A signature of circulating microRNAs predicts the response to treatment with FOLFIRI plus aflibercept in metastatic colorectal cancer patients.

The benefit of adding the antiangiogenic drug aflibercept to FOLFIRI regime in metastatic colorectal cancer (CRC) patients resistant to or progressive on an oxaliplatin-based therapy has been previously demonstrated. However, the absence of validated biomarkers to predict greater outcomes is a major challenge encountered when using antiangiogenic therapies. In this study we investigated profiles of circulating microRNAs (miRNAs) to build predictive models of response to treatment and survival. Plasma was obtained from 98 metastatic CRC patients enrolled in a clinical phase II trial before receiving FOLFIRI plus aflibercept treatment, and the circulating levels of 754 individual miRNAs were quantified using real-time PCR. A distinct signature of circulating miRNAs differentiated responder from non-responder patients. Remarkably, most of these miRNAs were found to target genes that are involved in angiogenic processes. Accordingly, some of these miRNAs had predictive value and entered in predictive models of response to therapy, progression of disease, and survival of patients treated with FOLFIRI plus aflibercept. Among these miRNAs, circulating levels of hsa-miR-33b-5p efficiently discriminated between responder and non-responder patients and predicted the risk of disease progression. Moreover, the combination of circulating VEGF-A and miR-33b-5p levels improved clinical stratification of metastatic CRC patients who were to receive FOLFIRI plus aflibercept treatment. In conclusion, our study supports circulating miRNAs as valuable biomarkers for predicting better outcomes in metastatic CRC patients treated with FOLFIRI plus aflibercept.

Morphological and ultrasonographic characterization of the three zones of supratesticular region of testicular artery in Assaf rams.

To fully understand the histological, morphometrical and heamodynamic variations of different supratesticular artery regions, 20 mature and healthy Assaf rams were examined through ultrasound and morphological studies. The testicular artery images of the spermatic cord as shown by B-mode analysis indicated a tortuous pattern along its course toward the testis, although it tends to be less tortuous close to the inguinal ring. Doppler velocimetric values showed a progressive decline in flow velocity, in addition to pulsatility and vessel resistivity when entering the testis, where there were significant differences in the Doppler indices and velocities among the different regions. The peak systolic velocity, pulsatility index and resistive index were higher in the proximal supratesticular artery region, followed by middle and distal ones, while the end diastolic velocity was higher in the distal supratesticular region. The total arterial blood flow and total arterial blood flow rate reported a progressive and significant increase along the testicular cord until entering the testis. Histological examination revealed presence of vasa vasorum in the tunica adventitia, with their diameter is higher in the proximal supratesticular zone than middle and distal ones. Morphometrically, the thickness of the supratesticular artery wall showed a significant decline downward toward the testis; meanwhile, the outer arterial diameter and inner luminal diameter displayed a significant increase distally. The expression of alpha smooth muscle actin and vimentin was higher in the tunica media of the proximal supratesticular artery zone than in middle and distal ones.

Cutaneous reactions after SARS-CoV-2 vaccination: a cross-sectional Spanish nationwide study of 405 cases.

BACKGROUND: Cutaneous reactions after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are poorly characterized. OBJECTIVE: To describe and classify cutaneous reactions after SARS-CoV-2 vaccination. METHODS: A nationwide Spanish cross-sectional study was conducted. We included patients with cutaneous reactions within 21 days of any dose of the approved vaccines at the time of the study. After a face-to-face visit with a dermatologist, information on cutaneous reactions was collected via an online professional survey and clinical photographs were sent by email. Investigators searched for consensus on clinical patterns and classification. RESULTS: From 16 February to 15 May 2021, we collected 405 reactions after vaccination with the BNT162b2 (Pfizer-BioNTech; 40·2%), mRNA-1273 (Moderna; 36·3%) and AZD1222 (AstraZeneca; 23·5%) vaccines. Mean patient age was 50·7 years and 80·2% were female. Cutaneous reactions were classified as injection site ('COVID arm', 32·1%), urticaria (14·6%), morbilliform (8·9%), papulovesicular (6·4%), pityriasis rosea-like (4·9%) and purpuric (4%) reactions. Varicella zoster and herpes simplex virus reactivations accounted for 13·8% of reactions. The COVID arm was almost exclusive to women (95·4%). The most reported reactions in each vaccine group were COVID arm (mRNA-1273, Moderna, 61·9%), varicella zoster virus reactivation (BNT162b2, Pfizer-BioNTech, 17·2%) and urticaria (AZD1222, AstraZeneca, 21·1%). Most reactions to the mRNA-1273 (Moderna) vaccine were described in women (90·5%). Eighty reactions (21%) were classified as severe/very severe and 81% required treatment. CONCLUSIONS: Cutaneous reactions after SARS-CoV-2 vaccination are heterogeneous. Most are mild-to-moderate and self-limiting, although severe/very severe reactions are reported. Knowledge of these reactions during mass vaccination may help healthcare professionals and reassure patients.

VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense desmoplastic stroma that limits the delivery of anticancer agents. VCN-01 is an oncolytic adenovirus designed to replicate in cancer cells with a dysfunctional RB1 pathway and express hyaluronidase. Here, we evaluated the mechanism of action of VCN-01 in preclinical models and in patients with pancreatic cancer. METHODS: VCN-01 replication and antitumor efficacy were evaluated alone and in combination with standard chemotherapy in immunodeficient and immunocompetent preclinical models using intravenous or intratumoral administration. Hyaluronidase activity was evaluated by histochemical staining and by measuring drug delivery into tumors. In a proof-of-concept clinical trial, VCN-01 was administered intratumorally to patients with PDAC at doses up to 1×1011 viral particles in combination with chemotherapy. Hyaluronidase expression was measured in serum by an ELISA and its activity within tumors by endoscopic ultrasound elastography. RESULTS: VCN-01 replicated in PDAC models and exerted antitumor effects which were improved when combined with chemotherapy. Hyaluronidase expression by VCN-01 degraded tumor stroma and facilitated delivery of a variety of therapeutic agents such as chemotherapy and therapeutic antibodies. Clinically, treatment was generally well-tolerated and resulted in disease stabilization of injected lesions. VCN-01 was detected in blood as secondary peaks and in post-treatment tumor biopsies, indicating virus replication. Patients had increasing levels of hyaluronidase in sera over time and decreased tumor stiffness, suggesting stromal disruption. CONCLUSIONS: VCN-01 is an oncolytic adenovirus with direct antitumor effects and stromal disruption capabilities, representing a new therapeutic agent for cancers with dense stroma. TRIAL REGISTRATION NUMBER: EudraCT number: 2012-005556-42 and NCT02045589.

Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases.

BACKGROUND: The cutaneous manifestations of COVID-19 disease are poorly characterized. OBJECTIVES: To describe the cutaneous manifestations of COVID-19 disease and to relate them to other clinical findings. METHODS: We carried out a nationwide case collection survey of images and clinical data. Using a consensus we described five clinical patterns. We later described the association of these patterns with patient demographics, the timing in relation to symptoms of the disease, the severity and the prognosis. RESULTS: The lesions may be classified as acral areas of erythema with vesicles or pustules (pseudo-chilblain) (19%), other vesicular eruptions (9%), urticarial lesions (19%), maculopapular eruptions (47%) and livedo or necrosis (6%). Vesicular eruptions appear early in the course of the disease (15% before other symptoms). The pseudo-chilblain pattern frequently appears late in the evolution of the COVID-19 disease (59% after other symptoms), while the rest tend to appear with other symptoms of COVID-19. The severity of COVID-19 shows a gradient from less severe disease in acral lesions to more severe in the latter groups. The results are similar for confirmed and suspected cases, in terms of both clinical and epidemiological findings. Alternative diagnoses are discussed but seem unlikely for the most specific patterns (pseudo-chilblain and vesicular). CONCLUSIONS: We provide a description of the cutaneous manifestations associated with COVID-19 infection. These may help clinicians approach patients with the disease and recognize cases presenting with few symptoms. What is already known about this topic? Previous descriptions of cutaneous manifestations of COVID-19 were case reports and mostly lacked illustrations. What does this study add? We describe a large, representative sample of patients with unexplained skin manifestations and a diagnosis of COVID-19, using a consensus method to define morphological patterns associated with COVID-19. We describe five clinical patterns associated with different patient demographics, timing and prognosis, and provide illustrations of these patterns to allow for easy recognition.

The correlation between immune subtypes and consensus molecular subtypes in colorectal cancer identifies novel tumour microenvironment profiles, with prognostic and therapeutic implications.

BACKGROUND: Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1-C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs). METHODS: Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs. RESULTS: Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-ß dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways. CONCLUSIONS: The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRC patients.

Lead(ii) soaps: crystal structures, polymorphism, and solid and liquid mesophases.

The long-chain members of the lead(ii) alkanoate series or soaps, from octanoate to octadecanoate, have been thoroughly characterized by means of XRD, PDF analysis, DSC, FTIR, ssNMR and other techniques, in all their phases and mesophases. The crystal structures at room temperature of all of the members of the series are now solved, showing the existence of two polymorphic forms in the room temperature crystal phase, different to short and long-chain members. Only nonanoate and decanoate present both forms, and this polymorphism is proven to be monotropic. At higher temperature, these compounds present a solid mesophase, defined as rotator, a liquid crystal phase and a liquid phase, all of which have a similar local arrangement. Since some lead(ii) soaps appear as degradation compounds in oil paintings, the solved crystal structures of lead(ii) soaps can now be used as fingerprints for their detection using X-ray diffraction. Pair distribution function analysis on these compounds is very similar in the same phases and mesophases for the different members, showing the same short range order. This observation suggests that this technique could also be used in the detection of these compounds in disordered phases or in the initial stages of formation in paintings.

Giant periurethral condyloma acuminata in a 2-year-old girl: Successful treatment with carbon dioxide laser / Condiloma acuminado periuretral gigante en niña de 2 años: tratamiento exitoso con láser de dióxido de carbono

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Probiotic administration improves sperm quality in asthenozoospermic human donors.

The objective of this study is to analyse the effect of the ingestion of two selected antioxidant probiotics strains (Lactobacillus rhamnosus CECT8361 and Bifidobacterium longum CECT7347) on sperm quality parameters in asthenozoospermic males after three and six weeks of administration. Nine asthenozoospermic men without any medical treatment under similar diet conditions participated in the study. The quality of individual sperm samples was evaluated before (previous to ingestion), during (after 3 and 6 weeks of ingestion) and after probiotic administration (3 and 6 weeks after finishing the treatment). Sperm motility was evaluated by computer-assisted sperm analysis system, DNA fragmentation by sperm chromatin structure assay, cell viability by flow cytometry and measurement of intracellular H2O2 (reactive oxygen species; ROS) by flow cytometry using dichloro-dihydrofluorescein diacetate. Sperm motility was drastically improved after the treatment (approximately 6 fold change), DNA fragmentation was statistically reduced after probiotic administration from (approximately 1.2 fold change) and intracellular H2O2 level was decreased (approximately 3.5 fold change). Cell viability was not affected by the treatment. The significant improvement in sperm motility and the decrease in DNA fragmentation reported in this study provide preliminary evidence that probiotics could be administrated to improve motility and decrease DNA fragmentation and ROS levels in asthenozoospermic human males.

Treatment of nail psoriasis with Pulse Dye Laser plus calcipotriol betametasona gel vs. Nd:YAG plus calcipotriol betamethasone gel: an intrapatient left-to-right controlled study / Tratamiento de psoriasis ungueal con Pulse dye laser frente a Nd: YAG, en asociación con gel de betametasona: un estudio con control intrapaciente izquierda-derecha

BACKGROUND: Treatment of nail psoriasis remains a challenging and often disappointing situation. OBJECTIVE: To compare the efficacy, adverse reactions and tolerability of treatment of nail psoriasis with PDL vs. Nd:YAG, in association with betametasona calcipotriol gel. METHODS: An open, prospective intrapatient left-to-right study was designed. The right hand of each patient received treatment with PDL and the left hand with Nd:YAG. Betamethasone calcipotriol gel was applied once a day during the first week after each laser session. A total of four sessions were administered. RESULTS: The clinical efficacy was evaluated according to the NAPSI score. All patients showed improvement in nail bed and nail matrix psoriasis. The global NAPSI mean declined in 15.46 (p < 0.000). There was neither statistical difference between the reduction in nail bed and matrix NAPSI nor in the treatment with PDL vs. Nd:YAG. The administration of Nd:YAG was more painful. No serious adverse effects were documented. Limitations. No random assignment and the small number of patients. CONCLUSIONS: PDL and Nd:YAG have proven to be an effective treatment for nail psoriasis with no serious adverse effect. No statistically significant difference was found between the two treatments

ANTECEDENTES: El tratamiento de la psoriasis ungueal es una situación de difícil manejo y a menudo decepcionante para el dermatólogo. OBJETIVO: Comparar la eficacia, las reacciones adversas y la tolerabilidad del tratamiento de la psoriasis ungueal con PDL vs. Nd: YAG en asociación con gel de betametasona calcipotriol. MÉTODOS: Estudio prospectivo abierto con control intrapaciente izquierda-derecha. La mano derecha de cada paciente recibió tratamiento con PDL y la mano izquierda con Nd: YAG. Se aplicó gel de betametasona calcipotriol una vez al día durante la primera semana después de cada sesión de láser en las 2 manos. Se administraron un total de 4 sesiones. RESULTADOS: La eficacia clínica se evaluó de acuerdo con la escala NAPSI. Todos los pacientes mostraron una mejoría en las lesiones del lecho y de la matriz ungueal. La media global del NAPSI disminuyó en 15,46 (p < 0,000). No hubo diferencia significativa entre la mejoría de las lesiones del lecho y la matriz ni en el tratamiento con el PDL vs. Nd: YAG. La administración de Nd: YAG fue más dolorosa. No se documentaron efectos adversos graves. Limitaciones. Falta de asignación aleatoria y muestra pequeña. CONCLUSIONES: PDL y Nd: YAG han demostrado ser tratamientos eficaces para la psoriasis ungueal sin documentarse efectos adversos graves. No se encontró diferencia estadística significativa entre los 2 tratamientos

Treatment of nail psoriasis with Pulse Dye Laser plus calcipotriol betametasona gel vs. Nd:YAG plus calcipotriol betamethasone gel: An intrapatient left-to-right controlled study.

BACKGROUND: Treatment of nail psoriasis remains a challenging and often disappointing situation. OBJECTIVE: To compare the efficacy, adverse reactions and tolerability of treatment of nail psoriasis with PDL vs. Nd:YAG, in association with betametasona calcipotriol gel. METHODS: An open, prospective intrapatient left-to-right study was designed. The right hand of each patient received treatment with PDL and the left hand with Nd:YAG. Betamethasone calcipotriol gel was applied once a day during the first week after each laser session. A total of four sessions were administered. RESULTS: The clinical efficacy was evaluated according to the NAPSI score. All patients showed improvement in nail bed and nail matrix psoriasis. The global NAPSI mean declined in 15.46 (p<0.000). There was neither statistical difference between the reduction in nail bed and matrix NAPSI nor in the treatment with PDL vs. Nd:YAG. The administration of Nd:YAG was more painful. No serious adverse effects were documented. LIMITATIONS: No random assignment and the small number of patients. CONCLUSIONS: PDL and Nd:YAG have proven to be an effective treatment for nail psoriasis with no serious adverse effect. No statistically significant difference was found between the two treatments.

Analysis of DNA damage after human sperm cryopreservation in genes crucial for fertilization and early embryo development.

Sperm cryopreservation is widely used in clinic for insemination, in vitro fertilization and other procedures such as intracytoplasmic sperm injection. The assessment after freezing/thawing of spermatozoa viability, motility and sometimes DNA integrity (mainly using fragmentation assays) has been considered enough to guarantee the safety and effectiveness of the technique. However, it is known that, even when fragmentation is absent, a significant DNA damage could be detected in some genome regions. This is particularly important considering that, during the last years, several studies have pointed out the importance of key paternal genes in early embryo development. In this study, using normozoospermic donors, we present a candidate gene approach in which we quantify the number of lesions produced by freezing/thawing over key genes (PRM1, BIK, FSHB, PEG1/MEST, ADD1, ARNT, UBE3A, SNORD116/PWSAS) using quantitative PCR. Our results demonstrated that the cryopreservation protocol used, which is routinely employed in clinic, produced DNA lesions. The genes studied are differentially affected by the process, and genome regions related to Prader-Willi and Angelman syndromes were among the most damaged: SNORD116/PWSAS (4.56 ± 1.84 lesions/10 kb) and UBE3A (2.22 ± 1.3 lesions/10 kb). To check if vitrification protocols could reduce these lesions, another experiment was carried out studying some of those genes with higher differences in the first study (FSHB, ADD1, ARNT and SNORD116/PWSAS). The number of lesions was not significantly reduced compared to cryopreservation. These results could be relevant for the selection of the most adequate available cryopreservation protocol in terms of the number of lesions that produced over key genes, when no differences with other traditional techniques for DNA assessment could be detected.

Evaluation of zebrafish (Danio rerio) PGCs viability and DNA damage using different cryopreservation protocols.

Cryopreservation of primordial germ cells (PGCs) is a better alternative for the conservation of the diploid genome in fish until embryo cryopreservation is achieved. A good cryopreservation protocol must guarantee high survival rates but also absence of genetic damage. In this study, a cell toxicity test using several internal and external cryoprotectants was carried out. The best combination of cryoprotectants (DMSO 5 mol/L, ethylene glicol (EG) 1 mol/L, polyvinyl pyrrolidone (PVP) 4%) was used with and without antifreeze proteins (AFPs) at two different concentrations (10 mg/mL and 20 mg/mL) for cryopreservation trials. Different cryopreservation methods were used with single PGCs, genital ridges, and whole zebrafish embryos using cryovials, 0.5 mL straws, microcapsules, and microdrops. All embryos were obtained from the vasa EGFP zf45 transgenic line and viability was evaluated using trypan blue. High cell viability rates after cryopreservation in 0.5 mL straws were obtained (around 90%) and a decrease in viability was only observed when cells were cryopreserved in microcapsules and when AFP at 20 mg/mL was added to the freezing media. Genetic damage was determined by comet assay and was compared in cells cryopreserved in 0.5 mL straws and microcapsules (lowest viability rate). There were significantly more DNA strand breaks after cryopreservation in the cells cryopreserved without cryoprotectants and in those cryopreserved in microcapsules. Genetic damage in the cells cryopreserved with cryoprotectants in 0.5 mL straws was similar to fresh control samples, regardless of the concentration of AFP used. The decrease in PGC viability with the addition of AFP 20 mg/mL did not correlate with an increase in DNA damage. This study reported a successful method for zebrafish PGC cryopreservation that not only guarantees high cell survival but also the absence of DNA damage.

Metabolic syndrome in adolescents in the Balearic Islands, a Mediterranean region.

BACKGROUND AND AIMS: To determine the prevalence of metabolic syndrome (MetS) and its components in adolescents in the Balearic Islands, in the western Mediterranean Sea. METHODS AND RESULTS: A cross-sectional nutritional survey was carried out in the Balearic Islands (2007-2008). A random sample (n=362, 143 boys and 219 girls) of the adolescent population (12-17 years) was interviewed, anthropometrically measured, and provided a fasting blood sample. The MetS prevalence was determined by the ATP III criteria adapted for youths. Adherence to the Mediterranean diet (MD) was defined according to a score constructed considering the consumption of MD components: high monounsaturated fatty acids (MUFA)/saturated fatty acids (SFA) ratio, moderate ethanol consumption, high legume, cereals and roots, fruit, vegetables, and fish consumption, and low meat and milk consumption. The overall MetS prevalence was 5.8% (boys 10.5%, girls 2.7%). MetS criteria were met by 10.0% of overweight, 45.5% of obese and in 1.8% of normal weight adolescents. Half of the adolescents (49.7%) had at least one MetS component. None of the adolescents had all five risk factors. High triglyceride level (90.5%), hypertension (85.7%), low HDL cholesterol level (78.9%) and central obesity (71.4%) were common among adolescents with MetS whereas hyperglycaemia (0.6%) was infrequent. Higher adherence to MD was associated with significantly lower odds ratio of having MetS, but half of the adolescents showed high adherence to MD. CONCLUSION: MetS prevalence was significant among adolescents in the Balearic Islands, especially among obese boys. A high adherence to MD in adolescents was associated with a low prevalence of the MetS criteria.

Thermal and structural study of the crystal phases and mesophases in the lithium and thallium(i) propanoates and pentanoates binary systems: formation of mixed salts and stabilization of the ionic liquid crystal phase.

The temperature and enthalpy vs composition phase diagrams of the binary systems [xC(2)H(5)CO(2)Li + (1 - x)C(2)H(5)CO(2)Tl], and [x(n-C(4)H(9)CO(2)Li) + (1 - x)n-C(4)H(9)CO(2)Tl], where x is the mole fraction, were determined by DSC. Both binary systems display the formation of one 2:1 mixed salt each (at x = 0.667) that appear as a peritectic (incongruent melting) at T(fus) = 512.0 K, and T(fus) = 461.1 K, with Delta(fus)H(m) = 13.76 and 8.08 kJ.mol(-1) for Li-Tl (I) propanoates, and n-pentanoate mixed salts, respectively. The thermotropic liquid crystal of the thallium(I) n-pentanoate transforms into a more stable liquid-crystal phase, which appears in the phase diagram between 380 and 488 K and for x = 0 up to x = 0.56. The crystal structure of thallium(I) propanoate and of the two mixed salts were obtained via X-ray synchrotron radiation diffraction measurements. These compounds present a bilayered structure similar to the two pure lithium salts previously found by our group.