Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell–induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.

Antibody-mediated immune checkpoint blockade is a transformative immunotherapy for cancer. These same mechanisms can be repurposed for the control of destructive alloreactive immune responses in the transplantation setting. Here, we implement a synthetic biomaterial platform for the local delivery of a chimeric streptavidin/programmed cell death-1 (SA-PD-L1) protein to direct “reprogramming” of local immune responses to transplanted pancreatic islets. Controlled presentation of SA-PD-L1 on the surface of poly(ethylene glycol) microgels improves local retention of the immunomodulatory agent over 3 weeks in vivo. Furthermore, local induction of allograft acceptance is achieved in a murine model of diabetes only when receiving the SA-PD-L1–presenting biomaterial in combination with a brief rapamycin treatment. Immune characterization revealed an increase in T regulatory and anergic cells after SA-PD-L1-microgel delivery, which was distinct from naïve and biomaterial alone microenvironments. Engineering the local microenvironment via biomaterial delivery of checkpoint proteins has the potential to advance cell-based therapies, avoiding the need for systemic chronic immunosuppression.

This therapy is a combination of medicines consisting of nicotine replacement therapy (NRT) using a prolonged modality such as the patch, along with a short-acting medicine such as chewing gum, lozenge, gum, or nasal inhaler).This means two or more drugs approved and demonstrated useful for cessation of smoking with or without the support of NRT. It is very important to consider medical and psychiatric comorbidity because the population that persists addicted is increasingly complex in terms of comorbidities and high addictive level. Most of the combination therapies use NRT associated with bupropion or varenicline. There is evidence on the effectiveness and safety of TRN used in both moda-litres (long and short acting) in combination with varenicline or bupropion. However, safety evidence is not robust for the combination modality as it is for, each drug as monotherapy, since adverse effects are added so it is suggested to reserve the combinations for people with high level of addiction and / or history of failure in previous attempts with monotherapy. In summary, therapy with demonstrated effectiveness as NRT, bupropion and varenicline can be used in double or triple combination, prefering the use of short acting NRT added to one of the oral drugs to alleviate smoking anxiety. Resumen La terapia combinada es la de mezcla de farmacos para al cesación del tabaquismo, tal como tera-pias de reemplazo nicotínico (TRN) en modalidad prolongada como es el parche junto a una modalidad de acción corta como puede ser chicle, goma, lozenge, pastillas o inhalador nasal), es decir dos o más fármacos aprobados y demostrados útlies para el cese del tabaco con o sin el apoyo de TRN. Es muy importante considerar la comorbilidad médica y psiquiatrica porque la población que persiste adicta es cada vez más compleja en términos de comorbilidades y elevado nivel adictivo. La mayor parte de las terapias combinadas usan TRN asociadas a bupropión o vareniclina. Existe evidencia sobre efectividad y seguridad de las TRN utilizadas entre ellas o en asociación a vareniclina o bupropión, sin embargo, la evidencia sobre seguridad en la modalidad combinada no es tan robusta como la que existe para cada fármaco en monoterapia, ya que los efectos adversos se suman de manera que se sugiere reservar las combinaciones para personas con alto nivel de adicción y/o con historia de fracaso en intentos previos con monoterapia. En suma, los fármacos de demostrada efectividad y seguridad como TRN, bupropión y vareniclina pueden usarse en combinación doble o triple, preferenciando el uso de TRN de corta acción cuando se adiciona a alguno de los fármacos orales para aliviar la ansiedad por fumar. Palabras clave: Dejar de fumar; productos para dejar de fumar; nicotina; bupropión; vareniclina. La terapia combinada se refiere fundamental-mente a la estrategia de combinación de terapias de reemplazo nicotínico (TRn) en que se combi-na una modalidad prolongada como es el parche a una de acción corta como puede ser chicle, losenge o pastillas, inhalador o spray...

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Understanding the immune response to hydrogel implantation is critical for the design of immunomodulatory biomaterials. To study the progression of inflammation around poly(ethylene glycol) hydrogels presenting Arg-Gly-Asp (RGD) peptides and vascular endothelial growth factor, we used temporal analysis of high-dimensional flow cytometry data paired with intravital imaging, immunohistochemistry, and multiplexed proteomic profiling. RGD-presenting hydrogels created a reparative microenvironment promoting CD206 + cellular infiltration and revascularization in wounded dorsal skin tissue. Unbiased clustering algorithms (SPADE) revealed significant phenotypic transition shifts as a function of the cell-adhesion hydrogel properties. SPADE identified an intermediate macrophage subset functionally regulating in vivo cytokine secretion that was preferentially recruited for RGD-presenting hydrogels, whereas dendritic cell subsets were preferentially recruited to RDG-presenting hydrogels. Last, RGD-presenting hydrogels controlled macrophage functional cytokine secretion to direct polarization and vascularization. Our studies show that unbiased clustering of single-cell data provides unbiased insights into the underlying immune response to engineered materials.

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Introduction Vincristine is vital in the treatment of acute lymphoblastic leukemia (ALL), but is dose-limited by the development of disabling neuropathies. Vincristine is metabolized extensively by polymorphically expressed CYP3A4/5, which contributes to its 10-fold inter-patient pharmacokinetic variability. Further, there is more recent evidence that an inherited polymorphism in the CEP72 rs924607 gene contributes to vincristine sensitivity. Hispanic children have among the lowest rates of ALL survival when compared to other ethnicities, and pharmacogenomic variability among races is postulated to contribute. This is the first study to examine specifically both CYP3A5 polymorphisms and CEP72 gene expression in correlation with vincristine neurotoxicity in a large cohort of Hispanic ALL patients. Methods Banked germline blood samples from 300 self-identified Hispanic patients with ALL treated at Texas Children's Hospital between 1990 and 2015 were interrogated for allelic discrimination of CEP72 and at the CYP3A5*3, *6, and *7 polymorphic loci using TaqMan assays. Patient medical records were electronically searched for evidence of neuropathic events. Neuropathies were categorized as motor or sensory and graded using the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies. Missing administered vincristine data was imputed using the patient's known treatment protocol and date of event coupled with protocol specifics retrieved from the literature. Multivariate analysis was run modeling the influences of CYP3A5 and CEP72 genotypes on the development and time to development of greater than or equal to Grade 3 neuropathies. Descriptive statistics were used to identify the prevalence of CYP3A5 and CEP72 genotypes and the associated phenotypes in this patient population. Time to neuropathy analysis was performed using the Kaplan-Meier failure estimates and log-rank test in Stata V.12.1 (College Station, TX). Results Based on CYP3A5 polymorphisms, overall, we found that 5% of our patients were extensive metabolizers of vincristine, 33% were intermediate metabolizers, and 62% were poor metabolizers. Additionally, we found that the TT risk CEP72 genotype is a rare finding in our cohort (9.3%). Clinically, we found that 18.4% of our patients experienced greater than or equal to Grade 3 neurotoxicity. Assessing the influence of being both a CYP3A5 intermediate or poor metabolizer and having the TT risk CEP72 genotype was limited by the paucity of patients with both genotypes (n=25). However, CYP3A5 poor metabolizers experienced neurotoxicity more often than intermediate or extensive metabolizers, although we did not find a statistically significant correlation between phenotype and incidence of neurotoxicity. Additionally, we found that there was a statistically significant difference in time to development of neurotoxicity within the first 100 days of treatment between intermediate and poor CYP3A5 metabolizers (P=0.036), with poor metabolizers experiencing greater than or equal to Grade 3 neurotoxicity sooner (Figure 1). Conclusions For the first time, we show that CYP3A5 poor metabolizers experienced greater than or equal to Grade 3 neurotoxicity significantly sooner than intermediate metabolizers within the first 100 days of treatment. We found a low prevalence of the minor allele of CEP72 rs924607TT in our Hispanic cohort. However, classification of CYP3A5 metabolizers and genotypes within our Hispanic population as well as our incidence of neurotoxicity are consistent with current literature. Further testing in a larger cohort should be performed but this study reinforces the significance of CYP3A5 metabolism of vincristine in leading to significant neurotoxicity and suggests that, at least in Hispanic patients, vigilance to early development of neurotoxicity should be performed by practitioners. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

One Sentence Summary: 3Recurrent DNA repair hotspots in neurons are linked to genes essential for identity and 4 function. 5 6 Abstract: 7 Neurons are the longest-living cells in our bodies, becoming post-mitotic in early 8 development upon terminal differentiation. Their lack of DNA replication makes them reliant on 9 DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, 10 potentially giving rise to genomic dysfunction that may influence cognitive decline and 11 neurodegenerative diseases. Despite this challenge, our knowledge of how genome instability 12 emerges and what mechanisms neurons and other long-lived cells may have evolved to protect 13 their genome integrity over the human life span is limited. Using a targeted sequencing approach, 14we demonstrate that neurons consolidate much of their DNA repair efforts into well-defined 15 hotspots that protect genes that are essential for their identity and function. Our findings provide a 16 basis to understand genome integrity as it relates to aging and disease in the nervous system. 17 18 Main Text: 19Neurons are highly specialized post-mitotic cells comprising the major functional cell type 20 of the central nervous system. While there is a limited capacity to generate new neurons throughout 21 life, the majority of neurons age in parallel with the organism, making them especially susceptible 22to decline from age-related disruptions in cellular homeostasis (1, 2). Neurons must repair ~10 4-5 23