Vitiligo-like Depigmentation in a Patient Undergoing Treatment with Nivolumab for Advanced Renal-cell Carcinoma

Nivolumab is a fully human monoclonal antibody that targets the programmed cell death 1 (PD-1) immune checkpoint. It has been approved for its use in several types of advanced solid tumors, including melanoma, lung cancer, and renal cell carcinoma (RCC). The inhibition of PD-1 leads to an enhanced adaptive immune response against tumor cells through the activation of T-cells

Vitiligo-like Depigmentation in a Patient Undergoing Treatment with Nivolumab for Advanced Renal-cell Carcinoma

Nivolumab is a fully human monoclonal antibody that targets the programmed cell death 1 (PD-1) immune checkpoint. It has been approved for its use in several types of advanced solid tumors, including melanoma, lung cancer, and renal cell carcinoma (RCC). The inhibition of PD-1 leads to an enhanced adaptive immune response against tumor cells through the activation of T-cells

Dissecting the microglial response in transgenic models of amyloidogenesis and tauopathy

Amyloid-beta (Abeta) peptide deposits and hyperphosphorylated tau protein (phospho-tau) accumulate in Alzheimer’s disease (AD) brains. These abnormal protein aggregates leads to glial activation, synaptic dysfunction, neuronal loss and cognitive decline. While microglial response has mostly been analyzed in relation to Abeta accumulation, little is still known about inflammatory processes associated with tau pathology. Microglial reactivity and defective glial responses have been involved in these proteinopathies. Our aim is to clarify the effects of Abeta and tau separately, in order to improve the comprehension of their differential contribution to neuroinflammation and neurodegeneration. We compared the progression of these processes in an amyloidogenic AD model (APPSL/PS1M146L) and two different models of tauopathy (ThyTau22 and hP301S) from 2 to 18 months of age. Accumulation of aggregated proteins was assessed using specific anti- Abeta and phospho-tau antibodies. Inflammatory response was studied using a battery of microglial markers (Iba1, CD45, CD68, Trem2 and Gal-3). In the hippocampus of these models, Tau and Abeta pathologies initiated as early as 2 months of age and increased progressively with aging. Neuritic plaques induced a strong microglial activation associated to plaques in APP/PS1 mice. Interestingly, inflammatory markers and microglial reactivity were barely increased in the hippocampus of ThyTau mice in contrast to not only APP/PS1, but also to P301S mice, which displayed a prominent microglial response. Deciphering the specific effects of Abeta, tau and their different toxic species, would indeed enable the development of novel therapeutic strategies and drugs targeting neuroinflammatory pathways related to these proteinopathies.Universidad de Málaga. Campus de excelencia Andalucía-Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union, and by grant PPIT.UMA.B1.2017/26 (RS-V)

Computational study of ligand binding in lipid transfer proteins: Structures, interfaces, and free energies of protein-lipid complexes

Plant nonspecific lipid transfer proteins (nsLTPs) bind a wide variety of lipids, which allows them to perform disparate functions. Recent reports on their multifunctionality in plant growth processes have posed new questions on the versatile binding abilities of these proteins. The lack of binding specificity has been customarily explained in qualitative terms on the basis of a supposed structural flexibility and nonspecificity of hydrophobic protein-ligand interactions. We present here a computational study of protein-ligand complexes formed between five nsLTPs and seven lipids bound in two different ways in every receptor protein. After optimizing geometries inmolecular dynamics calculations, we computed Poisson- Boltzmann electrostatic potentials, solvation energies, properties of the protein-ligand interfaces, and estimates of binding free energies of the resulting complexes. Our results provide the first quantitative information on the ligand abilities of nsLTPs, shed new light into protein-lipid interactions, and reveal new features which supplement commonly held assumptions on their lack of binding specificity

Use of Eculizumab in Pediatric Patients With Transplant Associated Thrombotic Microangiopathy

Complement inhibitor; Eculizumab; Hematopoietic stem cell transplant (HSCT)Inhibidor del complemento; Eculizumab; Trasplante de células madre hematopoyéticas (TCMH)Inhibidor del complement; Eculizumab; Trasplantament de cèl·lules mare hematopoètiques (HSCT)Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT) associated with high morbidity and mortality. High-risk TA-TMA (hrTA-TMA) is characterized by multifactorial endothelial damage caused by environmental stressors, dysregulation of the complement system, and genetic predisposition. Complement inhibitors have significantly decreased mortality and are the current treatment of choice. In this article, we describe our experience with the use of eculizumab in pediatric patients diagnosed with hrT-TMA after HSCT. Method: Retrospective study of pediatric patients with hrTA-TMA treated with eculizumab between January 2016 and December 2020. Results: Four pediatric patients aged 1, 12, 14, and 17 years at the time of HSCT were diagnosed with hrTA-TMA and treated with eculizumab during the study. At diagnosis, they all had renal impairment with proteinuria, and hypertension under treatment with at least two antihypertensive drugs. The patient who presented multisystemic involvement died instead of treatment. The three patients with exclusive renal involvement achieved TA-TMA resolution after treatment with eculizumab for 65, 52, and 40.6 weeks and were able to stop treatment. The two patients with follow-up data one year after eculizumab withdrawal sustained a favorable response. Eculizumab was well tolerated, and with adequate vaccination and antibiotic prophylaxis, did not increase the risk of infection. Conclusions: Eculizumab appears to be both safe and effective for the treatment of hrTA-TMA in patients with renal impairment. Early diagnosis and initiation of treatment may improve response. Eculizumab withdrawal can be contemplated in patients who achieve laboratory and clinical resolution of TA-TMA

The major allergens of birch pollen and cow milk, Bet v 1 and Bos d 5, are structurally related to human licocalin 2, enabling them to manipulate T-helper cells depending on their load with siderophore-bound iron

We conclude that Bet v 1 and Bos d 5 not only structurally mimic human LCN2, but also functionally by their ability to bind iron via siderophores. The apo-forms promote Th2 cells, whereas the holo-forms appear to be immunosuppressive. These results provide for the first time a functional understanding on the principle of allergenicity of major allergens from entirely independent sources, like birch and milk

The Spanish HIV BioBank: a model of cooperative HIV research

<p>Abstract</p> <p>Background</p> <p>The collection of samples from HIV-infected patients is the beginning of the chain of translational research. To carry out quality research that could eventually end in a personalized treatment for HIV, it is essential to guarantee the availability, quality and traceability of samples, under a strict system of quality management.</p> <p>Methods</p> <p>The Spanish HIV BioBank was created with the objectives of processing, storing and providing distinct samples from HIV/AIDS patients, categorized according to strictly defined characteristics, free of charge to research projects. Strict compliance to ethical norms is always guaranteed.</p> <p>Results</p> <p>At the moment, the HIV BioBank possesses nearly 50,000 vials containing different prospective longitudinal study sample types. More than 1,700 of these samples are now used in 19 national and international research projects.</p> <p>Conclusion</p> <p>The HIV BioBank represents a novel approach to HIV research that might be of general interest not only for basic and clinical research teams working on HIV, but also for those groups trying to establish large networks focused on research on specific clinical problems. It also represents a model to stimulate cooperative research among large numbers of research groups working as a network on specific clinical problems. The main objective of this article is to show the structure and function of the HIV BioBank that allow it to very efficiently release samples to different research project not only in Spain but also in other countries.</p

Analyzing hippocampal synaptic damage and glial response in a mouse model of tauopathy

Tau pathology is highly related to synaptic and neuronal loss, leading to cognitive decline and dementia in Alzheimer’s disease (AD) and other tauopathies. Tau transgenic mice are widely used to investigate the specific contribution of this protein to AD since they reproduce the synaptic and cognitive dysfunction in parallel to an age-dependent accumulation of hyperphosphorylated forms of tau (phospho-tau). The aim of this study was to investigate the progression of tau aggregation and analyze its relationship with microglial activation and synaptic damage within the hippocampus of a transgenic tau model. 2, 6, 9, 12 and 18 month-old THY-Tau22 transgenic and WT mice were analyzed. Tau pathology was assessed by western blotting and immunohistochemistry (AT8, AT100). Confocal microscopy was used to study microglial/phospho-tau relationship, and Thioflavin-S staining to evidence fibrillar aggregates. Levels of general (Synaptophysin) and subtype-specific (ChAT, VGAT, VGLUT-1) synaptic proteins were determined by WB and immunohistochemistry. Inflammatory markers were assessed by quantitative PCR (CD45, CD68, TREM2), immunohistochemistry (Iba-1) and image analysis. Tau pathology was detectable in the hippocampus from 2 months of age and increased progressively during aging. Presynaptic protein levels were significantly decreased from 9-12 months compared to age-matched WT mice. Even though some inflammatory markers were slightly increased in the hippocampus, microglial reactivity was found to be generally attenuated and some cells even exhibited reduction in their prolongations and a clear degenerative phenotype at advanced ages similar to that seen in the hippocampus of AD patients. Finally, this model could be a relevant tool to further understand the specific role of tau in both microglial response and synaptic pathology in AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Disentangling the contribution of tau and abeta pathologies in transgenic models of Alzheimer's disease

AIMS: Amyloid-beta (Abeta) deposits and intraneuronal hyperphosphorylated tau are major pathological hallmarks of Alzheimer’s disease (AD). The coexistence of these aggregates in AD brains leads to synaptic dysfunction, neuronal loss and cognitive decline. Failures in protein homeostasis, along with defective glial responses, have been identified as pathological mechanisms linked to this disorder. Thus, our main objective is to better understand the differential impact of Abeta- and tau-aggregates to these processes in the hippocampus of AD models. METHODS: We analyzed APP- (APPSL/PS1M146L) and Tau- (ThyTau22 and hP301S) based models from 2 to 18 months of age. Tau and Abeta pathologies were assessed by western blotting and immunohistochemistry. Confocal microscopy was used to study microglia/aggregates relationship. Levels of synaptic proteins, autophagy and inflammatory markers were determined by quantitative PCR, WB and immunohistochemistry. RESULTS: Tau and Abeta pathologies initiated as early as 2 months of age and increased progressively with aging. Even though only APP/PS1 hippocampus showed dystrophic neurites positive to proteostatic and presynaptic markers, their protein levels were altered in both types of models from 6-9 months compared to age-matched WT mice. Inflammatory markers and microglial reactivity were barely increased in the hippocampus of ThyTau mice in contrast to P301S and APP/PS1 mice which displayed a prominent microglial response. CONCLUSIONS: Clarifying the effects of Abeta and tau separately would indeed enable the development of novel therapeutic strategies and drugs targeting pathways related to these proteinopathies. Supported by grants FIS PI15/00796 and PI15/00957 co-financed by FEDER funds from European Union, by Junta de Andalucia Proyecto de Excelencia CTS385 2035 and by grant PPIT.UMA.B1/2017.26Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec