The GRP78-PERK axis contributes to memory and synaptic impairments in Huntington's disease R6/1 mice.

Increasing evidence indicates that a key factor in neurodegenerative diseases is the activation of the unfolded protein response (UPR) caused by an accumulation of misfolded proteins in the endoplasmic reticulum (ER stress). Particularly, in Huntington's disease (HD) mutant huntingtin (mHtt) toxicity involves disruption of the ER-associated degradation pathway and loss of the ER protein homeostasis leading to neuronal dysfunction and degeneration. Besides the role of the UPR in regulating cell survival and death, studies that demonstrate the contribution of sustained UPR activation, particularly of PERK signaling, in memory disturbances and synaptic plasticity deficiencies are emerging. Given the contribution of hippocampal dysfunction to emotional and cognitive deficits seen in HD, we have analyzed the involvement of ER stress in HD memory alterations. We have demonstrated that at early disease stages, ER stress activation manifested as an increase in GRP78 and CHOP is observed in the hippocampus of R6/1 mice. Genetic reduction of GRP78 expression resulted in preventing hippocampal-dependent memory alterations but no motor deficits. Accordingly, hippocampal neuropathology namely, dendritic spine loss and accumulation of mHtt aggregates was ameliorated by GRP78 reduction. To elucidate the signaling pathways, we found that the inactivation of PERK by GSK2606414 restored spatial and recognition memories in R6/1 mice and rescued dendritic spine density in CA1 pyramidal neurons and protein levels of some specific immediate early genes. Our study unveils the critical role of the GRP78/PERK axis in memory impairment in HD mice and suggests the modulation of PERK activation as a novel therapeutic target for HD intervention.

Unilateral lupus mastitis.

Lupus mastitis is a rare clinical manifestation associated with systemic lupus erythematosus or discoid lupus erythematosus. It is necessary to make a correct diagnosis to differentiate it from inflammatory breast cancer. The histological study shows involvement of the adipose tissue of the breast with histopathological findings of cutaneous lupus erythematosus. Direct immunofluorescence detects the lupus band at the dermal-epidermal junction. The treatment of choice is hydroxychloroquine. We present a case of unilateral lupus mastitis in a patient with no previous diagnosis of lupus with complete remission after the use of hydroxychloroquine and topical corticosteroids.

Results of the compassionate program of inotuzumab ozogamicin for adult patients with relapsed or refractory acute lymphoblastic leukemia in Spain.

INTRODUCTION: The prognosis of relapsed B cell precursor acute lymphoblastic leukemia (B-ALL) is poor and few patients can be successfully rescued with conventional therapies. Inotuzumab ozogamicin (IO), an antibody against the CD22 antigen linked to calicheamicin, has been approved as a rescue treatment in relapsed/refractory (R/R) B-ALL. PATIENTS AND METHODS: This was an observational, retrospective, multicenter study of adult patients included in the Spanish program of compassionate use of IO in centers from the PETHEMA group (Programa Español de Tratamientos en Hematología). RESULTS: Thirty-four patients with a median age of 43 years (range, 19-73) were included. Twenty patients (59%) were refractory to the last treatment, IO treatment was given as ≥3rd salvage treatment in 25 patients (73%) and 20 patients (59%) received allogeneic hematopoietic stem cell transplantation before IO treatment. After a median of 2 cycles of IO, 64% of patients achieved complete response (CR)/complete response with incomplete recovery. The median response duration, progression-free survival and overall survival (OS) were 4.7 (95%CI, 2.4-7.0 months), 3.5 (95%CI, 1.0-5.0 months) and 4 months (95%CI, 1.9-6.1 months) respectively, with better OS for patients with relapsed B-ALL versus refractory disease (10.4 vs. 2.5 months, respectively) (p = .01). There was a trend for better OS for patients with first CR duration >12 months (7.2 months [95%CI, 3.2-11.2] vs. 3 months [95% CI, 1.8-4.2] respectively) (p = .054). There was no sinusoidal obstruction syndrome (SOS) event during IO treatment, but three patients (9%) developed grade 3-4 SOS during alloHSCT after IO treatment. CONCLUSIONS: Our study showed slightly inferior outcomes of the pivotal trial probably due to poorer risk factors and late onset of IO therapy of recruited patients. Our results support early use of IO in relapsed/refractory ALL patients.

Postnatal Foxp2 regulates early psychiatric-like phenotypes and associated molecular alterations in the R6/1 transgenic mouse model of Huntington's disease.

Huntington's Disease (HD) is a devastating disorder characterized by a triad of motor, psychiatric and cognitive manifestations. Psychiatric and emotional symptoms appear at early stages of the disease which are consistently described by patients and caregivers among the most disabling. Here, we show for the first time that Foxp2 is strongly associated with some psychiatric-like disturbances in the R6/1 mouse model of HD. First, 4-week-old (juvenile) R6/1 mice behavioral phenotype was characterized by an increased impulsive-like behavior and less aggressive-like behavior. In this line, we identified an early striatal downregulation of Foxp2 protein starting as soon as at postnatal day 15 that could explain such deficiencies. Interestingly, the rescue of striatal Foxp2 levels from postnatal stages completely reverted the impulsivity-phenotype and partially the social impairments concomitant with a rescue of dendritic spine pathology. A mass spectrometry study indicated that the rescue of spine loss was associated with an improvement of several altered proteins related with cytoskeleton dynamics. Finally, we reproduced and mimicked the impulsivity and social deficits in wild type mice by reducing their striatal Foxp2 expression from postnatal stages. Overall, these results imply that early postnatal reduction of Foxp2 might contribute to the appearance of some of the early psychiatric symptoms in HD.

TLR4 Deficiency Affects the Microbiome and Reduces Intestinal Dysfunctions and Inflammation in Chronic Alcohol-Fed Mice.

Chronic alcohol abuse causes an inflammatory response in the intestinal tract with damage to the integrity of the mucosa and epithelium, as well as dysbiosis in the gut microbiome. However, the role of gut bacteria in ethanol effects and how these microorganisms interact with the immune system are not well understood. The aim of the present study was to evaluate if TLR4 alters the ethanol-induced intestinal inflammatory response, and whether the response of this receptor affects the gut microbiota profile. We analyzed the 16S rRNA sequence of the fecal samples from wild-type (WT) and TLR4-knockout (TLR4-KO) mice with and without ethanol intake for 3 months. The results demonstrated that chronic ethanol consumption reduces microbiota diversity and causes dysbiosis in WT mice. Likewise, ethanol upregulates several inflammatory genes (IL-1ß, iNOS, TNF-α) and miRNAs (miR-155-5p, miR-146a-5p) and alters structural and permeability genes (INTL1, CDH1, CFTR) in the colon of WT mice. Our results further demonstrated that TLR4-KO mice exhibit a different microbiota that can protect against the ethanol-induced activation of the immune system and colon integrity dysfunctions. In short, our results reveal that TLR4 is a key factor for determining the gut microbiota, which can participate in dysbiosis and the inflammatory response induced by alcohol consumption.

Uptake of perfluoroalkyl substances and halogenated flame retardants by crop plants grown in biosolids-amended soils.

The bioaccumulation behavior of perfluoroalkyl substances (PFASs) and halogenated flame retardants (HFRs) was examined in three horticultural crops and earthworms. Two species, spinach (Spinacia oleracea) and tomato (Solanum lycopersicum L.), were grown in field soil amended with a single application of biosolids (at agronomic rate for nitrogen), to represent the scenario using commercial biosolids as fertilizer, and the third crop, corn (Zea mays) was grown in spiked soil (~50mg PFOS/kg soil, ~5mg Deca-BDE/kg soil and a mixture of both, ~50mg PFOS and ~5mg Deca-BDE/kg soil) to represent a worst-case scenario. To examine the bioaccumulation in soil invertebrates, earthworms (Eisenia andrei) were exposed to the spiked soil where corn had been grown. PFASs and HFRs were detected in the three crops and earthworms. To evaluate the distribution of the compounds in the different plant tissues, transfer factors (TFs) were calculated, with TF values higher for PFASs than PBDEs in all crop plants: from 2 to 9-fold in spinach, 2 to 34-fold in tomato and 11 to 309-fold in corn. Bioaccumulation factor (BAF) values in earthworms were also higher for PFASs (4.06±2.23) than PBDEs (0.02±0.02).

Bioaccumulation of emerging organic compounds (perfluoroalkyl substances and halogenated flame retardants) by earthworm in biosolid amended soils.

In the present work, the bioaccumulation behavior of 49 target emerging organic compounds (20 perfluoroalkyl substances, PFASs, and 29 halogenated flame retardants, HFRs) was studied in soil invertebrates (Eisenia andrei). Multi species soil systems (MS·3) were used to assess the fate and the effects associated with the application of four biosolids in agricultural soil on terrestrial soil organisms. Biosolid amendment increased concentrations 1.5-14-fold for PFASs, 1.1-2.4-fold for polybrominated diphenyl ethers, PBDEs, and 1.1-3.6-fold for chlorinated flame retardants, CFRs. Perfluorooctanesulfonate, PFOS, (25%) and BDE-209 (60%) were the predominant PFAS and HFR compounds, respectively, in biosolids-amended soils. Total concentrations (ng/g dry weight) in earthworms from biosolid-amended soils ranged from 9.9 to 101 for PFASs, from 45 to 76 for PBDEs and 0.3-32 for CFRs. Bioaccumulation factors (BAFs) were calculated to evaluate the degree of exposure of pollutants in earthworms. The mean BAF ranged from 2.2 to 198 for PFASs, 0.6-17 for PBDEs and 0.5-20 for CFRs. The relationship of PFAS and PBDE BAFs in earthworms and their log Kow were compared: PFAS BAFs increased while PBDE BAFs declined with increasing log Kow values. The effect of the aging (21 days) on the bioavailability of the pollutants in amended soils was also assessed: the residence time affected differently to the compounds studied.

Comprehensive detection of CRLF2 alterations in acute lymphoblastic leukemia: a rapid and accurate novel approach.

Introduction: Acute lymphoblastic leukemia (ALL) is a prevalent childhood cancer with high cure rate, but poses a significant medical challenge in adults and relapsed patients. Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype, with approximately half of cases characterized by CRLF2 overexpression and frequent concomitant IKZF1 deletions. Methods: To address the need for efficient, rapid, and cost-effective detection of CRLF2 alterations, we developed a novel RT-qPCR technique combining SYBR Green and highresolution melting analysis on a single plate. Results: The method successfully identified CRLF2 expression, P2RY8::CRLF2 fusions, and CRLF2 and JAK2 variants, achieving a 100% sensitivity and specificity. Application of this method across 61 samples revealed that 24.59% exhibited CRLF2 overexpression, predominantly driven by IGH::CRLF2 (73.33%). High Resolution Melting analysis unveiled concurrent CRLF2 or JAK2 variants in 8.19% of samples, as well as a dynamic nature of CRLF2 alterations during disease progression. Discussion: Overall, this approach provides an accurate identification of CRLF2 alterations, enabling improved diagnostic and facilitating therapeutic decision-making.

Assessing pesticide residues occurrence and risks in water systems: A Pan-European and Argentina perspective.

Freshwater ecosystems face a particularly high risk of biodiversity loss compared to marine and terrestrial systems. The use of pesticides in agricultural fields is recognized as a relevant stressor for freshwater environments, exerting a negative impact worldwide on the overall status and health of the freshwater communities. In the present work, part of the Horizon 2020 funded SPRINT project, the occurrence of 193 pesticide residues was investigated in 64 small water bodies of distinct typology (creeks, streams, channels, ditches, rivers, lakes, ponds and reservoirs), located in regions with high agricultural activity in 10 European countries and in Argentina. Mixtures of pesticide residues were detected in all water bodies (20, median; 8-40 min-max). Total pesticide levels found ranged between 6.89 and 5860 ng/L, highlighting herbicides as the dominant type of pesticides. Glyphosate was the compound with the highest median concentration followed by 2,4-D and MCPA, and in a lower degree by dimethomorph, fluopicolide, prothioconazole and metolachlor(-S). Argentina was the site with the highest total pesticide concentration in water bodies followed by The Netherlands, Portugal and France. One or more pesticides exceeded the threshold values established in the European Water Framework Directive for surface water in 9 out of 11 case study sites (CSS), and the total pesticide concentration surpassed the reference value of 500 ng/L in 8 CSS. Although only 5 % (bifenthrin, dieldrin, fipronil sulfone, permethrin, and terbutryn) of the individual pesticides denoted high risk (RQ > 1), the ratios estimated for pesticide mixtures suggested potential environmental risk in the aquatic compartment studied.