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Abstract Patients with corticosteroid-refractory acute graft-versus-host disease (aGVHD) have a low one-year survival rate. Identification and validation of novel targetable kinases in patients who experience corticosteroid-refractory-aGVHD may help improve outcomes. Kinase-specific proteomics of leukocytes from patients with corticosteroid-refractory-GVHD identified rho kinase type 1 (ROCK1) as the most significantly upregulated kinase. ROCK1/2 inhibition improved survival and histological GVHD severity in mice and was synergistic with JAK1/2 inhibition, without compromising graft-versus-leukemia-effects. ROCK1/2-inhibition in macrophages or dendritic cells prior to transfer reduced GVHD severity. Mechanistically, ROCK1/2 inhibition or ROCK1 knockdown interfered with CD80, CD86, MHC-II expression and IL-6, IL-1β, iNOS and TNF production in myeloid cells. This was accompanied by impaired T cell activation by dendritic cells and inhibition of cytoskeletal rearrangements, thereby reducing macrophage and DC migration. NF-κB signaling was reduced in myeloid cells following ROCK1/2 inhibition. In conclusion, ROCK1/2 inhibition interferes with immune activation at multiple levels and reduces acute GVHD while maintaining GVL-effects, including in corticosteroid-refractory settings.

Increase in average global temperature over the last few decades has caused an accelerated retreat of tropical glaciers. Andean populations live in strict dependence on the water services provided by mountains and glaciers. The present study aims to generate a glacier melt projection map in the Peruvian Central Cordillera based on vulnerability maps over the 1990–2021 period. Seven satellite images were selected to determine the changes in glacier coverage based on normalized indexes. Subsequently, seven parametric maps consisting of terrain and climate characteristics were assimilated into a vulnerability analysis based on the frequency index and the Shannon entropy index model, allowing one to identify areas most susceptible to glacial retreat. The results show that the most important criteria for the southern and northern glacial study areas are surface temperature, elevation, precipitation, aspect, orientation, and slope. The validation results revealed the most accurate set of parameters from the vulnerability map in terms of projecting melting areas and were used to produce a spatial projection map for the period 2021–2055. From 2021, a glacier loss in the range 84–98% would be reached by the 2050s. HIGHLIGHTS A versatile method is proposed to study vulnerabilities in complex terrains and climatic uncertainty such as glacial context.; Updated glacier retreat maps over a long time period from 1990 to 2021 based on remote sensing in Central Andes have been used in this study.; A methodology to project glacier retreat in a context of scarce or limited information is used in this study.;

Abstract Background Splenic abscess is a serious complication associated with infective endocarditis. There is still contradicting evidence regarding the optimal treatment pathway including timing of valve intervention and the approach for managing splenic foci. Case presentation We present a case of a hybrid staged approach in which we successfully performed a laparoscopic splenectomy following percutaneous abscess drainage and a delayed aortic valve replacement. Conclusions A multidisciplinary teamwork is fundamental in providing optimal care for patients with distant complications associated with infective endocarditis. Our hybrid approach seems safe and feasible.

Abstract Background The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways. Here, we hypothesized that the eCB system is associated with an enhanced Kyn production in relation to the severity of depressive symptoms. Methods Eighty-two subjects (51 patients with a diagnosis of depressive disorder (DSM-5) and 31 healthy volunteers), were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Scale, and Global Clinical Impression. Serum concentrations of eCBs (N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)); structurally related fatty acyl compounds 2-oleoylglycerol (2-OG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA); Trp, Kyn, Kyn/Trp ratio (an index of Trp degradation into Kyn) and 5-HT were also determined. Results Following a principal component analysis including the severity of depression, Kyn and the Kyn/Trp ratio appear to be directly associated with 2-AG, AEA, and PEA. Interestingly, these biomarkers also permitted to distinguish the population into two main clusters: one of individuals having mild/severe depressive symptoms and the other with an absence of depressive symptoms. Using parametric analysis, higher serum levels of 2-AG, Kyn, and the ratio Kyn/Trp and lower levels of Trp and 5-HT were found in individuals with mild/severe depressive symptoms than in those without depressive symptoms. While in asymptomatic people, PEA was directly associated to Trp, and OEA indirectly linked to 5-HT, in individuals with depressive symptoms, these correlations were lost, and instead, positive correlations between AEA and 2-AG, PEA and AEA, and PEA vs 2-AG and OEA concentrations were found. Conclusions Parametric and non-parametric analyses suggest a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay among inflammation, stress, and depression. The enhanced relationships among the biomarkers of the 2-AG and AEA pathways and related lipids seen in individuals with depressive symptoms, but not in asymptomatics, suggest an altered metabolism of the eCB system in depression.

Abstract Over the past decade, we have conducted geochemical and isotopic monitoring of the fumarolic gases of the Peteroa volcano (Argentina‐Chile). Using the resulting data set, we constructed a conceptual model that describes the evolution of the magmatic‐hydrothermal system and identifies precursory geochemical signals of the last eruption. Our data set includes new chemical and isotopic analyses of fumarolic gas samples collected from 2016 to 2021, as well as previously published data from the 2010–2015 period. After an eruptive period in 2010–2011, the activity was characterized by low degassing rates and seismic activity. However, an increase in seismic activity and fumarolic gas emissions was observed from 2016 to 2018–2019 eruptive episode, leading to a major phreato‐magmatic eruption. Fumarole gases show different compositions during quiescent versus unrest/eruptive degassing related to the interaction of deep (magmatic) and shallow (hydrothermal) fluid contributions. During quiescent periods, fumaroles exhibited low SO2/H2S, HF/CO2, and HCl/CO2 ratios (

Dormancy of disseminated cancer cells has been described in patients with breast cancer and associated with late metastatic relapses. Here the authors show that CD39+PD-1+CD8+ T cells correlate with increased disease free survival post-resection in breast cancer patients, and promote dormancy in a preclinical model.

Glioblastoma multiform (GBM) is a common and aggressive type of primary brain cancer that currently has no effective therapy. Here, the authors show, using a mouse GBM model and EGFRvIII-targeting chimeric antigen receptor (CAR)-T cells, that Intratumoral injection of interleukin-12 helps condition the microenvironment and promote anti-tumor immunity.

El síndrome de fibromialgia (sf) es una patología que genera gran dificultad en los movimientos, fatiga y dolor en partes del cuerpo, afectando severamente la calidad de vida. El objetivo de este estudio fue determinar los indicadores de depresión, ansiedad, apoyo interpersonal, dolor autopercibido y su relación, en una muestra de pacientes con sf en Colombia. A 100 pacientes se les aplicaron las siguientes pruebas: Inventario de Ansiedad Rasgo Estado, Escala de depresión de Zung, Cuestionario para evaluación del apoyo interpersonal, y la Escala analógica del dolor. Se reportaron niveles moderados de depresión y ansiedad, dificultades específicas en el apoyo social y niveles altos en dolor autopercibido. Las puntuaciones en la escala de depresión se asociaron positivamente con la ansiedad estado y rasgo, pero se asociaron negativamente con el apoyo social. En conclusión, la salud mental, el apoyo interpersonal y el dolor autopercibido se encuentran afectados en los pacientes. Se requiere ajustar los protocolos de atención clínica con el propósito de conservar y potenciar la salud integral en los afectados.

Translation of mRNA contributes to neuronal function and complex behaviours, and inflammation is thought to contribute to depression. Here the authors show that mice lacking phosphorylation sites in eIF4E (eukaryotic initiation factor 4E) display anxiety- and depression-like behaviour and decreased IkBα expression; furthermore TNFα delivery to the medial prefrontal cortex induces depression-like behaviour and deficits in serotonergic transmission.

Clusterin is a glycoprotein able to mediate different physiological functions such as control of complement activation, promotion of unfolded protein clearance and modulation of cell survival. Clusterin is overexpressed in many types of cancers and a large body of evidence suggests that it promotes carcinogenesis and tumor progression. We have previously described a novel clusterin glycoform present in human semen, but not in serum, highly enriched in terminal fucose motifs. Here we show that human luminal breast cancer (LBC) clusterin also bears terminal fucosylated glycans, conferring clusterin the ability to interact with DC-SIGN, a C-type lectin receptor expressed by myeloid cells. This clusterin glycosylation pattern was absent or diminished in non-involved juxtatumoral tissue, suggesting that fucosylated clusterin might represent a cancer associated glycoform. We also found that DC-SIGN is expressed by luminal breast cancer intratumoral macrophages. Moreover, experiments performed in vitro using semen fucosylated clusterin and monocyte derived macrophages showed that the interaction of semen clusterin with DC-SIGN promoted a proangiogenic profile, characterized by a high production of VEGF, IL-8 and TNF-α. Our results reveal an unexpected complexity on the structure and function of secretory clusterin produced by tumors and suggest that fucosylated clusterin produced by luminal breast cancer cells might play a role in tumor progression by promoting the release of pro-angiogenic factors by intratumoral macrophages.

Epstein Barr virus (EBV) is one of the most ubiquitous human pathogens in the world, persistently infecting more than 90% of the adult human population. It drives some of the strongest human CD8+ T cell responses, which can be observed during symptomatic primary infection known as infectious mononucleosis (IM). Despite high viral loads and prolonged CD8+ T cell stimulation during IM, EBV enters latency and is under lifelong immune control in most individuals that experience this disease. We investigated whether changes in T cell function, as frequently characterized by PD-1 up-regulation, occur during IM due to the prolonged exposure to high antigen levels. We readily detected the expansion of PD-1 positive CD8+ T cells together with high frequencies of Tim-3, 2B4, and KLRG1 expression during IM and in mice with reconstituted human immune system components (huNSG mice) that had been infected with a high dose of EBV. These PD-1 positive CD8+ T cells, however, retained proliferation, cytokine production, and cytotoxic abilities. Multiple subsets of CD8+ T cells expanded during EBV infection, including PD-1+Tim-3+KLRG1+ cells that express CXCR5 and TCF-1 germinal center homing and memory markers, and may also contain BATF3. Moreover, blocking the PD-1 axis compromised EBV specific immune control and resulted in virus-associated lymphomagenesis. Finally, PD-1+, Tim-3+, and KLRG1+ CD8+ T cell expansion coincided with declining viral loads during low dose EBV infection. These findings suggest that EBV infection primes PD-1 positive CD8+ T cell populations that rely on this receptor axis for the efficient immune control of this ubiquitous human tumor virus.

The anesthetic block of the inferior alveolar nerve (IAN) is one of the most common techniques used in dental practice. The local complications are due to the failures on the anesthetic block or to anatomic variations in the tap site such as intravascular injection, skin ischemia and ocular problems. The aim of this article is to present a case and discuss the causes of itching and burning sensation, blanching, pain and face ischemia in the oral cavity during the IAN block.

Factor Xa (FXa), a vitamin K-dependent serine protease plays a pivotal role in the coagulation cascade, one of the most interesting targets for the development of new anticoagulants. In the present work, we performed a virtual screening campaign based on ligand-based shape and electrostatic similarity search and protein-ligand docking to discover novel FXa-targeted scaffolds for further development of inhibitors. From an initial set of 260,000 compounds from the NCI Open database, 30 potential FXa inhibitors were identified and selected for in vitro biological evaluation. Compound 5 (NSC635393, 4-(3-methyl-4H-1,4-benzothiazin-2-yl)-2,4-dioxo-N-phenylbutanamide) displayed an IC50 value of 2.02 nM against human FXa. The identified compound may serve as starting point for the development of novel FXa inhibitors.

Dendritic cells (DC) have the potential to control the outcome of autoimmunity by modulating the immune response. In this study, we tested the ability of Fasciola hepatica total extract (TE) to induce tolerogenic properties in CpG-ODN (CpG) maturated DC, to then evaluate the therapeutic potential of these cells to diminish the inflammatory response in collagen induced arthritis (CIA). DBA/1J mice were injected with TE plus CpG treated DC (T/C-DC) pulsed with bovine collagen II (CII) between two immunizations with CII and clinical scores CIA were determined. The levels of CII-specific IgG2 and IgG1 in sera, the histological analyses in the joints, the cytokine profile in the draining lymph node (DLN) cells and in the joints, and the number, and functionality of CD4+CD25+Foxp3+ T cells (Treg) were evaluated. Vaccination of mice with CII pulsed T/C-DC diminished the severity and incidence of CIA symptoms and the production of the inflammatory cytokine, while induced the production of anti-inflammatory cytokines. The therapeutic effect was mediated by Treg cells, since the adoptive transfer of CD4+CD25+ T cells, inhibited the inflammatory symptoms in CIA. The in vitro blockage of TGF-β in cultures of DLN cells plus CII pulsed T/C-DC inhibited the expansion of Treg cells. Vaccination with CII pulsed T/C-DC seems to be a very efficient approach to diminish exacerbated immune response in CIA, by inducing the development of Treg cells, and it is therefore an interesting candidate for a cell-based therapy for rheumatoid arthritis (RA).