Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins.

T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8+ T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer.

Menarcheal experience, beliefs about and attitudes toward menstruation in Mexico: Changes in the last 20 years.

We explored how menarcheal experiences and attitudes toward menstruation of Mexican adolescents have changed in the last 20 years. Two questionnaires were applied to female adolescent students, and the results were compared with those obtained in 2002-3 when adolescents of the same ages were surveyed using the same questionnaires. Although some aspects of menstrual education have not changed, the secrecy surrounding menstruation has diminished. In contrast, the belief that menstruation is disabling and keeps women from their normal activities has increased. It is important that adolescents receive adequate preparation about psychosocial and physical aspects of the menstrual cycle.

Risk and protective factors related to alcohol and drug use amongst American Indian youth: An application of the social development model.

The goal of this study is to assess the relevance of the Social Development Model (SDM) in predicting substance use across American Indian (AI) youth. We rely on self-reported data collected as part of the 2004 Arizona Youth Survey (AYS). The final sample included 2,912 AI students from 169 schools in 15 counties. Results indicate relatively high levels of alcohol and drug use amongst AI youth. Overall, we find the SDM as a promising framework for identifying risk factors associated with the increased likelihood of alcohol and drug use amongst AI youth.

Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations.

Tietz syndrome and Waardenburg syndrome type 2A are allelic conditions caused by MITF mutations. Tietz syndrome is inherited in an autosomal dominant pattern and is characterized by congenital deafness and generalized skin, hair, and eye hypopigmentation, while Waardenburg syndrome type 2A typically includes variable degrees of sensorineural hearing loss and patches of de-pigmented skin, hair, and irides. In this paper, we report two unrelated families with MITF mutations. The first family showed an autosomal dominant pattern and variable expressivity. The second patient was isolated. MITF gene analysis in the first family demonstrated a c.648A>C heterozygous mutation in exon 8 c.648A>C; p. (R216S), while in the isolated patient, an apparently de novo heterozygous c.1183_1184insG truncating mutation was demonstrated in exon 10. All patients except one had bilateral reduced ocular anteroposterior axial length and a high hyperopic refractive error corresponding to posterior microphthalmos, features that have not been described as part of the disease. Our results suggest that posterior microphthalmos might be part of the clinical characteristics of Tietz/Waardenburg syndrome type 2A and expand both the clinical and molecular spectrum of the disease. © 2016 Wiley Periodicals, Inc.

Serological based monitoring of a cohort of patients with chronic Chagas disease treated with benznidazole in a highly endemic area of northern Argentina.

This study aimed to evaluate well-documented diagnostic antigens, named B13, 1F8 and JL7 recombinant proteins, as potential markers of seroconversion in treated chagasic patients. Prospective study, involving 203 patients treated with benznidazole, was conducted from endemic areas of northern Argentina. Follow-up was possible in 107 out of them and blood samples were taken for serology and PCR assays before and 2, 3, 6, 12, 24 and 36 months after treatment initiation. Reactivity against Trypanosoma cruzi lysate and recombinant antigens was measured by ELISA. The rate of decrease of antibody titers showed nonlinear kinetics with an abrupt drop within the first three months after initiation of treatment for all studied antigens, followed by a plateau displaying a low decay until the end of follow-up. At this point, anti-B13, anti-1F8 and anti-JL7 titers were relatively close to the cut-off line, while anti-T. cruzi antibodies still remained positive. At baseline, 60.8% (45/74) of analysed patients tested positive for parasite DNA by PCR and during the follow-up period in 34 out of 45 positive samples (75.5%) could not be detected T. cruzi DNA. Our results suggest that these antigens might be useful as early markers for monitoring antiparasitic treatment in chronic Chagas disease.

Early menarche, depressive symptoms, and coping strategies.

During the time around menarche, young women must make many emotional and social adjustments to adapt to a new life stage. We compared depressive symptomatology and coping strategies between early and average maturer Mexican adolescents girls. The relationships between elapsed time since menarche and both depressive symptomatology and coping strategies were also studied. Three hundred eighty post-menarcheal students from 11 to 15 years completed the Children's Depression Scale and the Children's Situational Coping Scale. Early maturers showed more depressive symptoms than their peers, but they reported having used fewer non-productive coping strategies. Early maturers who experienced menarche one to three years previously reported more non-productive coping strategies than those who had experienced menarche four to six years ago. However, no differences were found in the results of the average maturers depending on the time elapsed since menarche. These findings are discussed in light of the psychosocial context of early maturers.

Printability of Nixtamalized Corn Dough during Screw-Based Three-Dimensional Food Printing.

This study aimed to analyze the printability of corn-based dough during screw-based three-dimensional (3D) food printing (3DFP) by relating its rheological and mechanical properties to its screw-based 3DFP performance, with the objective of providing insights into the utilization of corn-based dough to produce 3D-printed foods. Screw-based 3DFP was performed using seven corn-based doughs with different nixtamalized corn flour (NCF) and water contents. Afterward, their rheological and mechanical properties were analyzed and associated with their screw-based 3DFP performance. The results showed that stable printability was obtained within a specific range of NCF content in the dough (30-32.5 wt%). Below this range, the 3D-printed foods flattened, while above it, the extrudability of the dough was affected. The printability of the dough was influenced by different rheological and mechanical properties, depending on the stage of the screw-based 3DFP process. During the extrusion stage, the loss tangent at nozzle strain, yield stress, apparent viscosity, and adhesiveness mainly affected the extrudability of the dough. In contrast, the loss tangent at minimum strain, elastic modulus, Young's modulus, and hardness influenced the self-supporting stage. Therefore, it is important to find a balance between all of these properties, where stable extrudability and self-supporting of the 3D structure are achieved.

Multimodal immune phenotyping reveals microbial-T cell interactions that shape pancreatic cancer.

Microbes are an integral component of the tumor microenvironment. However, determinants of microbial presence remain ill-defined. Here, using spatial-profiling technologies, we show that bacterial and immune cell heterogeneity are spatially coupled. Mouse models of pancreatic cancer recapitulate the immune-microbial spatial coupling seen in humans. Distinct intra-tumoral niches are defined by T cells, with T cell-enriched and T cell-poor regions displaying unique bacterial communities that are associated with immunologically active and quiescent phenotypes, respectively, but are independent of the gut microbiome. Depletion of intra-tumoral bacteria slows tumor growth in T cell-poor tumors and alters the phenotype and presence of myeloid and B cells in T cell-enriched tumors but does not affect T cell infiltration. In contrast, T cell depletion disrupts the immunological state of tumors and reduces intra-tumoral bacteria. Our results establish a coupling between microbes and T cells in cancer wherein spatially defined immune-microbial communities differentially influence tumor biology.

Cancer immunotherapy via synergistic coactivation of myeloid receptors CD40 and Dectin-1.

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability in mouse models of pancreatic cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor Dectin-1 and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, coactivation of Dectin-1, via systemic ß-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Antitumor activity was dependent on cDC1s and T cells but did not require classical T cell-mediated cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-mediated IFN-γ signaling, which converged with Dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance in pancreatic tumors resistant to checkpoint inhibition can be invoked by coactivation of complementary myeloid signaling pathways.

First, do no harm: why anti-immigrant policies in the United States are a public health concern.

It can be argued that anti-immigrant policies, such as the 287(g) program, can have a direct impact on the health and well-being of the immigrant community in general, particularly undocumented immigrants in the United States. While there is yet to be a comprehensive and conclusive empirical assessment of this issue, what is known is that the immigrant community faces many stress factors and structural barriers that negatively impact health. We argue that it is urgent that public health responds to the unique experiences and challenges of the undocumented and wider immigrant community. In doing so, we propose three recommendations for addressing this issue: (1) Assess the causal relationship between anti-immigration policies and immigrant health, (2) Increase funding and access to health care services for immigrant communities in jurisdictions implementing anti-immigrant policies, and (3) For public health to engage in a conscious effort to service the undocumented immigrant community. Even though we focus specifically on the United States, our recommendations are applicable on a global scale since anti-immigration policies are prevalent across nations and are a pervasive human rights issue around the world.

Implementation of virtual patients in the training for occupational health in Latin America.

Health professionals trained in occupational health are essential to reduce the burden of occupational accidents and diseases. However, training resources are limited globally. We aimed to promote occupational health and safety (OHS) using virtual patients (VPs) in Brazil, Chile, and Germany. Virtual patients were created in three Latin-American health centers. So-called "partner VPs" comparing the distinct health care systems were designed. Translation, adaptation to different medical and legal systems, expert review, implementation into under- and postgraduate teaching, and user evaluation were performed. Twelve VPs covering traditional and contemporary OHS issues are available in Spanish, Portuguese, and English. Overall, 2371 students used the VPs. The number of Latin American users who evaluated VP content and relevance for their professional career was statistically significantly higher than the number of German students. VPs are a feasible learning method for OHS in middle-income countries. Partner VPs seem to be useful for teaching global aspects.

Systemic inflammation is a determinant of outcomes of CD40 agonist-based therapy in pancreatic cancer patients.

Agonistic anti-CD40 monoclonal antibody (mAb) therapy in combination with chemotherapy (chemoimmunotherapy) shows promise for the treatment of pancreatic ductal adenocarcinoma (PDA). To gain insight into immunological mechanisms of response and resistance to chemoimmunotherapy, we analyzed blood samples from patients (n = 22) with advanced PDA treated with an anti-CD40 mAb (CP-870,893) in combination with gemcitabine. We found a stereotyped cellular response to chemoimmunotherapy characterized by transient B cell, CD56+CD11c+HLA-DR+CD141+ cell, and monocyte depletion and CD4+ T cell activation. However, these cellular pharmacodynamics did not associate with outcomes. In contrast, we identified an inflammatory network in the peripheral blood consisting of neutrophils, cytokines (IL-6 and IL-8), and acute phase reactants (C-reactive protein and serum amyloid A) that was associated with outcomes. Furthermore, monocytes from patients with elevated plasma IL-6 and IL-8 showed distinct transcriptional profiles, including upregulation of CCR2 and GAS6, genes associated with regulation of leukocyte chemotaxis and response to inflammation. Patients with systemic inflammation, defined by neutrophil/lymphocyte ratio (NLR) greater than 3.1, had a shorter median overall survival (5.8 vs. 12.3 months) as compared with patients with NLR less than 3.1. Taken together, our findings identify systemic inflammation as a potential resistance mechanism to a CD40-based chemoimmunotherapy and suggest biomarkers for future studies.

TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy.

Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity. However, treatment with anti-CD40 is commonly accompanied by both systemic cytokine release and liver transaminase elevations, which together account for the most common dose-limiting toxicities. Moreover, anti-CD40 treatment increases the potential for chemotherapy-induced hepatotoxicity. Here, we report a mechanistic link between cytokine release and hepatotoxicity induced by anti-CD40 when combined with chemotherapy and show that toxicity can be suppressed without impairing therapeutic efficacy. We demonstrate in mice and humans that anti-CD40 triggers transient hepatotoxicity marked by increased serum transaminase levels. In doing so, anti-CD40 sensitizes the liver to drug-induced toxicity. Unexpectedly, this biology is not blocked by the depletion of multiple myeloid cell subsets, including macrophages, inflammatory monocytes, and granulocytes. Transcriptional profiling of the liver after anti-CD40 revealed activation of multiple cytokine pathways including TNF and IL-6. Neutralization of TNF, but not IL-6, prevented sensitization of the liver to hepatotoxicity induced with anti-CD40 in combination with chemotherapy without impacting antitumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.

Necrotizing cellulitis due to Rhizopus arrhizus in an extremely premature infant.

We report an extremely premature infant with necrotizing cellulitis. After minor trauma to the left arm when removing an adhesive sensor, patient developed rapidly progressive cellulitis, which evolved into a necrotic ulcer. Microbiological studies (mass spectroscopy and molecular assay) identified Rhizopus arrhizus as the responsible fungus.

Publisher Correction: Science diplomacy for plant health.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Determinants of pediatric cataract program outcomes and follow-up in a large series in Mexico.

PURPOSE: To report determinants of outcomes and follow-up in a large Mexican pediatric cataract project. SETTING: Hospital Luis Sanchez Bulnes, Mexico City, Mexico. METHODS: Data were collected prospectively from a pediatric cataract surgery program at the Hospital Luis Sanchez Bulnes, implemented by Helen Keller International. Preoperative data included age, sex, baseline visual acuity, type of cataract, laterality, and presence of conditions such as amblyopia. Surgical data included vitrectomy, capsulotomy, complications, and use of intraocular lenses (IOLs). Postoperative data included final visual acuity, refraction, number of follow-up visits, and program support for follow-up. RESULTS: Of 574 eyes of 415 children (mean age 7.1 years +/- 4.7 [SD]), IOLs were placed in 416 (87%). At least 1 follow-up was attended by 408 patients (98.3%) (mean total follow-up 3.5 +/- 1.8 months); 40% of eyes achieved a final visual acuity of 6/18 or better. Children living farther from the hospital had fewer postoperative visits (P = .04), while children receiving program support had more visits (P = .001). Factors predictive of better acuity included receiving an IOL during surgery (P = .04) and provision of postoperative spectacles (P = .001). Predictive of worse acuity were amblyopia (P = .003), postoperative complications (P = .0001), unilateral surgery (P = .0075), and female sex (P = .045). CONCLUSIONS: The results underscore the importance of surgical training in reducing complications, early intervention before amblyopia (observed in 40% of patients) can develop, and vigorous treatment if amblyopia is present. The positive impact of program support on follow-up is encouraging, although direct financial support may pose a problem for sustainability. More work is needed to understand reasons for worse outcomes in girls.

[Extensive left-leg venous thrombosis in young patients: Should we perform extended tests?] / Trombosis venosa extensa de la extremidad inferior izquierda en sujetos jóvenes: ¿debemos realizar estudio de extensión?

EN: We report 3 cases of left iliac vein thrombosis whose underlying cause was right iliac artery compression syndrome, also known as May-Thurner syndrome. Endovascular treatment with anatomical correction (stent placement) was applied in 2 of the cases; anticoagulant therapy was maintained given the presence of associated hypercoagulability. A thorough understanding of this diagnosis is important so that an attempt at anatomical correction can be proposed to complement anticoagulant therapy in the interest of improving prognosis.

ES: Se presentan 3 casos de trombosis de la vena ilíaca izquierda que como causa subyacente presentaban una compresión por parte de la arteria ilíaca derecha, lo cual es conocido como síndrome de May-Thurner. Se procedió en 2 de ellos a tratamiento endovascular con corrección anatómica mediante colocación de un stent, manteniendo la anticoagulación por presentar trombofilia asociada. Es importante conocer esta entidad, para además de aplicar la anticoagulación, intentar realizar una corrección anatómica que mejore el pronóstico del enfermo.