted an analysis of molecular markers (cytochrome-b gene) and quantitative morphological studies (comparisons of skull measurements). Our results showed that: (1) all sequenced specimens of the A. boliviensis group from Mendoza form a monophyletic clade closely related to A. spegazzinii; (2) contrary to previous hypothesis, specimens of Akodon from Mendoza are morphologically distinctive in size and shape of the skull, from A. spegazzinii; and (3) within the A. boliviensis species group, specimens from Mendoza are distinctive. We argue that the synonymy of A. oenos under A. spegazzinii must await further studies, including molecular markers other than mitochondrial and samples of DNA sequences from topotypical specimens of A. oenos.

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.

Background According to WHO, succinate dehydrogenase (SDH)–deficient renal cell carcinoma is characterized by negative immunostaining for SDHB, which remains positive in non-tumor tissue despite germline mutations in the SDHB gene. We now report a patient with a SDHB mutation, c.166_170del (p.Pro56Tyrfs*5) who developed renal cell carcinomas with characteristic morphological features of SDH-deficient renal cell carcinoma but had positive SDHB immunostaining. Case presentation Within a 6-year period, the patient developed two different renal cell carcinomas, which had characteristic morphological features of SDH-deficient renal cell carcinoma (uniform cells characteristically displaying eosinophilic granular material intermixed with fewer cells exhibiting clear intracytoplasmic inclusions and bland centered nuclei) but displayed immunohistochemistry for SDHB with a cytoplasmic granular positivity (mitochondrial pattern) in tumor cells. For the second case, this was initially interpreted as positive by IHC, but on review some subtle differences were identified. Conclusions SDHB immunostaining may be positive in renal cell carcinoma associated to germline SDHB deficiency which have other typical morphological features. Immunohistochemistry interpretation may be complex. Electronic supplementary material The online version of this article (10.1186/s13000-019-0812-6) contains supplementary material, which is available to authorized users.

García-Silva et al. show for the first time that extracellular vesicles isolated from the exudative seroma obtained from the lymphatic drainage implanted in melanoma patients after lymphadenectomy can be interrogated for melanoma markers and BRAF mutations. Profiling the BRAFV600E mutation in this biofluid is a novel approach to predict disease relapse., Liquid biopsies from cancer patients have the potential to improve diagnosis and prognosis. The assessment of surrogate markers of tumor progression in circulating extracellular vesicles could be a powerful non-invasive approach in this setting. We have characterized extracellular vesicles purified from the lymphatic drainage also known as exudative seroma (ES) of stage III melanoma patients obtained after lymphadenectomy. Proteomic analysis showed that seroma-derived exosomes are enriched in proteins resembling melanoma progression. In addition, we found that the BRAFV600E mutation can be detected in ES-derived extracellular vesicles and its detection correlated with patients at risk of relapse., Graphical Abstract

Legal constitutionalism – Political constitutionalism – Emergence of illiberal constitutionalism as a tertium genus – Examination of constitutional courts under three illiberal governments: Poland, Hungary, and Turkey – Illiberal governments’ strategies to seize control of constitutional courts – Illiberal governments’ aim to secure leverage over constitutional judges and restrict the powers of review of the court – Constitutional courts under illiberal rule invert the traditional functions that were assigned to them under the original Kelsenian approach – Instead of a check on power, illiberal constitutional courts become a device to circumvent constitutional constraints and concentrate power in the hands of the ruling actors.

In recent decades, constitutional courts have become essential institutions in the political systems of many European countries. At the legal level, constitutional courts are designed as organs intended to protect and enforce the normative constitution. At the political level, they are also expected to play a role in the protection of democratic systems of government and human rights. However, the stability of a democracy does not only depend on efficient institutional designs, but also on acceptable levels of public support for democratic institutions. Using data from the European Social Survey, this article shows that constitutional courts have negative effects on public views of the court system in at least two dimensions: perceptions of judicial independence and perceptions of judicial fairness. These effects, however, decrease with the age of the democratic system. Given the core role that diffuse support for the judiciary plays in the stability of the rule of law in a country, our findings suggest that, paradoxically, constitutional courts might have detrimental effects to the very goal that justifies their existence: the protection of democratic systems of government.

Endosulfan is a DDT-era organochlorine pesticide. Due to past and current environmental contamination, investigation of endosulfan exposure is of current importance. Acute high dose exposure precipitates neural/endocrine system damage, but the effects on the immune system and of lower doses are not well-characterized. Two relatively low concentrations of endosulfan (i.e. 0.1 and 17 µM ENDO) were investigated in an in vitro study using human peripheral blood mononuclear cells (PBMC) to understand effects of relatively low doses (0.1–25.0 µM [≈0.04–10 ppm/40–10,000 ppb]) of ENDO upon normal human T- and B-lymphocytes and NK cells. The study here found that 17 µM ENDO inhibited phytohemagglutinin-M (PHA)-induced human PBMC proliferation. It was also seen that senescence and apoptosis among non-stimulated cells was increased, specifically within CD8 and NK populations, and that CD4:CD8 ratios also were increased. Treatment of non-stimulated PBMC with ENDO led to overall increases in production of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, -4, and -6, and decreased production of anti-inflammatory IL-10, suggesting an immunosenescence secretory phenotype. Interestingly, when the cells were pre-stimulated with mitogen (PHA), ENDO became inhibitory against the mitogen-induced proliferation and cytokine formation – with the exception of that of TNFα and IL-6, suggesting differential effects of ENDO on activated cells. Thus, at the organismal level, ENDO might also display differential effects during states of autoimmune disease or chronic viral infection in the exposed host.

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.

El presente artículo presenta la situación de los migrantes centroamericanos hacia México y los Estados Unidos. El estudio se centra en el caso de la frontera Petén- Tabasco, bajo la perspectiva de los Derechos Humanos y a través del trabajo de campo, se constata la situación de vulnerabilidad en la que se encuentran los migrantes, quienes con el sueño de mejorar su situación económica terminan pasando por diversos obstáculos en su recorrido.

Background/aim Retinoblastoma (RB) is the most common primary intraocular malignancy. Carboplatin (CPt) is a DNA damage-inducing agent that is widely used for the treatment of RB. Unfortunately, this drug also activates the transcription factor nuclear factor-kappa B (NF-ĸB), leading to promotion of tumor survival. Pentoxifylline (PTX) is a drug that inhibits the phosphorylation of I kappa B-alpha (IĸBα) in serines 32 and 36, and this disrupts NF-ĸB activity that promotes tumor survival. The goal of this study was to evaluate the effect of the PTX on the antitumor activity of CPt. Materials and methods Y79 RB cells were treated with CPt, PTX, or both. Cell viability, apoptosis, loss of mitochondrial membrane potential, the activity of caspase-9, -8, and -3, cytochrome c release, cell-cycle progression, p53, and phosphorylation of IĸBα, and pro- and anti-apoptotic genes were evaluated. Results Both drugs significantly affected the viability of the Y79 RB cells in a time- and dose-dependent manner. The PTX+CPt combination exhibited the highest rate of apoptosis, a decrease in cell viability and significant caspase activation, as well as loss of mitochondrial membrane potential, release of cytochrome c, and increased p53 protein levels. Cells treated with PTX alone displayed decreased I kappa B-alpha phosphorylation, compared to the CPt treated group. In addition, the PTX+CPt combination treatment induced up-regulation of the proapoptotic genes Bax, Bad, Bak, and caspases- 3, -8, and -9, compared to the CPt and PTX individual treated groups. Conclusion PTX induces apoptosis per se and increases the CPt-induced apoptosis, augmenting its antitumor effectiveness.

The following work shows, for the first time, the synthesis and characterization of a new family of polyelectrolytes, along with their preliminary assessments in terms of desalin water treatment. These materials fall into the category of aromatic co-polyamides, which are obtained by the direct condensation of monomers 4,4′-oxydianiline (ODA), isophthaloyl chloride, and 3,5-diamino-N-(pyridin-4-ylmethyl)benzamide (PyMDA). Thereby, the charged nature exhibited by these materials was achieved through the quaternization of PyMDA moieties using linear iodoalkanes of different lengths (CnI with n = 1, 2, 4, and 6). After completing the quaternization process, polyelectrolytes were subjected to a one-step anion substitution process, where iodide counterions were replaced by bis(trifluoromethane)sulfonamide entities. For all the obtained materials, solubility tests were carried out, showing that those alkylated with methyl and ethyl chains exhibit high solubility in rutinary aprotic polar solvents, while those containing n-butyl and n-hexyl units resulted in the formation of insoluble gels. Due to the above, the latest were discarded from this study early on. The structural characterization of the initial neutral co-polyamide was carried out by means of infrared spectroscopy (FT-IR), nuclear magnetic resonance (1H, 13C-NMR), and size-exclusion chromatography (SEC), while the structure of methylated and ethylated polyelectrolytes was successfully confirmed through FT-IR, 1H, 13C, and 19F-NMR. Additionally, the thermal behavior of these materials was analyzed in terms of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), showing thermal degradation temperatures above 300 °C and glass transition temperatures (Tg) above 200 °C, resulting in polymers with outstanding thermal properties for water treatment applications. On the other hand, through the solvent-casting method, both neutral and charged polymers were found to be easily prepared into films, exhibiting a remarkably flexibility. The mechanical properties of the films were analyzed using the traction test, from which tensile strength values ranging between 83.5 and 87.9 Mpa, along with Young’s modulus values between 2.4 and 2.5 Gpa were obtained. Moreover, through contact angle measurements and absorption analysis by immersion, polyelectrolytes showed important changes in terms of affinity against polar and polar substances (water, n-heptane, and benzene), exhibiting a higher rejection regarding the neutral polymer. Finally, as a preliminary test against the seepage of saline waters, thin polymer films (from 11.4 to 17.1 µm) were deposited on top of commercial filter discs and tested as filters of saline solutions ([NaCl] = 1000 and 2000 ppm). These tests revealed a decrease of the salt concentration in the obtained filtrates, with retention values ranging between 6.2 and 20.3%, depending on the concentration of the former solution and the polymer used.

The vertebrate fossil record of the Pampean Region of Argentina occupies an important place in South American vertebrate paleontology. An abundance of localities has long been the main basis for constructing the chronostratigraphical/geochronological scale for the late Neogene–Quaternary of South America, as well as for understanding major patterns of vertebrate evolution, including the Great American Biotic Interchange. However, few independently-derived dates are available for constraining this record. In this contribution, we present new 40Ar/39Ar dates on escorias (likely the product of meteoric impacts) from the Argentinean Atlantic coast and statistically-based biochronological analyses that help to calibrate Late Miocene–Pliocene Pampean faunal successions. For the type areas of the Montehermosan and Chapadmalalan Ages/Stages, our results delimit their age ranges to 4.7–3.7 Ma and ca. 3.74–3.04 Ma, respectively. Additionally, from Buenos Aires Province, dates of 5.17 Ma and 4.33 Ma were recovered for “Huayquerian” and Montehermosan faunas. This information helps to better calibrate important first appearances of allochthonous taxa in South America, including one of the oldest records for procyonids (7.24–5.95 Ma), cricetids (6.95–5.46 Ma), and tayassuids (> 3.74 Ma, oldest high-confidence record). These results also constrain to ca. 3 Ma the last appearances of the autochthonous sparassodonts, as well as terror birds of large/middle body size in South America. South American faunal turnover during the late Neogene, including Late Pliocene extinctions, is interpreted as a consequence of knock-on effects from global climatic changes and initiation of the icehouse climate regime. Fil: Prevosti, Francisco Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de la Rioja. Secretaria de Ciencia y Tecnología; Argentina Fil: Romano Muñoz, Cristo Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina Fil: Forasiepi, Analia Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina Fil: Hemming, Sidney. Columbia University; Estados Unidos Fil: Bonini, Ricardo Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano. Universidad Nacional del Centro de la Provincia de Buenos Aires. Investigaciones Arqueológicas y Paleontológicas del Cuaternario Pampeano; Argentina Fil: Candela, Adriana Magdalena. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Paleontología Vertebrados; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina Fil: Cerdeño Serrano, Maria Esperanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina Fil: Madozzo Jaén, María Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Correlación Geológica. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Departamento de Geología. Cátedra Geología Estructural. Instituto Superior de Correlación Geológica; Argentina. Museo Paleontológico Egidio Feruglio; Argentina Fil: Ortiz, Pablo Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Correlación Geológica. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Departamento de Geología. Cátedra Geología Estructural. Instituto Superior de Correlación Geológica; Argentina Fil: Pujos, François Roger Francis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina Fil: Rasia, Luciano Luis. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Paleontología Vertebrados; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina Fil: Schmidt, Gabriela Ines. Provincia de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Universidad Autónoma de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción; Argentina Fil: Taglioretti, Matias Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Geología de Costas y del Cuaternario. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Geología de Costas y del Cuaternario; Argentina. Litoral Atlántico Norte. Observatorio Patrimonio Arqueológico y Paleontológico; Argentina Fil: Macphee, Ross Douglas Earle. American Museum of Natural History; Estados Unidos Fil: Pardiñas, Ulises Francisco J.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto de Diversidad y Evolución Austral; Argentina. Instituto Nacional de Biodiversidad; Ecuador

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p

Peyronie and Dupuytren are pathologies characterized by the appearance of localized fibrotic lesions in an organ. These disorders originate from an excessive production of collagen in the tissue provoking dysfunction and functional limitations to the patients. Local administration of collagenase is the most used treatment for these fibrotic-type diseases, but a high lability of the enzyme limits its therapeutic efficacy. Herein, we present a novel methodology for the preparation of collagenase nanocapsules without affecting its enzymatic activity and capable of releasing the enzyme in response to an ultraviolet A (UVA) light stimulus. Polymeric coating around collagenase was formed by free-radical polymerization of acrylamide-type monomers. Their degradation capacity under UVA irradiation was provided by incorporating a novel photocleavable acrylamide-type crosslinker within the polymeric framework. This property allowed collagenase release to be triggered in a controlled manner by employing an easily focused stimulus. Additionally, UVA irradiation presents considerable benefits by itself due to its capacity to induce collagenase production in situ. An expected synergistic effect of collagenase nanocapsules in conjunction with UVA effect may present a promising treatment for these fibrotic diseases.

Simple Summary In the last few years, the field of cutaneous T-cell lymphomas has experienced major advances. In the context of an active translational and clinical research field, next-generation sequencing data have boosted our understanding of the main molecular mechanisms that govern the biology of these entities, thus enabling the development of novel tools for diagnosis and specific therapy. Here, we focus on mycosis fungoides and Sézary syndrome; we review essential aspects of their pathophysiology, provide a rational mechanistic interpretation of the genomic data, and discuss the current and upcoming therapies, including the potential crosstalk between genomic alterations and the microenvironment, offering opportunities for targeted therapies. Abstract Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of diseases that affect the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) account for the majority of these lesions and have recently been the focus of extensive translational research. This review describes and discusses the main pathobiological manifestations of MF/SS, the molecular and clinical features currently used for diagnosis and staging, and the different therapies already approved or under development. Furthermore, we highlight and discuss the main findings illuminating key molecular mechanisms that can act as drivers for the development and progression of MF/SS. These seem to make up an orchestrated constellation of genomic and environmental alterations generated around deregulated T-cell receptor (TCR)/phospholipase C, gamma 1, (PLCG1) and Janus kinase/ signal transducer and activator of transcription (JAK/STAT) activities that do indeed provide us with novel opportunities for diagnosis and therapy.

At the onset of the COVID-19 pandemic, the United States Cutaneous Lymphoma Consortium (USCLC) and the European Organisation for Research and Treatment of Cancer Cutaneous Lymphoma Task Force (EORTC-CLTF) developed emergency guidelines for the management of patients with cutaneous lymphomas (CLs) during the pandemic. These emergency protocols were intended to ensure patient safety and called for dose modifications, treatment delays and treatment interruptions as necessary to minimize exposure risks to COVID-19. Because there are no established maintenance protocols for CLs, the impact of such delays or interruptions on disease outcomes was not known. The ISCL created an International Cutaneous Lymphomas Pandemic Section (ICLYPS) to collect data from the institutions around the world to assess the impact of these changes on patients' outcomes and to determine if these measures were effective in preventing infection. We summarize the outcomes from a preliminary cohort of patients from Brazil, Greece, Italy, Spain, Switzerland, the UK and the US. Actively managed patients with an established diagnosis of CL from March to October 2020 were included according to the Institutional Protection of Human Subjects guidelines at the respective centers. We included 149 patients in this retrospective review. The average age was 61.88 years (range: 22–95). 2 patients (1.3%) had diagnoses of CD30+ lymphoproliferative disorders (LyP and pcALCL), 112 (75.2%) had mycosis fungoides (MF), and 35 (23.5%) had Sezary syndrome (SS). 77 patients (68.7%) had stages IA–IIA MF, 23 (20.5%) had Stage IIB MF, 6 (5.4%) had stage III MF, and 41 (27.5%) had Stage IV disease, of which 6 had Stage IV MF (5.4%) and 35 had SS (23.5%). Treatment was delayed for more than half (53.0%) of the patients for a mean of 3.2 months (range: 10 days to 10 months). Treatment delay was associated with a significant risk of disease relapse or progression across all stages (65.8% vs 32.9%, p

INTRODUCTION: Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study. METHODS: Baseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30min

Background The COVID-19 pandemic led to world-wide restrictions on social activities to curb the spread of this disease. Very little is known about the impact of these restrictions on trauma centers. Our objective was to determine the effect of the pandemic-associated lockdown on trauma admissions, patient’s demographics, mechanisms of injury, injury severity, and outcomes in the Puerto Rico Trauma Hospital. Methods An IRB-approved quasi-experimental study was performed to assess the impact of the restrictions by comparing trauma admissions during the lockdown (March 15, 2020 – June 15, 2020) with a control period (same period in 2017–2019). Comparisons were done using the Pearson’s chi-square test, Fisher exact test, or Mann-Whitney U test, as appropriate. A negative binomial model was fitted to estimate the incidence rate ratio for overall admissions among pre-lockdown and during-lockdown periods. Statistical significance was set at p Results A total of 308 subjects were admitted during the quarter of study for 2017; 323, for 2018; 347, for 2019; and 150, for 2020. The median (interquartile range) age of patients rose significantly from 40 (33) years to 49 (30) years (p p = 0.026). Moreover, the proportion of severe cases decreased, as measured by an injury severity score (ISS) > 15 (37.3% vs. 26.8%; p = 0.014); while there were no differences in the median hospital length of stay and the mortality rate between the comparison groups. Finally, the decrease in overall admissions registered during the lockdown accounts for a 59% (IRR 0.41; 95% CI 0.31–0.54) change compared to the pre-lockdown period, when controlling for sex, age, mechanism of injury, and ISS. Conclusions Following periods of social isolation and curfews, trauma centers can expect drastic reductions in their overall patient volume with associated changes in trauma patterns. Our findings will help inform new interventions and improve healthcare preparedness for future or similar circumstances.

Background Apomixis, an asexual mode of plant reproduction, is a genetically heritable trait evolutionarily related to sexuality, which enables the fixation of heterozygous genetic combinations through the development of maternal seeds. Recently, reference floral transcriptomes were generated from sexual and apomictic biotypes of Paspalum notatum, one of the most well-known plant models for the study of apomixis. However, the transcriptome dynamics, the occurrence of apomixis vs. sexual expression heterochronicity across consecutive developmental steps and the orientation of transcription (sense/antisense) remain unexplored. Results We produced 24 Illumina TruSeq®/ Hiseq 1500 sense/antisense floral transcriptome libraries covering four developmental stages (premeiosis, meiosis, postmeiosis, and anthesis) in biological triplicates, from an obligate apomictic and a full sexual genotype. De novo assemblies with Trinity yielded 103,699 and 100,114 transcripts for the apomictic and sexual samples respectively. A global comparative analysis involving reads from all developmental stages revealed 19,352 differentially expressed sense transcripts, of which 13,205 (68%) and 6147 (32%) were up- and down-regulated in apomictic samples with respect to the sexual ones. Interestingly, 100 differentially expressed antisense transcripts were detected, 55 (55%) of them up- and 45 (45%) down-regulated in apomictic libraries. A stage-by-stage comparative analysis showed a higher number of differentially expressed candidates due to heterochronicity discrimination: the highest number of differential sense transcripts was detected at premeiosis (23,651), followed by meiosis (22,830), postmeiosis (19,100), and anthesis (17,962), while the highest number of differential antisense transcripts were detected at anthesis (495), followed by postmeiosis (164), meiosis (120) and premeiosis (115). Members of the AP2, ARF, MYB and WRKY transcription factor families, as well as the auxin, jasmonate and cytokinin plant hormone families appeared broadly deregulated. Moreover, the chronological expression profile of several well-characterized apomixis controllers was examined in detail. Conclusions This work provides a quantitative sense/antisense gene expression catalogue covering several subsequent reproductive developmental stages from premeiosis to anthesis for apomictic and sexual P. notatum, with potential to reveal heterochronic expression between reproductive types and discover sense/antisense mediated regulation. We detected a contrasting transcriptional and hormonal control in apomixis and sexuality as well as specific sense/antisense modulation occurring at the onset of parthenogenesis.

The aging process places the elderly, a worldwide increasing age group, at an increased risk for trauma. This study aims to explore changes over time in admission rates, sociodemographical, clinical, and injury-related data in elderly patients (aged ≥65 y) admitted to the Puerto Rico Trauma Hospital (PRTH) during 2000-2019.A time-series analysis was conducted. Admission rates were analyzed by fitting an exponential growth curve model. Trends were assessed using the Cochrane-Armitage and Cuzick tests for categorical and continuous data, respectively.Elderly admission rates to the PRTH have shown growth over the past 2 decades, from 6.2 cases per 100 overall admissions in 2000 to 18.2 in 2019. This trend is projected to continue with estimated 24.8 (95% CI: 21.7-27.8) cases per 100 overall admissions in 2023. Trends for mechanisms of injury such as motor vehicle accidents and pedestrians showed a significant decrease, whereas falls presented a clear positive trend, showing an increase from 25.6% in 2000-2004 to 46.2% in 2015-2019. Both Injury Severity Score ≥25 and Glasgow Coma Scale ≤8 declined significantly through time. Finally, in-hospital mortality presented a decreasing trend from 31.7% in 2000-2004 to 21.5% in 2015-2019.Our analysis demonstrates an increase over time in elderly admissions, especially fall-related trauma. Also, it projects this upward trend will continue. This imposes new challenges for PRTH and other healthcare services and is a gateway for the implementation of adapted clinical management.

The presence of fossil camelids in Tucuman, northwestern Argentina, has been recognized for many years but its relevance has not been fully evaluated so far. Here, we review previous mentions of fossil camelids for this province, present new material, and compare it with fossil and extant specimens of South American camelids, clarifying its taxonomic context and discussing its paleobiogeographic significance. For Tucuman we recognize Vicugna vicugna (Tafi del Valle Formation, late Pleistocene–early Holocene) and Palaeolama sp. (Tucuman Formation, late Pleistocene), mainly based on size and dental features. The current distribution of V. vicugna is restricted to the Central Andes, in the Puna and High Andean environments over 3200 m altitude; there is no mention, neither current nor historical, for Tucuman. Its presence at around 2200 m in the Tafi valley during the Quaternary indicates cooler and drier conditions than those currently established. The observations made in the context of this contribution allow us to establish that the species V. provicugna is a synonym of V. vicugna. In turn, we consider that the validity of the species Palaeolama hoffstetteri, only based on postcranial remains, should be properly evaluated in the future.

The novel coronavirus disease (COVID-19) is a rapidly spreading pandemic, secondary to severe acute respiratory syndrome coronavirus 2. The severity and the little knowledge that we have of the disease have made us focus mostly on the respiratory symptoms. As we bend the curve, other findings reported in association with COVID-19 become of importance for specialists to recognize. We describe the spectrum of clinicopathologic lesions in the skin that can be the only symptom or the first manifestation of COVID-19 and demonstrate the origin of the virus. We collected 25 patients with skin lesions in this context. We recognized 5 types of cutaneous manifestations including acute acroischemic or chilblain-like lesions (11), purpura palpable (2), exanthemas (9), urticarial eruptions (1), and other lesions (2) that might appear with more unspecific pictures. Chilblain-like lesions were the most common form of presentation, which tend to appear as self-healing, erythematous-necrotic plaques mostly on the feet, in young patients with no systemic symptoms associated. Importantly, we visualized viral particles with electron microscopy in 5 of 13 cases analyzed. In this study, we seek to draw a picture of the spectrum of clinicopathologic lesions that may appear in the skin in the context of COVID-19. Although apparently skin lesions are not correlated with disease severity, it may help in some cases to recognize and control the spread of the infection sooner.

While some papers report an increased risk of COVID-19 and worse outcomes1 in oncological patients, others have found no differences2 . We are not aware of studies assessing risk for COVID-19 and clinical outcomes of patients with Primary Cutaneous Lymphomas (PCL).

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12 p.-4 fig.-4 tab., Rationale & objective: A previous study that evaluated associations of kidney biopsy findings with disease progression in patients with C3 glomerulopathy (C3G) proposed a prognostic histologic index (C3G-HI) that has not yet been validated. Our objective was to validate the performance of the C3G-HI in a new patient population., Study design: Multicenter, retrospective cohort study., Setting & participants: 111 patients fulfilling diagnostic criteria of C3G between January 1995 and December 2019, from 33 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN)., Predictors: Demographic, clinical parameters, C3G-HI total activity score, and the C3G-HI total chronicity score., Outcome: Time to kidney failure., Analytical approach: Intraclass correlation coefficients and κ statistic were used to summarize inter-rater reproducibility for assessment of histopathology in kidney biopsies. The nonlinear relationships of risk of kidney failure with the total activity score and total chronicity score were modeled using Cox proportional hazards analysis that incorporated cubic splines., Results: The study group included 93 patients with C3 glomerulonephritis and 18 with dense-deposit disease. Participants had an overall meanage of 35±22 (SD) years. Forty-eight patients (43%) developed kidney failure after a mean follow-up of 65±27 months. The overall inter-rater reproducibility was very good for the total activity score (intraclass correlation coefficient [ICC]=0.63) and excellent for total chronicity score (ICC=0.89). Baseline estimated glomerular filtration rate (eGFR), 24-hour proteinuria, and treatment with immunosuppression were the main determinants of kidney failure in a model with only clinical variables. Only tubular atrophy and interstitial fibrosis were identified as predictors in a model with histological variables. When the total activity score and total chronicity score were added to the model, only the latter was identified as an independent predictor of kidney failure., Limitations: Only a subset of the kidney biopsies was centrally reviewed. Residual confounding., Conclusions: We validated the performance of C3G-HI as a predictor of kidney failure in patients with C3G. The total chronicity score was the principal histologic correlate of kidney failure., Work in this study was supported by the Instituto de Salud Carlos III /Fondo Europeo de Desarrollo Regional (ISCIII/FEDER) grant PI16/01685 and Red de Investigación Renal (RedInRen) (RD12/0021/0029) (to MP), the Autonomous Region of Madrid (S2017/BMD-3673) (to MP); EGdeJ is supported by the Spanish “Ministerio de Ciencia, Innovación y Universidades" (RYC-2013-13395 and RTI2018-095955-B-100).

We re-evaluate the tribal allocation of Olympicomys vossi, an extinct member of Sigmodontinae (Rodentia, Cricetidae). Originally described from fragmentary jaws, this taxon was considered as a Phyllotini. In light of new remains, including hemimandibles and for the first time an anterior part of the cranium with the upper dentition, we propose that it belongs to the Reithrodontini. The studied materials were collected in coastal outcrops of the Vorohu�� Formation (late Pliocene-early Pleistocene) south of Mar del Plata, Buenos Aires Province, Central Argentina. The reallocation of Olympicomys into Reithrodontini is based on the presence in this genus of several diagnostic characters of this tribe including a deeply excised anterior border of the zygomatic plate, a well-developed zygomatic spine, a shallow area of insertion of the anterior deep masseter muscle, a posteriorly depressed palate, labial accessory roots on upper and lower first molars, three-rooted lower third molar, and a bifid metaflexus on the second upper molar. Chukimys favaloroi and Dankomys vorohuensis, two other Pliocene Argentinean sigmodontines, are suggested as extinct reithrodontines. The restudy of Olympicomys provides elements to discuss the pattern of radiation of Sigmodontinae and to improve the chronostratigraphy of the coastal Neogene sedimentary succession of the Buenos Aires province.

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.