Lymph node colonization induces tumor-immune tolerance to promote distant metastasis.

For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.

Systemic Immunity Is Required for Effective Cancer Immunotherapy.

Immune responses involve coordination across cell types and tissues. However, studies in cancer immunotherapy have focused heavily on local immune responses in the tumor microenvironment. To investigate immune activity more broadly, we performed an organism-wide study in genetically engineered cancer models using mass cytometry. We analyzed immune responses in several tissues after immunotherapy by developing intuitive models for visualizing single-cell data with statistical inference. Immune activation was evident in the tumor and systemically shortly after effective therapy was administered. However, during tumor rejection, only peripheral immune cells sustained their proliferation. This systemic response was coordinated across tissues and required for tumor eradication in several immunotherapy models. An emergent population of peripheral CD4 T cells conferred protection against new tumors and was significantly expanded in patients responding to immunotherapy. These studies demonstrate the critical impact of systemic immune responses that drive tumor rejection.

Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer.

Oncogenic mutations in the BRAF kinase occur in 6-8% of nonsmall cell lung cancers (NSCLCs), accounting for more than 90,000 deaths annually worldwide. The biological and clinical relevance of these BRAF mutations in NSCLC is incompletely understood. Here we demonstrate that human NSCLC cells with BRAF(V600E), but not other BRAF mutations, initially are sensitive to BRAF-inhibitor treatment. However, these BRAF(V600E) NSCLC cells rapidly acquire resistance to BRAF inhibition through at least one of two discrete molecular mechanisms: (i) loss of full-length BRAF(V600E) coupled with expression of an aberrant form of BRAF(V600E) that retains RAF pathway dependence or (ii) constitutive autocrine EGF receptor (EGFR) signaling driven by c-Jun-mediated EGFR ligand expression. BRAF(V600E) cells with EGFR-driven resistance are characterized by hyperphosphorylated protein kinase AKT, a biomarker we validated in BRAF inhibitor-resistant NSCLC clinical specimens. These data reveal the multifaceted molecular mechanisms by which NSCLCs establish and regulate BRAF oncogene dependence, provide insights into BRAF-EGFR signaling crosstalk, and uncover mechanism-based strategies to optimize clinical responses to BRAF oncogene inhibition.

Effects of a nursing care program focused on basic self-care in older acute medical in-patients: a randomized controlled trial.

BACKGROUND: Acute illness and hospitalization are often associated with decreased independence in basic activities of daily living. The aim of this study was to test the hypothesis that a nursing care program focused on basic self-care (N_BSC) improves functional outcomes in older patients admitted to an acute medical unit. METHODS: This was a 2-group randomized controlled trial with repeated measures: 182 older patients admitted to an acute medical unit were randomly allocated to the usual care group (n = 91) and intervention group (n = 91). The intervention consisted of nursing care centered on basic self-care that includes promotion of daily walking and all daytime meals seated, out of bed. The main outcome was changes in the number of independent basic activities of daily living (BADL) from 2 weeks before admission (baseline) to discharge. RESULTS: There was significant effect of the N_BSC on the outcomes. Changes from baseline to discharge in the number of independent BADL differ significantly between the intervention and usual care group. Intervention group patients were discharged with a superior functional status than usual care group. On discharge they were able to perform independently 2.93 BADL, whereas usual care patients performed independently 1.90 BADL (P < .001). CONCLUSIONS: N_BSC for hospitalized older adults was feasible and program participants were discharged with better functional status than a clinically similar comparison group. N_BSC could be readily adapted for use in other hospitals and warrants further evaluation as a potential new tool for improving outcomes for hospitalized older patients.

Ornithodoros cerradoensis n. sp. (Acari: Argasidae), a member of the Ornithodoros talaje (Guérin-Méneville, 1849) group, parasite of rodents in the Brazilian Savannah.

Ornithodoros cerradoensis n. sp. is described from field-collected and laboratory reared nymphs, males, females, and larvae parasitizing the rodents Cavia aperea and Thrichomys sp. in the Brazilian Savannah. This new species is morphologically and genetically related with the Ornithodoros talaje group and can be separated from other Neotropical species using the following combination of characters: larva with 18 pairs of setae on dorsum (seven anterolateral, four central and seven posterolateral), hypostome with median dentition 2/2; adults provided with large mammillae; dorsal disks surrounded by bulked marginal ridges delimiting barely pebbled areas; three disks in the anterolateral file, and median disk not merging with the posteromedian file. Feeding assays in the laboratory demonstrated that (1) larvae of O. cerradoensis are slow-feeders (∼6 days), (2) first nymphal instar (N1) molts to second instar (N2) without feeding, and (3) N2 and third nymphal instar (N3) engorge rapidly (minutes). With the exception of Ornithodoros hasei nymphs that depict flattened bodies, O. cerradoensis N1, N2, and N3 highly resemble homologous instars of other species in O. talaje sensu lato, therefore are not suitable for morphological comparisons within the group. In addition to morphological signature of larvae and adults that separate this new species; results of cross-mating attempts between O. cerradoensis and Ornithodoros guaporensis a morphologically and phylogenetically closely related species that also parasitizes rodents in the Brazilian Savannah; a Principal Component Analysis using larval characters; and a phylogenetic analysis using mitochondrial markers, support O. cerradoensis as an independent lineage within the Ornithodorinae.

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.

The effect of the ProBalance Programme on health-related quality of life of community-dwelling older adults: A randomised controlled trial.

BACKGROUND: Health-related quality of life (HRQoL) is an important health outcome in older adults. This study aimed to assess the efficacy of the ProBalance rehabilitation programme on HRQoL of community-dwelling older adults with balance impairments and to investigate whether effects differ between age groups and/or HRQoL components. METHODS: A single-blind, randomised controlled trial included community-dwelling older adults, aged 65-85, with balance impairments. Participants (n=52) were randomly allocated to an intervention group (IG) or a control group (CG). A rehabilitation programme included gait, balance, functional training, strengthening, flexibility, and 3D training. A group-based intervention was administered over a period of 12 weeks (90-min sessions, 2days per week). A wait-list control group was instructed to maintain their usual activities during the same period. Participants' HRQoL was assessed using the SF-36 questionnaire. The time points for assessment were at zero (pre-test), 12 (post-test), and 24 weeks (follow up). RESULTS: A trend for higher HRQoL in the IG compared to the CG and a significant interaction of group with time were found, with significantly higher increases in HRQoL from the pre-test to the post-test (and to follow-up) in the IG, compared to the CG. RESULTS: were independent of age group (young-old vs. old-old) and HRQoL component (physical vs. mental). CONCLUSIONS: Present results suggest that the ProBalance programme had a beneficial effect on HRQoL of community-dwelling older adults, which held across young and old adults and not only comprised physical but also mental HRQoL. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12612000301864.

Functional strength training: Seated machine vs standing cable training to improve physical function in elderly.

BACKGROUND: The majority of the strength training studies in older adults have incorporated fixed-form exercises using seated resistance training machines. In light of the modest improvements in physical function shown in these studies, functional or task-specific exercises, involving movement patterns that mimic daily activities, have been studied. Free-form exercises, using free-weights or cable, is another form of functional strength training. Currently, no intervention studies exist comparing free-form exercises, using cable machines, and fixed-form exercises, using seated machines in older adults. METHODS: A total of 29 independently-living older adults, 65years or older, were randomized into two groups, seated machine (SM, n=10) and standing cable (SC, n=12). After 12weeks of training twice per week, groups were compared. The primary outcome was the Physical Performance Battery (PPB), a measure of physical function. Secondary outcomes were lower and upper body strength and power, activities of daily living evaluated by multiple tests including: Physical Performance Test (PPT), pan carry and gallon jug transfers, ratings of perceived exertion (RPE), and self-reported function using Patient Reported Outcomes Measurement Information System (PROMIS). Outcome assessors were blinded to participants' intervention assignments. RESULTS: The PPB (SC=0.23 points; SM=0.15 points) showed clinical and significant improvements, but there was no significant difference between the groups (g=0.2, 95% CI (-0.6, 1.0). For secondary outcomes, chair stand (g=0.7, 95% CI (0.2, 1.6), p=0.03) and pan carry (g=0.8, 95% CI (0.07, 1.07), p=0.04) favored SC, while chest press 1RM (g=0.2, 95% CI (0.06, 1.1), p=0.02) favored SM. There were no statistically significant group differences between PPB, gallon jug transfer, leg press 1RM, power, RPE or self-reported function. CONCLUSIONS: Standing cable training was not superior to seated machine training in improving physical performance in older adults. However, both training interventions were effective in improving function. The findings also suggest that exercise specificity should be considered when prescribing resistance exercises to improve physical function in older adults.

Ornithodoros cerradoensis n. sp. (Acari: Argasidae), a member of the Ornithodoros talaje (Guérin-Méneville, 1849) group, parasite of rodents in the Brazilian Savannah

Ornithodoros cerradoensis n. sp. is described from field-collected and laboratory reared nymphs, males, females, and larvae parasitizing the rodents Cavia aperea and Thrichomys sp. in the Brazilian Savannah. This new species is morphologically and genetically related with the Ornithodoros talaje group and can be separated from other Neotropical species using the following combination of characters: larva with 18 pairs of setae on dorsum (seven anterolateral, four central and seven posterolateral), hypostome with median dentition 2/2; adults provided with large mammillae; dorsal disks surrounded by bulked marginal ridges delimiting barely pebbled areas; three disks in the anterolateral file, and median disk not merging with the posteromedian file. Feeding assays in the laboratory demonstrated that (1) larvae of O. cerradoensis are slow-feeders (∼6 days), (2) first nymphal instar (N1) molts to second instar (N2) without feeding, and (3) N2 and third nymphal instar (N3) engorge rapidly (minutes). With the exception of Ornithodoros hasei nymphs that depict flattened bodies, O. cerradoensis N1, N2, and N3 highly resemble homologous instars of other species in O. talaje sensu lato, therefore are not suitable for morphological comparisons within the group. In addition to morphological signature of larvae and adults that separate this new species; results of cross-mating attempts between O. cerradoensis and Ornithodoros guaporensis a morphologically and phylogenetically closely related species that also parasitizes rodents in the Brazilian Savannah; a Principal Component Analysis using larval characters; and a phylogenetic analysis using mitochondrial markers, support O. cerradoensis as an independent lineage within the Ornithodorinae.

Linking tumor mutations to drug responses via a quantitative chemical-genetic interaction map.

UNLABELLED: There is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic-lethal genetic interactions or dependencies that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated a systematic and quantitative chemical-genetic interaction map that charts the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly predicts drug responses found in cancer cell line collections, indicating that isogenic cells can model complex cellular contexts. Applying this dataset to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene, including resistance to AKT-PI3K pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic lethal manner, providing new drug and biomarker pairs for clinical investigation. This scalable approach enables the prediction of drug responses from patient data and can accelerate the development of new genotype-directed therapies. SIGNIFICANCE: Determining how the plethora of genomic abnormalities that exist within a given tumor cell affects drug responses remains a major challenge in oncology. Here, we develop a new mapping approach to connect cancer genotypes to drug responses using engineered isogenic cell lines and demonstrate how the resulting dataset can guide clinical interrogation.

Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World.

Pentavalent antimonials are first-line drugs for the treatment of the cutaneous form of American tegumentary leishmaniasis. Second-line drugs include amphotericin B and pentamidine. Although these drugs have been used for decades, there are no systematic reviews about their safety. The objective of this review was to identify and classify the main adverse effects associated with these drugs and to estimate the frequency of these effects, whenever possible. Intervention studies, case series and case reports containing information regarding clinical, laboratory or electrocardiographic adverse effects of drugs used for the treatment of cutaneous leishmaniasis were systematically retrieved from 10 databases searched between August 13, 2008 and March 31, 2009. The 65 studies included in this review had treated a total of 4359 patients from 12 countries infected with eight different Leishmania species. Despite the small number of drugs used in these studies, a wide variability in the therapeutic regimens was observed. As a consequence, the adverse effects of pentavalent antimonials and pentamidine needed to be classified jointly according to system, irrespective of formulation, daily dose, duration of treatment, and route of administration. The frequencies of adverse effects were calculated based on the data of 32 articles involving 1866 patients. The most frequently reported clinical adverse effects of pentavalent antimonials and pentamidine were musculoskeletal pain, gastrointestinal disturbances, and mild to moderate headache. Electrocardiographic QTc interval prolongation and a mild to moderate increase in liver and pancreatic enzymes were additional adverse effects of pentavalent antimonials. Patients treated with liposomal amphotericin B had mild dyspnea and erythema. The adverse effects associated with miltefosine were vomiting, nausea, kinetosis, headache, diarrhea, and a mild to moderate increase in aminotransferases and creatinine. Although closer surveillance is needed for the treatment of cutaneous leishmaniasis, antileishmanial drugs are basically safe and severe side effects requiring the discontinuation of treatment are relatively uncommon.

Small bowel tumors detection in capsule endoscopy by Gaussian modeling of color curvelet covariance coefficients.

This paper is concerned with the classification of tumoral tissue in the small bowel by using capsule endoscopic images. The followed approach is based on texture classification. Texture descriptors are derived from selected scales of the Discrete Curvelet Transform (DCT). The goal is to take advantage of the high directional sensitivity of the DCT (16 directions) when compared with the Discrete Wavelet Transform (DWT) (3 directions). Second order statistics are then computed in the HSV color space and named Color Curvelet Covariance (3C) coefficients. Finally, these coefficients are modeled by a Gaussian Mixture Model (GMM). Sensitivity of 99% and specificity of 95.19% are obtained in the testing set.