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14-3-3 proteins are a family of structurally similar phospho-binding proteins that regulate essentially every major cellular function. Decades of research on 14-3-3s have revealed a remarkable network of interacting proteins that demonstrate how 14-3-3s integrate and control multiple signaling pathways. In particular, these interactions place 14-3-3 at the center of the signaling hub that governs critical processes in cancer, including apoptosis, cell cycle progression, autophagy, glucose metabolism, and cell motility. Historically, the majority of 14-3-3 interactions have been identified and studied under nutrient-replete cell culture conditions, which has revealed important nutrient driven interactions. However, this underestimates the reach of 14-3-3s. Indeed, the loss of nutrients, growth factors, or changes in other environmental conditions (e.g., genotoxic stress) will not only lead to the loss of homeostatic 14-3-3 interactions, but also trigger new interactions, many of which are likely stress adaptive. This dynamic nature of the 14-3-3 interactome is beginning to come into focus as advancements in mass spectrometry are helping to probe deeper and identify context-dependent 14-3-3 interactions—providing a window into adaptive phosphorylation-driven cellular mechanisms that orchestrate the tumor cell’s response to a variety of environmental conditions including hypoxia and chemotherapy. In this review, we discuss emerging 14-3-3 regulatory mechanisms with a focus on post-translational regulation of 14-3-3 and dynamic protein–protein interactions that illustrate 14-3-3’s role as a stress-adaptive signaling hub in cancer.

Smoking is an established risk factor for pancreatic cancer (PC), but late diagnosis limits the evaluation of its mechanistic role in the progression of PC. We used a well-established genetically engineered mouse model (LSL-K-ras G12D ) of PC to elucidate the role of smoking during initiation and development of pancreatic intraepithelial neoplasia (PanIN). The 10-week-old floxed mice (K-ras G12D ; Pdx-1cre) and their control unfloxed (LSL-K-ras G12D ) littermates were exposed to cigarette smoke (total suspended particles: 150 mg/m 3 ) for 20 weeks. Smoke exposure significantly accelerated the development of PanIN lesions in the floxed mice, which correlated with tenfold increase in the expression of cytokeratin19. The systemic accumulation of myeloid-derived suppressor cells (MDSCs) decreased significantly in floxed mice compared with unfloxed controls ( P <0.01) after the smoke exposure with the concurrent increase in the macrophage ( P <0.05) and dendritic cell (DCs) ( P <0.01) population. Further, smoking-induced inflammation (IFN-γ, CXCL2; P <0.05) was accompanied by enhanced activation of pancreatic stellate cells and elevated levels of serum retinoic acid-binding protein 4, indicating increased bioavailability of retinoic acid which contributes to differentiation of MDSCs to tumor-associated macrophages (TAMs) and DCs. TAMs predominantly contribute to the increased expression of heparin-binding epidermal growth factor-like growth factor (EGFR ligand) in pre-neoplastic lesions in smoke-exposed floxed mice that facilitate acinar-to-ductal metaplasia (ADM). Further, smoke exposure also resulted in partial suppression of the immune system early during PC progression. Overall, the present study provides a novel mechanism of smoking-induced increase in ADM in the presence of constitutively active K-ras mutation.

Objectives 1. To assess the efficacy of Mesenchymal Stromal Cells (MSC) versus a control arm as described in the primary endpoint. 2. To evaluate the effects of MSC on the secondary efficacy endpoints. 3. To evaluate the safety and tolerability profiles of MSC. 4. To study soluble and cellular biomarkers that might be involved in the course of the disease and the response to the investigational product. Trial design A double-blind, randomized, controlled, trial to evaluate the efficacy and safety of MSC intravenous administration in patients with COVID-induced Acute Respiratory Distress Syndrome (ARDS) compared to a control arm. Participants The trial is being conducted at a third level hospital, Hospital Universitario Puerta de Hierro, in Majadahonda, Madrid (Spain). Inclusion criteria 1. Informed consent prior to performing study procedures (witnessed oral consent with written consent by representatives will be accepted to avoid paper handling). Written consent by patient or representatives will be obtained whenever possible. 2. Adult patients ≥18 years of age at the time of enrolment. 3. Laboratory-confirmed SARS-CoV-2 infection as determined by Polymerase Chain Reaction (PCR), in oropharyngeal swabs or any other relevant specimen obtained during the course of the disease. Alternative tests (e.g., rapid antigen tests) are also acceptable as laboratory confirmation if their specificity has been accepted by the Sponsor. 4. Moderate to severe ARDS (PaO2/FiO2 ratio equal or less than 200 mmHg) for less than 96 hours at the time of randomization. 5. Patients requiring invasive ventilation are eligible within 72 hours from intubation. 6. Eligible for ICU admission, according to the clinical team. Exclusion criteria 1. Imminent and unavoidable progression to death within 24 hours, irrespective of the provision of treatments (in the opinion of the clinical team). 2. “Do Not Attempt Resuscitation” order in place. 3. Any end-stage organ disease or condition, which in the investigator’s opinion, makes the patient an unsuitable candidate for treatment. 4. History of a moderate/severe lung disorder requiring home-based oxygen therapy. 5. Patient requiring Extracorporeal Membrane Oxygenation (ECMO), haemodialysis or hemofiltration at the time of treatment administration. 6. Current diagnosis of pulmonary embolism. 7. Active neoplasm, except carcinoma in situ or basalioma. 8. Known allergy to the products involved in the allogeneic MSC production process. 9. Current pregnancy or lactation (women with childbearing potential should have a negative pregnancy test result at the time of study enrolment). 10. Current participation in a clinical trial with an experimental treatment for COVID-19 (the use of any off-label medicine according to local treatment protocols is not an exclusion criteria). 11. Any circumstances that in the investigator’s opinion compromises the patient’s ability to participate in the clinical trial. Intervention and comparator - Experimental treatment arm: Allogeneic MSC (approximately 1 x 10 6 cells/kg). - Control arm: placebo solution (same composition as the experimental treatment, without the MSC). One single intravenous dose of the assigned treatment will be administered on Day 0 of the study. All trial participants will receive standard of care (SOC). In the context of the current worldwide pandemic, SOC can include medicines that are being used in clinical practice (e.g. lopinavir/ritonavir; hydroxy/chloroquine, tocilizumab, etc.), as well as those authorised for COVID (e.g., remdesivir). Main outcomes Primary endpoint: Change in the PaO2/FiO2 ratio from baseline to day 7 of treatment administration, or to the last available PaO2/FiO2 ratio if death occurs before day 7. Secondary endpoints: - All-cause mortality on days 7, 14, and 28 after treatment. - PaO2/FiO2 ratio at baseline and days 2, 4, 7, 14 and 28 after treatment. - Oxygen saturation (by standardized measurement) at baseline, daily until day 14, and on day 28 after treatment. - Time to PaO2/FiO2 ratio greater than 200 mmHg. - Subjects’ clinical status on the WHO 7-point ordinal scale at baseline, daily until day 14, and on day 28 after treatment. - Time to an improvement of one category from admission on the WHO 7-point ordinal scale. - Percentage of patients that worsen at least one category on the WHO 7-point ordinal scale. - Percentage of patients that improve at least one category (maintained 48h) on the WHO 7-point ordinal scale. - Sequential Organ Failure Assessment (SOFA) scale at baseline and days 2, 4, 7, 14 and 28 after treatment. - Duration of hospitalization (days). - Duration of ICU stay (days). - Oxygen therapy-free days in the first 28 days after treatment. - Duration of supplemental oxygen. - Incidence of and duration of non-invasive and invasive mechanical ventilation in the first 28 days after treatment. - Mechanical ventilation-free days in the first 28 days after treatment. - Ventilation parameters. - Incidence of new onset pulmonary fibrosis at 3 and 12 months after treatment, based on CT scan and pulmonary function tests. - Survival at 3 and 12 months. - Cumulative incidence of Serious Adverse events (SAEs) and Grade 3 and 4 Adverse Events (AEs). - Cumulative incidence of Adverse Drug Reactions (ADR) in the experimental treatment arm. - Cumulative incidence of AEs of special interest. - Levels of analytical markers (C-Reactive Protein, lymphocyte and neutrophil counts, lymphocyte subpopulations, LDH, ferritin, D-dimer, coagulation tests and cytokines...) at baseline and days 2, 4, 7, 14 and 28 after treatment. - Other soluble and cellular biomarkers that might be involved in the course of the disease and the response to MSC. Randomisation The assignment to treatment will be carried out randomly and blinded, with a 1:1 allocation. Randomization will be done through a centralized system embedded in the electronic Case Report Form (CRF). Blinding (masking) To ensure blinding, treatments will be prepared for administration at the Cell Production Unit and the administration of the treatment will be masked, not allowing the identification of the Investigational Medicinal Product (IMP). Numbers to be randomised (sample size) A total of 20 participants are planned to be randomized, 10 to each treatment group. Trial Status Protocol version: 1.2, dated October 14th, 2020 Start of recruitment: 01/10/2020 End of recruitment (estimated): December 2020. Trial registration EudraCT Number: 2020-002193-27 , registered on July 14 th , 2020. NCT number: NCT04615429 , registered on November 4 th , 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Complications after unilateral acquired brain injury (ABI) can affect various areas of expertise causing (depending on the location of the lesion) impairment in occupational performance. The aim of this study was to analyze and compare the concepts of occupational performance and functional independence, both before and after a multicomponent intervention including occupational therapy, in persons with unilateral brain damage. This was a longitudinal quasi-experimental pretest post-test study in a sample of 58 patients with unilateral brain injury (28 with traumatic brain injury and 30 with ischemic stroke). The patients' level of independence was measured using the short version of the International Classification of Functioning, Disability and Health. We also measured quality of performance using the Assessment of Motor and Process Skills. The findings of this study showed that patients with injury in the right hemisphere improved more than those with left hemisphere damage (p<0.001). All the patients with ABI, especially those with right-sided injury, derived benefit from the multicomponent intervention, except in the area of motor skills. More research is needed on the specific techniques that might address such skills.

Neurocysticercosis is the main cause of acquired epilepsy in developing countries and is an emerging disease in the United States. Introduction of the immunoblot assay provided a new tool for the diagnosis and monitoring of neurocysticercosis. This study analyzed the relationship between clinical characteristics of cerebral infection (number and type of lesions) plus the baseline response on immunoblot and the changes observed after therapy. Reaction to all 7 diagnostic bands was associated with severe infection (more lesions). Seventeen patients (35%) had no active lesions on computed tomography (CT) 3 months after therapy and were considered cured. Although most cured patients remained seropositive after 1 year, 3 became seronegative before 9 months. In these 3 cases, the lesions had resolved on CT at 3 months. Persistent seropositivity does not necessarily indicate active infection. Serologic follow-up will be clinically helpful only in rare cases in which early antibody disappearance occurs.

We studied temporal variation in adult size and sexual size dimorphism (SSD) of seven hunting spider species, Ctenus amphora, C. crulsi, C. manauara, C. villasboasi (Ctenidae), Phoneutria fera, P. reidyi (Ctenidae), and Ancylometes rufus (Pisauridae) in a tropical rainforest, and one species from a relatively open vegetation habitat, C. minor, in central Amazonia. Size variation was great within and among field trips. Spiders were generally smaller in October (end of dry season) when compared with other months: adults of C. amphora, C. crulsi and C. manauara were significantly smaller in October 1995 when compared to February 1996; P. fera were smaller in October 1998 than in June 1998; and A. rufus were smaller in October 1998 than in August 1998. The temporal variation in size is possibly a result of low prey availability during the dry season. Six species had significant differences in prosoma length between males and females: C. amphora, C. crulsi, C. manauara and C. minor had larger males (which is considered rare in spiders), and P. reidyi and P. fera had larger females. However, considering an alternative index of size, the “rough area” (an approximate measure of the area of the spider as seen from above), the males were significantly larger for all species (up to 2.8 times in C. minor), because they have longer legs relative to their prosoma length. We suggest that selection for high mobility may be the reason for adult males with longer legs, and that the smaller species had higher degrees of sexual dimorphism in leg length because of the relative size of obstacles in the leaf litter. RESUMO. Estudamos a variação temporal de tamanho de adultos e o dimorfismo sexual de tamanho de sete espécies simpátricas de aranhas errantes, Ctenus amphora, C. crulsi, C. manauara, C. villasboasi (Ctenidae), Phoneutria fera, P. reidyi (Ctenidae), e Ancylometes rufus (Pisauridae) em uma floresta tropical úmida, e uma espécie em um habitat de vegetação relativamente aberta, C. minor, na Amazônia Central. A variação de tamanho foi grande dentro e entre excursões de coleta. As aranhas foram geralmente menores em outubro (final da estação seca) comparado com outros meses: adultos de C. amphora, C. crulsi, C. manauara e C. minor foram significativamente menores em outubro de 1995 comparado a fevereiro de 1996: P. fera foram menores em outubro de 1998 do que em junho de 1998 e A. rufus foram menores em outubro de 1998 do que em agosto de 1998. A variação temporal em tamanhos observada é possivelmente um resultado de baixa disponibilidade de presas durante a estação seca. Seis espécies tiveram diferenças significativas em comprimento do cefalotórax entre machos e fêmeas, C. amphora, C. crulsi, C. manauarae C. minor tiveram machos maiores (o que é considerado raro em aranhas), P. reidyi e P. fera tiveram fêmeas maiores. Entretanto, considerando um índice alternativo de tamanho, a “área aproximada” (uma medida da área da aranha em vista superior), os machos foram significativamente maiores em todas as espécies (até 2,8 vezes em C. minor), porque eles têm pernas mais longas em relação ao tamanho do cefalotórax. Nós sugerimos que uma seleção para alta mobilidade pode ser a razão para machos com pernas maiores, e que as menores espécies tem maior dimorfismo sexual no comprimento das pernas devido ao tamanho relativo dos obstáculos na serapilheira.

Angiogenesis is a complex process involving endothelial cell (EC) proliferation, migration, differentiation, and organization into patent capillary networks. Nitric oxide (NO), an EC mediator, has been reported to be antigenic as well as proangiogenic in different models of in vivo angiogenesis. Our aim was to investigate the role of NO in capillary organization using rat microvascular ECs (RFCs) grown in three-dimensional (3D) collagen gels. RFCs placed in 3D cultures exhibited extensive tube formation in the presence of transforming growth factor-beta 1. Addition of the NO synthase (NOS) inhibitors L-nitro-arginine methylester (L-NAME, 1 mmol/L) or L-monomethyl-nitro-l-arginine (1 mmol/L) inhibited tube formation and the accumulation of nitrite in the media by approximately 50%. Incubation of the 3D cultures with excess L-arginine reversed the inhibitory effect of L-NAME on tube formation. In contrast to the results obtained in 3D cultures, inhibition of NO synthesis by L-NAME did not influence RFC proliferation in two-dimensional (2D) cultures or antagonize the ability of transforming growth factor-beta 1 to suppress EC proliferation in 2D cultures. Reverse transcriptase-polymerase chain reaction revealed the constitutive expression of all three NOS isoforms, neuronal, inducible, and endothelial NOSs, in 2D and 3D cultures. Moreover, Western blot analysis demonstrated the presence of immunoreactive protein for all NOS isoforms in 3D cultures of RFCs. In addition, in the face of NOS blockade, co-treatment with the NO donor sodium nitroprusside or the stable analog of cGMP, 8-bromo-cGMP, restored capillary tube formation. Thus, the autocrine production of NO and the activation of soluble guanylate cyclase are necessary events in the process of differentiation and in vitro capillary tube organization of RFCs.

Respiratory syncytial virus causes clinically significant illness in children and adults. In a placebo-controlled trial, a prefusion stabilized F protein vaccine led to an 83% lower risk of RSV infection.

Endothelial dysfunction and intima-media thickness of common carotid arteries (IMT-CC) are considered subclinical markers of atherosclerotic cardiovascular disease (ASCVD). Advanced glycation end products (AGEs) are increased in type 2 diabetes mellitus (T2DM) patients, compared with non-diabetics, being implicated in micro- and macrovascular complications. Our aim was to compare serum AGEs levels and subclinical atherosclerotic markers between patients with established and newly diagnosed T2DM. Among 540 patients with T2DM and coronary heart disease from the CORDIOPREV study, 350 patients had established T2DM and 190 patients had newly diagnosed T2DM. Serum levels of AGEs (methylglyoxal (MG) and N-carboxymethyl lysine (CML)) and subclinical atherosclerotic markers (brachial flow-mediated vasodilation (FMD) and IMT-CC) were measured. AGEs levels (all p < 0.001) and IMT-CC (p = 0.025) were higher in patients with established vs. newly diagnosed T2DM, whereas FMD did not differ between the two groups. Patients with established T2DM and severe endothelial dysfunction (i.e., FMD < 2%) had higher serum MG levels, IMT-CC, HOMA-IR and fasting insulin levels than those with newly diagnosed T2DM and non-severe endothelial dysfunction (i.e., FMD ≥ 2%) (all p < 0.05). Serum CML levels were greater in patients with established vs. newly diagnosed T2DM, regardless of endothelial dysfunction severity. Serum AGEs levels and IMT-CC were significantly higher in patients with established vs. newly diagnosed T2DM, highlighting the progressively increased risk of ASCVD in the course of T2DM. Establishing therapeutic strategies to reduce AGEs production and delay the onset of cardiovascular complications in newly diagnosed T2DM patients or minimize ASCVD risk in established T2DM patients is needed.