Phylogenetic description of Trypanosoma cruzi isolates from Dipetalogaster maxima: Occurrence of TcI, TcIV, and TcIV-USA.

Trypanosoma cruzi is the parasite responsible for Chagas disease. The parasite has been classified into six taxonomic assemblages: TcI-TcVI and TcBat (aka Discrete Typing Units or Near-Clades). No studies have focused on describing the genetic diversity of T. cruzi in the northwestern region of Mexico. Within the Baja California peninsula lives Dipetalogaster maxima, the largest vector species for CD. The study aimed to describe the genetic diversity of T. cruzi within D. maxima. A total of three Discrete Typing Units (DTUs) were found (TcI, TcIV, and TcIV-USA). TcI was the predominant DTU found (∼75% of samples), in concordance with studies from the southern USA, one sample was described as TcIV while the other ∼20% pertained to TcIV-USA, which has recently been proposed to have enough genetic divergence from TcIV, to merit its own DTU. Potential phenotype differences between TcIV and TcIV-USA should be assessed in future studies.

Governance and the design of post-disaster policies: a comparative analysis from Latin America and the Caribbean.

Latin America and the Caribbean is one of the regions threatened most by natural events owing to the highly vulnerable circumstances of its urban centres. Consequently, its cities are occasionally affected by one or more disaster types, exposing problems of governance and public policy in relation to risk management. The aim of this research is to investigate the factors that influence the design of post-disaster policies. It hypothesises that in those countries with modes of governance characterised by greater articulation between State and non-State actors, the design of post-disaster policies tends to be more coherent. Methodologically, the study proposes a comparative analysis of post-disaster policies in three countries of the region affected by earthquakes: Haiti and Chile (in 2010) and Ecuador (in 2016). The findings show that co-governance in Chile resulted in optimal post-disaster policies, whereas hierarchical governance in the cases of Haiti and Ecuador led to unsuccessful and misdirected post-disaster policies, respectively.

Histone H2A variant H2A.B is enriched in transcriptionally active HSV-1 lytic chromatin.

Herpes simplex virus 1 (HSV-1) transcription is restricted in latently infected neurons and the genomes are in mostly silenced chromatin, whereas all viral genes are transcribed in lytically infected cells, in which the genomes are dynamically chromatinized. Epigenetic regulation modulates HSV-1 transcription during lytic, latent, and reactivating infections, but the precise mechanisms are not fully defined. Nucleosomes are dynamic; they slide, breathe, assemble and disassemble. We and others have proposed that the most dynamic HSV-1 chromatin is transcriptionally competent whereas the least dynamic is silenced. However, the mechanisms yielding the unusually dynamic viral chromatin remain unknown. Histone variants affect nucleosome dynamics. The dynamics of H2A, H2A.X and macroH2A were enhanced in infected cells, whereas those of H2A.B uniquely decreased. We constructed stably transduced cells expressing tagged histone H2A, H2A.B, macroH2A, or H2B, which assembles the H2A/H2B nucleosome dimers with all H2A variants. All H2A variants, ectopic, and endogenous H2B, were assembled into HSV-1 chromatin evenly throughout the genome, but canonical H2A was relatively depleted from the viral chromatin whereas H2A.B was enriched in the most dynamic viral chromatin. When viral transcription was restricted, H2A.B became as depleted from the viral chromatin through the entire genome as H2A. We propose that lytic HSV-1 nucleosomes are enriched in the dynamic variant H2A.B/H2B dimers to promote HSV-1 chromatin dynamics and transcriptional competency, and conclude that the dynamics of HSV-1 chromatin are determined in part by the H2A variants. Importance: HSV-1 transcription is epigenetically regulated during latent and lytic infections, and epigenetic inhibitors have been proposed as potential antiviral drugs to modulate latency and reactivation. However, the detailed mechanisms of regulation of HSV-1 transcription by epigenetics have not been fully characterized and may differ from those regulating cellular transcription. In particular, the lytic HSV-1 chromatin is unusually dynamic, whereas the latent silenced one is not, but the mechanisms resulting in the unique dynamics of the lytic chromatin remain unknown. Here we identify the enrichment on the highly dynamic histone 2A variant H2A in the most dynamic viral chromatin, which provides a mechanistic understanding for its unique dynamics. Future work to identify the mechanisms of enrichment in H2A.B on the viral chromatin may identify novel druggable epigenetic regulators that modulate HSV-1 latency and reactivation.

Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome.

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence.Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated.Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome.Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416-28. ©2018 AACR.

Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion: The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma.

In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy-the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8 TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8CD3 TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in <3 weeks. Finally, providing the 3 signals attributed to optimal T-cell activation led to expansion of TIL capable of recognizing their tumor counterpart in cutaneous and uveal melanoma. This new methodology for the initial phase of TIL expansion brings a new opportunity for translation of TIL therapy in challenging malignancies such as uveal melanoma.

A Novel Method to Generate and Expand Clinical-Grade, Genetically Modified, Tumor-Infiltrating Lymphocytes.

Following the clinical success achieved with the first generation of adoptive cell therapy (ACT) utilizing in vitro expanded tumor-infiltrating lymphocytes (TILs), the second and third generations of TIL ACT are evolving toward the use of genetically modified TIL. TIL therapy generally involves the transfer of a high number of TIL, ranging from 109 to 1011 cells. One of the technical difficulties in genetically modifying TIL, using a retroviral vector, is the ability to achieve large expansion of transduced TIL, while keeping the technique suitable to a Good Manufacturing Practices (GMP) environment. Consequently, we developed and optimized a novel method for the efficient production of large numbers of GMP-grade, gene-modified TIL for the treatment of patients with ACT. The chemokine receptor CXCR2 was used as the gene of interest for methodology development. The optimized procedure is currently used in the production of gene-modified TIL for two clinical trials for the treatment of metastatic melanoma at MD Anderson Cancer Center.

Parallel profiling of immune infiltrate subsets in uveal melanoma versus cutaneous melanoma unveils similarities and differences: A pilot study.

The low response rates to immunotherapy in uveal melanoma (UM) sharply contrast with reputable response rates in cutaneous melanoma (CM) patients. To characterize the mechanisms responsible for resistance to immunotherapy in UM, we performed immune profiling in tumors from 10 metastatic UM patients and 10 metastatic CM patients by immunohistochemistry (IHC). Although there is no difference in infiltrating CD8+ T cells between UM and CM, a significant decrease in programmed death-1 (PD-1)-positive lymphocytes was observed and lower levels of programmed death ligand-1 (PD-L1) in UM metastases compared with CM metastases. Tumors from metastatic UM patients showed a lower success rate of tumor-infiltrating lymphocyte (TIL) growth compared with metastatic CM (45% vs. 64% success), with a significantly lower quantity of UM TIL expanded overall. These studies suggest that UM and CM are immunologically distinct, and provide potential explanation for the impaired success of immunotherapy in UM.

Recomendaciones para los cuidados respiratorios del niño y adolescente con enfermedades neuromusculares / Respiratory care for the children and adolescents with neuromuscular diseases

El compromiso del sistema respiratorio repercute directamente en la morbimortalidad de niños y adolescentes con enfermedades neuromusculares (ENM). Un enfoque integral que incluya la aproximación a un diagnostico neurológico específico, evaluación funcional respiratoria, de los trastornos respiratorios de sueño, comorbilidades y afecciones secundarias, permiten orientar a el tipo, grado y pronóstico respiratorio; además de otorgar herramientas objetivas para modificar la historia natural de la enfermedad. Utilizar criterios estrictos de selección, una mirada interdisciplinaria y actividades complementarias de rehabilitación; que incorporen en forma programática la ventilación no invasiva domiciliaria, protocolos de tos asistida y métodos para aumentar la capacidad máxima de insuflación, cambia la evolución, disminuye la morbimortalidad y evita la traqueostomía, en una alta proporción de niños y adolescentes portadores de ENM.

Neuroblastoma, un caso clinico / Neuroblastoma, a clinical case

Se describe un caso de neuroblastoma en un lactante de 6 meses, edad poco habitual para su presentacion en neustro medio, primero que nos toca asistir en el Servicio de Pediatria en el Hospital Jaime Mendoza, caracterizado por su evolucion rapida e insidiosa, encontraste con lo reportado en la literatura, en que generalmente los afectados son niños al rededor de 2 años de edad, con mejor pornostico en su evolucion en cuanto el diagnostico sea mas rapido y como consecuancia con mayor posibilidad de aplicar la terapeutica debida.