Tryptophan Modulation in Cancer-Associated Cachexia Mouse Models.

Cancer cachexia is a multifactorial syndrome that interferes with treatment and reduces the quality of life and survival of patients. Currently, there is no effective treatment or biomarkers, and pathophysiology is not clear. Our group reported alterations on tryptophan metabolites in cachectic patients, so we aim to investigate the role of tryptophan using two cancer-associated cachexia syngeneic murine models, melanoma B16F10, and pancreatic adenocarcinoma that is KPC-based. Injected mice showed signs of cancer-associated cachexia as reduction in body weight and raised spleen weight, MCP1, and carbonilated proteins in plasma. CRP and Myostatin also increased in B16F10 mice. Skeletal muscle showed a decrease in quadriceps weight and cross-sectional area (especially in B16F10). Higher expression of atrophy genes, mainly Atrogin1, was also observed. Plasmatic tryptophan levels in B16F10 tumor-bearing mice decreased even at early steps of tumorigenesis. In KPC-injected mice, tryptophan fluctuated but were also reduced and in cachectic patients were significantly lower. Treatment with 1-methyl-tryptophan, an inhibitor of tryptophan degradation, in the murine models resulted in the restoration of plasmatic tryptophan levels and an improvement on splenomegaly and carbonilated proteins levels, while changes in plasmatic inflammatory markers were mild. After the treatment, CCR2 expression in monocytes diminished and lymphocytes, Tregs, and CD8+, were activated (seen by increased in CD127 and CD25 expression, respectively). These immune cell changes pointed to an improvement in systemic inflammation. While treatment with 1-MT did not show benefits in terms of muscle wasting and atrophy in our experimental setting, muscle functionality was not affected and central nuclei fibers appeared, being a feature of regeneration. Therefore, tryptophan metabolism pathway is a promising target for inflammation modulation in cancer-associated cachexia.

Topical heparin as an effective and safe treatment for patients with capecitabine-induced hand-foot syndrome: results of a phase IIA trial supported by proteomic profiling of skin biopsies.

Background: Hand-foot syndrome (HFS) is a common adverse reaction associated with capecitabine chemotherapy that significantly affects the quality of life of patients. This study evaluates the safety and effectiveness of a topical heparin (TH) treatment on the clinical manifestations and anatomopathological alterations of capecitabine-induced HFS. In addition, we performed proteome profiling of skin biopsies obtained from patients with HFS at baseline and after heparin treatment. Methods: Patients with grade ⩽ 2 HFS associated with capecitabine were included in this study. The primary end point was the effectiveness of TH in reducing HFS of any grade. Clinical improvement was evaluated by clinicians, and an improvement was perceived by patients who performed a weekly visual analog scale questionnaire. Secondary end points included a comparative histological analysis and protein expression in skin biopsies at baseline and after 3 weeks of HT treatment. Proteomic profiling was carried out using quantitative isobaric labelling and subsequently validated by a T-array. Results: Twenty-one patients were included in the study. The median TH treatment time was 7.6 weeks (range = 3.6-41.6 weeks), and the median response time was 3.01 weeks (95% CI = 2.15-3.97). At the end of treatment, 19 of 21 patients (90.48%) responded to treatment with a decrease in one or more grades of HFS. None of the patients experienced adverse effects related to TH usage, nor did they suspend chemotherapy treatment. The main findings observed in skin biopsies after treatment were a decrease in hyperkeratosis and lymphocytic infiltrates. The proteomic analysis showed altered expression of 34 proteins that were mainly related to wound healing, cell growth, and the immune response. Conclusion: Based on our results, topical heparin is an effective and safe treatment for clinical manifestations of HFS, probably due to the restauration of skin homeostasis after heparin treatment, as supported by our proteomics-derived data. Trial registration: EudraCT 2009-018171-13.

Overactivated transport in the localized phase of the superconductor-insulator transition.

Beyond a critical disorder, two-dimensional (2D) superconductors become insulating. In this Superconductor-Insulator Transition (SIT), the nature of the insulator is still controversial. Here, we present an extensive experimental study on insulating NbxSi1-x close to the SIT, as well as corresponding numerical simulations of the electrical conductivity. At low temperatures, we show that electronic transport is activated and dominated by charging energies. The sample thickness variation results in a large spread of activation temperatures, fine-tuned via disorder. We show numerically and experimentally that this originates from the localization length varying exponentially with thickness. At the lowest temperatures, there is an increase in activation energy related to the temperature at which this overactivated regime is observed. This relation, observed in many 2D systems shows that conduction is dominated by single charges that have to overcome the gap when entering superconducting grains.

Tumor-Stromal Interactions in a Co-Culture Model of Human Pancreatic Adenocarcinoma Cells and Fibroblasts and Their Connection with Tumor Spread.

One key feature of pancreatic ductal adenocarcinoma (PDAC) is a dense desmoplastic reaction that has been recognized as playing important roles in metastasis and therapeutic resistance. We aim to study tumor-stromal interactions in an in vitro coculture model between human PDAC cells (Capan-1 or PL-45) and fibroblasts (LC5). Confocal immunofluorescence, Enzyme-Linked Immunosorbent Assay (ELISA), and Western blotting were used to evaluate the expressions of activation markers; cytokines arrays were performed to identify secretome profiles associated with migratory and invasive properties of tumor cells; extracellular vesicle production was examined by ELISA and transmission electron microscopy. Coculture conditions increased FGF-7 secretion and α-SMA expression, characterized by fibroblast activation and decreased epithelial marker E-cadherin in tumor cells. Interestingly, tumor cells and fibroblasts migrate together, with tumor cells in forming a center surrounded by fibroblasts, maximizing the contact between cells. We show a different mechanism for tumor spread through a cooperative migration between tumor cells and activated fibroblasts. Furthermore, IL-6 levels change significantly in coculture conditions, and this could affect the invasive and migratory capacities of cells. Targeting the interaction between tumor cells and the tumor microenvironment might represent a novel therapeutic approach to advanced PDAC.

Prevalence of Hypoproteinemia and Hypoalbuminemia in Pregnant Women from Three Different Socioeconomic Populations.

Protein requirements of pregnant women are increased due to anatomical and physiological changes. However, optimal levels of plasma proteins do not receive adequate attention from health professionals and researchers. We aimed to evaluate the plasma protein status in pregnant women receiving care at health centers, with the intention of identifying potential deficiency states and their relationship with quality of life during pregnancy. This is a population-based, prospective, and observational study among a cohort of 215 pregnant women from three different socioeconomic areas (urban, semi-urban, and rural). Blood samples in the first (T1), second (T2), and third (T3) trimester of pregnancy were obtained to quantify the proteins and albumin levels. Statically significant differences regarding the age of pregnant women (p = 0.002), education status (p = 0.034), and socioeconomic level (p = 0.000), were found among groups. Prevalence of protein and albumin deficits was much higher in women from rural and semi-urban areas than in women from urban areas (p = 0.001). Moreover, these deficits were associated with the appearance of edema. Plasma total protein deficit could be an undervalued public health problem in pregnant women receiving prenatal care that could affect the quality of life in the gestational period. It would be important to establish reference intervals for plasma protein monitoring in each trimester of pregnancy, and protein levels should be measured routinely throughout pregnancy.

Use of semisynthetic dura mater substitute as a patch graft for prosthesis extrusion in anophthalmic socket. / Uso de sustituto semisintético de duramadre como injerto tras extrusión de prótesis en una cavidad anoftálmica.

We present a case report of a three-year old patient diagnosed with retinoblastoma in her left eye. The course of the disease made enucleation of the latter eye and a prosthesis implant necessary. Two years after surgery, partial prosthesis extrusion occurred and a semisynthetic dura mater substitute was used as a patch graft to cover the defect. To our knowledge, semisynthetic dura mater substitutes' use in this scenario has not been previously reported.

A spatial ecology study in a high-diversity host community to understand blood-feeding behaviour in Phlebotomus sandfly vectors of Leishmania.

Molecular studies indicate that Phlebotomine sandflies (Diptera: Psychodidae) blood feed on many vertebrate species, of which only a few are proven parasite reservoirs. Investigating sandfly vector feeding preferences is therefore important and requires taking into account the availability and accessibility of host species. In terms of the latter, it is necessary to consider the metabolic cost to the insect of reaching the host and moving on to a suitable breeding site. The present study used statistical modelling to compare the feeding patterns of Phlebotomus perniciosus (n = 150), Phlebotomus papatasi (n = 35) and Phlebotomus ariasi (n = 7) on each of an average of 30 host species in a wildlife park in Murcia, Spain. Sandfly feeding movement costs were estimated as a function of the distance and altitude gradients saved by the insect, assuming that they displayed 'site fidelity'. Most (87%) engorged females were caught <100 m from the host on which they had fed. Although the percentage of bloodmeals was highest on fallow deer (Dama dama) (30%) and red deer (Cervus elaphus) (26%), the predicted feeding probability after considering movement cost was highest for red deer and common eland (Taurotragus oryx), and positively associated with host census. These results suggest that, under similar circumstances, sandflies prefer to feed on some host species more than on others.

Topological phase transition in superconductors with mirror symmetry.

We provide analytical and numerical evidence that the attractive two-dimensional Kitaev model on a lattice with mirror symmetry demonstrates an unusual 'intrinsic' phase at half filling. This phase emerges in the phase diagram at the boundary separating two topological superconductors with opposite Chern numbers and exists due to the condensation of non-zero momentum Cooper pairs. Unlike Fulde-Ferrell-Larkin-Ovchinnikov superconductivity, the Cooper pairs momenta are lying along two lines in the Brillouin zone meaning simultaneous condensation of a continuum of Cooper pairs.

Blood Predictive Biomarkers for Patients With Non-small-cell Lung Cancer Associated With Clinical Response to Nivolumab.

BACKGROUND: Immunotherapy is a promising cancer treatment, but surrogate biomarkers of clinical efficacy have not been fully validated. The aim of this work was to evaluate several biomarkers as predictors of response to nivolumab monotherapy in patients with non-small-cell lung cancer. PATIENTS AND METHODS: Blood samples was collected at baseline, at 2 months after treatment start, and at disease progression. Lactate dehydrogenase level (LDH), neutrophils, and leukocyte values were obtained from medical record. Interleukin (IL)-8, IL-11, and kynurenine/tryptophan levels were determined by enzyme-linked immunosorbent assay. Total protein was extracted from circulating CD8+ T cells, and BCL-2 interacting mediator of cell death (BIM) protein expression tested by western blotting. RESULTS: Baseline LDH levels were significantly higher in non-responder patients than in those who responded (P = .045). The increase in indoleamine 2,3 dioxygenase activity was related to progression of disease, mainly in patients who did not respond to nivolumab treatment (P = .001). Increased levels of circulating IL-8 were observed in initially responding patients at time of progression, and it was related to lower overall survival (hazard ratio, 7.49; P = .025). A highest expression of BIM in circulating CD8+ T cells could be related to clinical benefit. The Student t test and Mann-Whitney U test were used to compare groups for continuous variables. Time to events was estimated using the Kaplan-Meier method, and compared by the log-rank test. CONCLUSIONS: Changes in plasma LDH and IL-8, indoleamine 2,3 dioxygenase activity, and BIM expression in CD8+ T cells could be used to monitor and predict clinical benefit from nivolumab treatment in these patients.

Blood mRNA expression of REV3L and TYMS as potential predictive biomarkers from platinum-based chemotherapy plus pemetrexed in non-small cell lung cancer patients.

PURPOSE: Therapeutic options for cancer patients have increased in the last years, although drugs resistance problem remains unresolved. Genetic background in individual susceptibility to cancer treatment could influence the therapy responses. The aim of this study was to explore the feasibility of using blood 4 genes (AEG-1, BRCA-1, REV3L and TYMS) expression levels as a predictor of the efficacy of pemetrexed therapy in patients with advanced non-small cell lung cancer. METHODS: Sixteen patients from the Medical Oncology Department at "12 de Octubre" Hospital, were included in the study. Total mRNA was isolated from blood samples, and gene expression was analyzed by RT-qPCR. A panel of lung tumor cell lines were used in cell proliferation tests and siRNA-mediated silencing assays. RESULTS: Similarity between blood gene expression levels and protein expression in matched tumor tissue was observed in 54.54% (REV3L) and 81.81% (TYMS) of cases. Gene expression of REV3L and TYMS in blood correlated directly and inversely, respectively, with progression-free survival and overall survival in the patients from our cohort. In tumor cell lines, the knockdown of REV3L conferred resistance to pemetrexed treatment, and the TYMS silencing increased the pemetrexed sensitivity of tumor cells. CONCLUSIONS: The use of peripheral blood samples for expression quantification of interest genes is an affordable method with promising results in the evaluation of response to pemetrexed treatment. Therefore, expression levels of REV3L and TYMS genes might be used as predictive biomarkers in advanced NSCLC patients.

Delayed infectious keratitis in a patient with radial keratotomy and floppy eyelid syndrome treated with simple interrupted stitches. / Queratitis infecciosa tardía en paciente con queratotomía radial y síndrome del párpado flácido tratado con puntos sueltos.

A 55-year-old male presented with an infectious keratitis in his left eye, affecting one of the incisions of the radial keratotomy he had undergone thirty-four years ago. Suturing the incision with two simple interrupted stitches was key to the resolution of the infection. Floppy eyelid syndrome was also found in this patient. Could this act as a risk factor for infectious keratitis in radial keratotomy? To our knowledge, this is the first reported case describing the association between both conditions, and the second reported case where sutures have been used as an adjuvant treatment in these types of cases.

Gender-Related Differences on Polyamine Metabolome in Liquid Biopsies by a Simple and Sensitive Two-Step Liquid-Liquid Extraction and LC-MS/MS.

Polyamines are involved in the regulation of many cellular functions and are promising biomarkers of numerous physiological conditions. Since the concentrations of these compounds in biological fluids are low, sample extraction is one of the most critical steps of their analysis. Here, we developed a comprehensive, sensitive, robust, and high-throughput LC-MS/MS stable-isotope dilution method for the simultaneous determination of 19 metabolites related to polyamine metabolism, including polyamines, acetylated and diacetylated polyamines, precursors, and catabolites from liquid biopsies. The sample extraction was optimized to remove interfering compounds and to reduce matrix effects, thus being useful for large clinical studies. The method consists of two-step liquid-liquid extraction with a Folch extraction and ethyl acetate partitioning combined with dansyl chloride derivatization. The developed method was applied to a small gender-related trial concerning human serum and urine samples from 40 obese subjects. Sex differences were found for cadaverine, putrescine, 1,3-diaminopropane, γ-aminobutyric acid, N8-acetylspermidine, and N-acetylcadaverine in urine; N1-acetylspermine in serum; and spermine in both serum and urine. The results demonstrate that the developed method can be used to analyze biological samples for the study of polyamine metabolism and its association with human diseases.

Cyclosporine 0.1% (Ikervis®) treatment in steroid-dependent dupilumab-associated conjunctivitis. / Tratamiento con ciclosporina al 0,1% (Ikervis®) en conjuntivitis corticodependiente asociada a dupilumab.

Dupilumab is a drug that has recently been approved by the Food and Drug Administration (FDA) and European Medical Agency (EMA) for the treatment of moderate-to-severe atopic dermatitis in adults. An increase in frequency of conjunctivitis related to dupilumab treatment has been reported in recent publications and clinical trials. We report two steroid-dependent cases satisfactorily treated with cyclosporine 0.1% (Ikervis®). To our knowledge there are no reported cases of dupilumab-associated conjunctivitis treated with cyclosporine 0.1% (Ikervis®).

Multiple immunofluorescence assay identifies upregulation of Active ß-catenin in prostate cancer.

OBJECTIVES: To apply a systems pathology-based approach to the quantification of nuclear Active ß-catenin and human leukocyte antigen class I, and assess the biomarker involvement in a cohort of prostate tumor patients. RESULTS: The systems pathology approach applied allows a precise quantification of the marker expression in the different cell compartments as well as the determination of the areas that coexpress two markers. Our data shows that the accumulation of ß-catenin in the nuclear compartment is significantly decreased in the adjacent normal areas when compared to tumor of the same patients (p < 0.001). In conclusion, the application of this novel multiple immunofluorescence assay demonstrates that the upregulation of Active ß-catenin is a relatively common feature of prostate tumor development, and further supports the activation of the Wnt/ß-catenin pathway in prostate cancer progression.

Hypertensive choroidopathy and adrenal carcinoma: A new association. / Coroidopatía hipertensiva y carcinoma adrenal: una nueva asociación.

A 17 year-old Caucasian female presented with decreased vision, with no other symptoms reported at that time. Ophthalmological examination revealed typical signs of hypertensive choroidopathy, Elschnig spots, and Siegrist streaks. Further medical examination found high blood pressure (220/155mmHg), with a metastatic hormone-secreting adrenal carcinoma being the underlying cause of these alterations. To our knowledge, this is the first reported case of hypertensive choroidopathy associated with adrenal carcinoma.

Coexistent central retinal vein and artery occlusion in a patient with psoriasis receiving ustekinumab. / Oclusión coexistente de vena y arteria central de la retina en un paciente con psoriasis en tratamiento con ustekinumab.

A 44 year-old Caucasian male with a history of plaque psoriasis currently being treated with ustekinumab presented with sudden loss of vision in his left eye. Fundus examination showed central retinal vein occlusion coexisting with central retinal artery occlusion. Posterior examination revealed mild polycythemia, being the underlying cause unknown.

Therapy with Ulipristal Acetate in a Hypertensive Patient.

Ulipristal acetate (UPA) is a medical therapy for patients with symptomatic uterine fibroids. The drug has shown efficacy in the control of heavy menstrual bleeding and, as a consequence, in anaemia improvement. We report the case of a hypertensive patient treated with two courses of UPA. In addition to its observed benefits on hypermenorrhea caused by uterine fibroids, no exacerbation of the underlying disease was observed. No adverse effects were observed, and blood pressure levels were well controlled throughout.

Epidemiological and genetic studies suggest a common Leishmania infantum transmission cycle in wildlife, dogs and humans associated to vector abundance in Southeast Spain.

Leishmania infantum infection was investigated in 202 wild carnivores, rodents and lagomorphs in Southeast Spain using a real-time PCR (rtPCR) in skin and organ samples, mostly spleen. Lesions compatible with leishmaniosis were not observed in any of the animals. Prevalence defined as the percentage of rtPCR-positive animals was 32% overall, and 45% in foxes (n = 69), 30% in rabbits (n = 80) and stone martens (n = 10), 19% in wood mice (n = 16), 0% in black rats (n = 10) and ranged between 0% and 100% in other minoritarian species including badgers, wild cats, wolves, raccoons, genets and hares. Most infected rabbits were rtPCR-positive in skin and not in spleen samples and the opposite was the case for foxes (p < 0.05). L. infantum prevalence was lowest in spring following months of non-exposure to phlebotomine sand fly vectors, and spatially matched recently estimated Phlebotomus perniciosus vector abundance and the prevalence of subclinical infection in dogs and humans. Prevalence increased with altitude and was greater in drier and less windy South and West compared to the coastal Southeast of the study area (p < 0.05). Genetic diversity of L. infantum from foxes, investigated by PCR-restriction fragment length polymorphisms of kinetoplast DNA, revealed B genotype in all animals, which is frequent in people and dogs in the Iberian Peninsula and Morocco. The study provides further evidence that subclinical L. infantum infection is widespread in wildlife with prevalence depending on environmental factors and that parasite tissue tropism may vary according to host species. Moreover, it suggests that sylvatic and domestic transmission cycles are closely interconnected.