Description of new species of Mycobacterium terrae complex isolated from sewage at the São Paulo zoological park foundation in Brazil.

Five mycobacterial isolates from sewage were classified as members of the genus Mycobacterium but presented inconclusive species assignments. Thus, the isolates (MYC017, MYC098, MYC101, MYC123 and MYC340) were analyzed by phenotypical, biochemical, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and genomic features to clarify their taxonomic position. Phenotypic analysis and biochemical tests did not distinguish these isolates from other non-pigmented mycobacteria. In contrast, MALDI-TOF MS analysis showed that isolates were not related to any previously described Mycobacterium species. Comparative genomic analysis showed values of ANI and dDDH between 81.59-85.56% and 24.4-28.8%, respectively, when compared to the genomes of species of this genus. In addition, two (MYC101 and MYC123) presented indistinguishable protein spectra from each other and values of ANI = 98.57% and dDDH = 97.3%, therefore being considered as belonging to the same species. Phylogenetic analysis grouped the five isolates within the Mycobacterium terrae complex (MTC) but in a specific subclade and separated from the species already described and supported by 100% bootstrap value, confirming that they are part of this complex but different from earlier described species. According to these data, we propose the description of four new species belonging to the Mycobacterium genus: (i) Mycobacterium defluvii sp. nov. strain MYC017T (= ATCC TSD-296T = JCM 35364T), (ii) Mycobacterium crassicus sp. nov. strain MYC098T (= ATCC TSD-297T = JCM 35365T), (iii) Mycobacterium zoologicum sp. nov. strain MYC101T (= ATCC TSD-298T = JCM 35366T) and MYC123 (= ATCC BAA-3216 = JCM 35367); and (iv) Mycobacterium nativiensis sp. nov. strain MYC340T (= ATCC TSD-299T = JCM 35368T).

Clinical outcomes of a digitally supported approach for self-management of type 2 diabetes mellitus.

Background: Self-management of Type 2 diabetes mellitus (T2D) is challenging. Regular self-monitoring of blood glucose and healthy lifestyles are required to improve glycometabolic control, thus delaying diabetes complications, and reducing hospitalizations. Digital technologies can empower patients in their disease management promoting self-management and motivation to change behaviors. We report the results of an exploratory trial aimed at evaluating the metabolic outcomes of using digital solutions for T2D self-management developed in the ProEmpower project, a European Commission funded Pre-Commercial Procurement. Methods: Two digital solutions, DM4All and DiaWatch, which were codesigned with providers, patients, and caregivers, enabled the collection of clinical parameters by the patient using a smartphone integrated with the medical devices (glucometer, sphygmomanometer, scale, smart watch for heart rate monitoring and step counter). Data were automatically sent to the shared care plan allowing professionals to monitor adherence to treatment, set goals, and communicate more effectively with patients. At baseline and after an average follow-up of 8 months, glycosylated hemoglobin (HbA1c), body weight, blood pressure, and blood lipids were measured in 100 T2D patients using the ProEmpower solutions across different diabetes centers in Campania Region, age 45-79 years, both genders, and compared with a Control cohort of T2D patients (n = 100) with similar clinical characteristics and followed for a comparable period of observation in the same centers. Results: At baseline, the ProEmpower participants and the Control subjects were on average overweight, with a similar BMI in the two cohorts, and mean HbA1c was at acceptable levels (around 7.0%). After the 8 month exploratory trial, body weight, HbA1c, systolic and diastolic blood pressure, and plasma and LDL-cholesterol significantly decreased in the ProEmpower participants compared to baseline (p < 0.05 for all). The changes in systolic and diastolic blood pressure, and plasma and LDL-cholesterol were significantly different from those observed in the Control cohort (p < 0.05 for all). Conclusion: This pilot study showed positive effects on metabolic outcomes relevant to cardiovascular risk in T2D of adopting digital telemedicine self-monitoring solutions based on automation of measurements and coaching on healthy lifestyles promotion.

ß2-AR inhibition enhances EGFR antibody efficacy hampering the oxidative stress response machinery.

The ß2-Adrenergic receptor (ß2-ARs) is a cell membrane-spanning G protein-coupled receptors (GPCRs) physiologically involved in stress-related response. In many cancers, the ß2-ARs signaling drives the tumor development and transformation, also promoting the resistance to the treatments. In HNSCC cell lines, the ß2-AR selective inhibition synergistically amplifies the cytotoxic effect of the MEK 1/2 by affecting the p38/NF-kB oncogenic pathway and contemporary reducing the NRF-2 mediated antioxidant cell response. In this study, we aimed to validate the anti-tumor effect of ß2-AR blockade and the synergism with MEK/ERK and EGFR pathway inhibition in a pre-clinical orthotopic mouse model of HNSCC. Interestingly, we found a strong ß2-ARs expression in the tumors that were significantly reduced after prolonged treatment with ß2-Ars inhibitor (ICI) and EGFR mAb Cetuximab (CTX) in combination. The ß2-ARs down-regulation correlated in mice with a significant tumor growth delay, together with the MAPK signaling switch-off caused by the blockade of the MEK/ERK phosphorylation. We also demonstrated that the administration of ICI and CTX in combination unbalanced the cell ROS homeostasis by blocking the NRF-2 nuclear translocation with the relative down-regulation of the antioxidant enzyme expression. Our findings highlighted for the first time, in a pre-clinical in vivo model, the efficacy of the ß2-ARs inhibition in the treatment of the HNSCC, remarkably in combination with CTX, which is the standard of care for unresectable HNSCC.

Multi-Approach Characterization of Novel Pyrene-Degrading Mycolicibacterium austroafricanum Isolates Lacking nid Genes.

Polycyclic aromatic hydrocarbons (PAHs) are chemical compounds that are widespread in the environment, arising from the incomplete combustion of organic material, as well as from human activities involving petrol exploitation, petrochemical industrial waste, gas stations, and environmental disasters. PAHs of high molecular weight, such as pyrene, have carcinogenic and mutagenic effects and are considered pollutants. The microbial degradation of PAHs occurs through the action of multiple dioxygenase genes (nid), which are localized in genomic island denominate region A, and cytochrome P450 monooxygenases genes (cyp) dispersed in the bacterial genome. This study evaluated pyrene degradation by five isolates of Mycolicibacterium austroafricanum using 2,6-dichlorophenol indophenol (DCPIP assay), gas chromatography/mass spectrometry (CG/MS), and genomic analyses. Two isolates (MYC038 and MYC040) exhibited pyrene degradation indexes of 96% and 88%, respectively, over a seven-day incubation period. Interestingly, the genomic analyses showed that the isolates do not have nid genes, which are involved in PAH biodegradation, despite their ability to degrade pyrene, suggesting that degradation may occur due to the presence of cyp150 genes, or even genes that have not yet been described. To the best of our knowledge, this is the first report of isolates without nid genes demonstrating the ability to degrade pyrene.

Systematic review of the relationship between rumen acidosis and laminitis in cattle.

Laminitis is usually considered a consequence of digestive disorders that reduce ruminal pH. However, it is still not clear the direct relation between low ruminal pH provoked by excessive fast-digesting carbohydrate ingestion and laminitis, considering indicators, signs, and diagnosis aspects. This study aimed to clarify the association between different clinical presentations of laminitis with ruminal acidosis provoked by diet using the systematic review methodology. Three electronic databases were used: ISI Web of Science, PubMed, and Scopus. A total of 339 manuscripts were identified and only 16 were included. Manuscripts were published between 2000 and 2021 in 11 different peer-reviewed journals. Fifteen studies confirmed the occurrence of ruminal acidosis. The main indicators used were ruminal pH and clinical signs, such as anorexia, depression, discomfort and diarrhea. Two of the studies that administered oligofructose to induce acidosis and acute laminitis did not observe clinical signs of laminitis, using lameness score or hooves' sensitivity as an indicator. Various diagnostic methods were used to describe laminitis, like thermography, hoof biopsy, sensitivity test, and visual inspection. Although the variety of laminitis indicators used in the included studies, we evidence the existence of an association between diet (high level of fast-digesting carbohydrates), ruminal acidosis, and acute laminitis, mostly in the short-term acidosis' induction protocols, but the mechanism of action is still not clear.

PATZ1 in Non-Small Cell Lung Cancer: A New Biomarker That Negatively Correlates with PD-L1 Expression and Suppresses the Malignant Phenotype.

Non-small cell lung cancer (NSCLC), the leading cause of cancer death worldwide, is still an unmet medical problem due to the lack of both effective therapies against advanced stages and markers to allow a diagnosis of the disease at early stages before its progression. Immunotherapy targeting the PD-1/PD-L1 checkpoint is promising for many cancers, including NSCLC, but its success depends on the tumor expression of PD-L1. PATZ1 is an emerging cancer-related transcriptional regulator and diagnostic/prognostic biomarker in different malignant tumors, but its role in lung cancer is still obscure. Here we investigated expression and role of PATZ1 in NSCLC, in correlation with NSCLC subtypes and PD-L1 expression. A cohort of 104 NSCLCs, including lung squamous cell carcinomas (LUSCs) and adenocarcinomas (LUADs), was retrospectively analyzed by immunohistochemistry for the expression of PATZ1 and PD-L1. The results were correlated with each other and with the clinical characteristics, showing on the one hand a positive correlation between the high expression of PATZ1 and the LUSC subtype and, on the other hand, a negative correlation between PATZ1 and PD-L1, validated at the mRNA level in independent NSCLC datasets. Consistently, two NSCLC cell lines transfected with a PATZ1-overexpressing plasmid showed PD-L1 downregulation, suggesting a role for PATZ1 in the negative regulation of PD-L1. We also showed that PATZ1 overexpression inhibits NSCLC cell proliferation, migration, and invasion, and that Patz1-knockout mice develop LUAD. Overall, this suggests that PATZ1 may act as a tumor suppressor in NSCLC.

AMMI-Bayesian perspective in the selection of pre-cultivars of carioca beans in Agreste-Sertão of Pernambuco, Brazil.

The productivity of beans is greatly influenced by the different edaphoclimatic conditions in the Agreste-Sertão region, requiring the identification of adapted and stable genotypes to minimize the effects of the interaction between genotypes per environments (GxE). The objective of this work was to analyze the adaptability and stability of carioca bean pre-cultivars in three municipalities in the Agreste-Sertão of Pernambuco using the AMMI model in its Bayesian version BAMMI and compare the results with the frequentist approach. According to the results, the BAMMI analysis showed better predictive capacity, as well as better performance in the study of adaptability and stability. The cultivar BRS Notável stood out in terms of main effect and stability. Adaptability of genotypes to specific locations was also observed, enabling the use of the positive effect of the GxE interaction, which was more evident with the BAMMI model. From this work, the flexibility of BAMMI model to deal with data resulting from multi-environmental experiments can be seen, overcoming limitations of the standard analysis of the AMMI model.

Microbiota Effect on Trimethylamine N-Oxide Production: From Cancer to Fitness-A Practical Preventing Recommendation and Therapies.

Trimethylamine N-oxide (TMAO) is a microbial metabolite derived from nutrients, such as choline, L-carnitine, ergothioneine and betaine. Recently, it has come under the spotlight for its close interactions with gut microbiota and implications for gastrointestinal cancers, cardiovascular disease, and systemic inflammation. The culprits in the origin of these pathologies may be food sources, in particular, high fat meat, offal, egg yolk, whole dairy products, and fatty fish, but intercalated between these food sources and the production of pro-inflammatory TMAO, the composition of gut microbiota plays an important role in modulating this process. The aim of this review is to explain how the gut microbiota interacts with the conversion of specific compounds into TMA and its oxidation to TMAO. We will first cover the correlation between TMAO and various pathologies such as dysbiosis, then focus on cardiovascular disease, with a particular emphasis on pro-atherogenic factors, and then on systemic inflammation and gastrointestinal cancers. Finally, we will discuss primary prevention and therapies that are or may become possible. Possible treatments include modulation of the gut microbiota species with diets, physical activity and supplements, and administration of drugs, such as metformin and aspirin.

Corrigendum: Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways.

[This corrects the article DOI: 10.3389/fcvm.2022.930797.].

Non-covalent strategies to functionalize polymeric nanoparticles with NGR peptides for targeting breast cancer.

Surface functionalization of nanoparticles (NPs) with tumor-targeting peptides is an emerging approach with a huge potential to translate in the clinic and ameliorate the efficacy of nano-oncologicals. One major challenge is to find straightforward strategies for anchoring peptides on the surface of biodegradable NPs and ensuring their correct exposure and orientation to bind the target receptor. Here, we propose a non-covalent strategy to functionalize polyester aminic NPs based on the formation of either electrostatic or lipophilic interactions between NPs and the peptide modified with an anchoring moiety. We selected an iNGRt peptide containing a CendR motif (CRNGR) targeting neuropilin receptor 1 (NRP-1), which is upregulated in several cancers. iNGRt was linked with either a short poly(glutamic acid) chain (polyE) or a palmitoyl chain (Palm) and used to functionalize the surface of NPs made of a diamine poly(ε-caprolactone). iNGRt-PolyE was adsorbed on preformed cationic NPs through electrostatic interaction, whereas iNGRt-Palm was integrated into the forming NPs through interactions. In both cases, peptides were strongly associated with NPs of ∼100 nm, low polydispersity indexes, and positive zeta potential values. NPs entered MDA-MB231 breast cancer cells overexpressing NRP-1 via receptor-mediated endocytosis and showed a different cell localization depending on the mode of peptide anchoring. When loaded with the lipophilic anticancer drug docetaxel (DTX), NPs functionalized with the iNGRt-Palm variant exerted a time- and dose-dependent cytotoxicity similar to DTX in MDA-MB-231 cells but were less toxic than DTX toward control MRC-5 human fibroblasts, not expressing NRP-1. In a heterotopic mouse model of triple negative breast cancer, iNGRt-Palm NPs were tolerated better than free DTX and demonstrated superior anticancer activity and survival compared to both free DTX and NPs without peptide functionalization. We foresee that the functionalization strategy with palmitoylated peptides proposed here can be extended to other biodegradable NPs and peptide sequences designed for therapeutic or targeting purposes.

Use of the reversible jump Markov chain Monte Carlo algorithm to select multiplicative terms in the AMMI-Bayesian model.

The model selection stage has become a central theme in applying the additive main effects and multiplicative interaction (AMMI) model to determine the optimal number of bilinear components to be retained to describe the genotype-by-environment interaction (GEI). In the Bayesian context, this problem has been addressed by using information criteria and the Bayes factor. However, these procedures are computationally intensive, making their application unfeasible when the model's parametric space is large. A Bayesian analysis of the AMMI model was conducted using the Reversible Jump algorithm (RJMCMC) to determine the number of multiplicative terms needed to explain the GEI pattern. Three a priori distributions were assigned for the singular value scale parameter under different justifications, namely: i) the insufficient reason principle (uniform); ii) the invariance principle (Jeffreys' prior) and iii) the maximum entropy principle. Simulated and real data were used to exemplify the method. An evaluation of the predictive ability of models for simulated data was conducted and indicated that the AMMI analysis, in general, was robust, and models adjusted by the Reversible Jump method were superior to those in which sampling was performed only by the Gibbs sampler. In addition, the RJMCMC showed greater feasibility since the selection and estimation of parameters are carried out concurrently in the same sampling algorithm, being more attractive in terms of computational time. The use of the maximum entropy principle makes the analysis more flexible, avoiding the use of procedures for correcting prior degrees of freedom and obtaining improper posterior marginal distributions.

Combination of Spirulina platensis, Ganoderma lucidum and Moringa oleifera Improves Cardiac Functions and Reduces Pro-Inflammatory Biomarkers in Preclinical Models of Short-Term Doxorubicin-Mediated Cardiotoxicity: New Frontiers in Cardioncology?

Anthracyclines are essential adjuvant therapies for a variety of cancers, particularly breast, gastric and esophageal cancers. Whilst prolonging cancer-related survival, these agents can induce drug-related cardiotoxicity. Spirulina, Reishi (Ganoderma lucidum) and Moringa are three nutraceuticals with anti-inflammatory effects that are currently used in cancer patients as complementary and alternative medicines to improve quality of life and fatigue. We hypothesize that the nutraceutical combination of Spirulina, Reishi and Moringa (Singo) could reduce inflammation and cardiotoxicity induced by anthracyclines. Female C57Bl/6 mice were untreated (Sham, n = 6) or treated for 7 days with short-term doxorubicin (DOXO, n = 6) or Singo (Singo, n = 6), or pre-treated with Singo for 3 days and associated with DOXO for remaining 7 days (DOXO−Singo, n = 6). The ejection fraction and radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100, Fujifilm, Tokyo, Japan). The myocardial expressions of NLRP3, DAMPs (galectin-3 and calgranulin S100) and 13 cytokines were quantified through selective mouse ELISA methods. Myocardial fibrosis, necrosis and hypertrophy were analyzed through immunohistochemistry (IHC). Human cardiomyocytes were exposed to DOXO (200 nM) alone or in combination with Singo (at 10, 25 and 50 µg/mL) for 24 and 48 h. Cell viability and inflammation studies were also performed. In preclinical models, Singo significantly improved ejection fraction and fractional shortening. Reduced expressions of myocardial NLRP3 and NF-kB levels in cardiac tissues were seen in DOXO−Singo mice vs. DOXO (p < 0.05). The myocardial levels of calgranulin S100 and galectin-3 were strongly reduced in DOXO−Singo mice vs. DOXO (p < 0.05). Immunohistochemistry analysis indicates that Singo reduces fibrosis and hypertrophy in the myocardial tissues of mice during exposure to DOXO. In conclusion, in the preclinical model of DOXO-induced cardiotoxicity, Singo is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis.

Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways.

Background: Immune checkpoint inhibitors (ICIs) have significantly changed the oncology clinic in recent years, improving survival expectations in cancer patients. ICI therapy have a broad spectrum of side effects from endocrinopathies to cardiovascular diseases. In this study, pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models were analyzed. Methods: Firstly, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (with CTLA-4 or PD-1 blocking agents, at 200 nM) for 72 h. After treatment, production of DAMPs and 12 cytokines were analyzed in the supernatant through colorimetric and enzymatic assays. C57/Bl6 mice were treated with CTLA-4 or PD-1 blocking agents (15 mg/kg) for 10 days. Before (T0), after three days (T3) and after treatments (T10), ejection fraction, fractional shortening, radial and longitudinal strain were calculated by using bidimensional echocardiography (Vevo 2100, Fujfilm). Fibrosis, necrosis, hypertrophy and vascular NF-kB expression were analyzed through Immunohistochemistry. Myocardial expression of DAMPs (S100- Calgranulin, Fibronectin and Galectine-3), MyD88, NLRP3 and twelve cytokines have been analyzed. Systemic levels of SDF-1, IL-1ß, and IL-6 were analyzed before, during and after ICIs therapy. Results: Radial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. No myocardial hypertrophy was seen with the exception of the pembrolizumab group. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 inflammasome and MyD88 and induced both in vitro and in vivo the secretion of IL-1ß, TNF-α and IL-6. Systemic levels of SDF-1, IL-1ß and IL-6 were increased during and after treatment with ICIs. Conclusions: Short therapy with PD-1 and CTLA-4 blocking agents increases vascular expression of NF-kB, systemic SDF-1, IL-1ß, IL-6 levels and myocardial NLRP3, MyD88 and DAMPs expression in preclinical models. A pro-inflammatory cytokine storm was induced in myocardial tissues and in cultured cardiac cells after ICIs therapy. The overall picture of the study suggests new putative biomarkers of ICIs-mediated systemic and myocardial damages potentially useful in clinical cardioncology.

An additive repression mechanism sets the anterior limits of anterior pair-rule stripes 1.

Segments are repeated anatomical units forming the body of insects. In Drosophila, the specification of the body takes place during the blastoderm through the segmentation cascade. Pair-rule genes such as hairy (h), even-skipped (eve), runt (run), and fushi-tarazu (ftz) are of the intermediate level of the cascade and each pair-rule gene is expressed in seven transversal stripes along the antero-posterior axis of the embryo. Stripes are formed by independent cis-regulatory modules (CRMs) under the regulation of transcription factors of maternal source and of gap proteins of the first level of the cascade. The initial blastoderm of Drosophila is a syncytium and it also coincides with the mid-blastula transition when thousands of zygotic genes are transcribed and their products are able to diffuse in the cytoplasm. Thus, we anticipated a complex regulation of the CRMs of the pair-rule stripes. The CRMs of h 1, eve 1, run 1, ftz 1 are able to be activated by bicoid (bcd) throughout the anterior blastoderm and several lines of evidence indicate that they are repressed by the anterior gap genes slp1 (sloppy-paired 1), tll (tailless) and hkb (huckebein). The modest activity of these repressors led to the premise of a combinatorial mechanism regulating the expression of the CRMs of h 1, eve 1, run 1, ftz 1 in more anterior regions of the embryo. We tested this possibility by progressively removing the repression activities of slp1, tll and hkb. In doing so, we were able to expose a mechanism of additive repression limiting the anterior borders of stripes 1. Stripes 1 respond depending on their distance from the anterior end and repressors operating at different levels.

In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent and deadly tumors worldwide. The majority of CRC is resistant to anti-programmed cell death-1 (PD-1)-based cancer immunotherapy, with approximately 15% with high-microsatellite instability, high tumor mutation burden, and intratumoral lymphocytic infiltration. Programmed death-ligand 1 (PD-L1)/PD-1 signaling was described in solid tumor cells. In melanoma, liver, and thyroid cancer cells, intrinsic PD-1 signaling activates oncogenic functions, while in lung cancer cells, it has a tumor suppressor effect. Our work aimed to evaluate the effects of the anti-PD-1 nivolumab (NIVO) on CRC cells. METHODS: In vitro NIVO-treated human colon cancer cells (HT29, HCT116, and LoVo) were evaluated for cell growth, chemo/radiotherapeutic sensitivity, apoptosis, and spheroid growth. Total RNA-seq was assessed in 6-24 hours NIVO-treated human colon cancer cells HT29 and HCT116 as compared with NIVO-treated PES43 human melanoma cells. In vivo mice carrying HT29 xenograft were intraperitoneally treated with NIVO, OXA (oxaliplatin), and NIVO+OXA, and the tumors were characterized for growth, apoptosis, and pERK1/2/pP38. Forty-eight human primary colon cancers were evaluated for PD-1 expression through immunohistochemistry. RESULTS: In PD-1+ human colon cancer cells, intrinsic PD-1 signaling significantly decreased proliferation and promoted apoptosis. On the contrary, NIVO promoted proliferation, reduced apoptosis, and protected PD-1+ cells from chemo/radiotherapy. Transcriptional profile of NIVO-treated HT29 and HCT116 human colon cancer cells revealed downregulation of BATF2, DRAM1, FXYD3, IFIT3, MT-TN, and TNFRSF11A, and upregulation of CLK1, DCAF13, DNAJC2, MTHFD1L, PRPF3, PSMD7, and SCFD1; the opposite regulation was described in NIVO-treated human melanoma PES43 cells. Differentially expressed genes (DEGs) were significantly enriched for interferon pathway, innate immune, cytokine-mediated signaling pathways. In vivo, NIVO promoted HT29 tumor growth, thus reducing OXA efficacy as revealed through significant Ki-67 increase, pERK1/2 and pP38 increase, and apoptotic cell reduction. Eleven out of 48 primary human colon cancer biopsies expressed PD-1 (22.9%). PD-1 expression is significantly associated with lower pT stage. CONCLUSIONS: In PD-1+ human colon cancer cells, NIVO activates tumor survival pathways and could protect tumor cells from conventional therapies.

Long-term memory T cells as preventive anticancer immunity elicited by TuA-derived heteroclitic peptides.

The host's immune system may be primed against antigens during the lifetime (e.g. microorganisms antigens-MoAs), and swiftly recalled upon growth of a tumor expressing antigens similar in sequence and structure. C57BL/6 mice were immunized in a preventive setting with tumor antigens (TuAs) or corresponding heteroclitic peptides specific for TC-1 and B16 cell lines. Immediately or 2-months after the end of the vaccination protocol, animals were implanted with cell lines. The specific anti-vaccine immune response as well as tumor growth were regularly evaluated for 2 months post-implantation. The preventive vaccination with TuA or their heteroclitic peptides (hPep) was able to delay (B16) or completely suppress (TC-1) tumor growth when cancer cells were implanted immediately after the end of the vaccination. More importantly, TC-1 tumor growth was significantly delayed, and suppressed in 6/8 animals, also when cells were implanted 2-months after the end of the vaccination. The vaccine-specific T cell response provided a strong immune correlate to the pattern of tumor growth. A preventive immunization with heteroclitic peptides resembling a TuA is able to strongly delay or even suppress tumor growth in a mouse model. More importantly, the same effect is observed also when tumor cells are implanted 2 months after the end of vaccination, which corresponds to 8 - 10 years in human life. The observed potent tumor control indicates that a memory T cell immunity elicited during the lifetime by a antigens similar to a TuA, i.e. viral antigens, may ultimately represent a great advantage for cancer patients and may lead to a novel preventive anti-cancer vaccine strategy.

MHC-Optimized Peptide Scaffold for Improved Antigen Presentation and Anti-Tumor Response.

Tumor Associated Antigens (TAAs) may suffer from an immunological tolerance due to expression on normal cells. In order to potentiate their immunogenicity, heteroclitic peptides (htcPep) were designed according to prediction algorithms. In particular, specific modifications were introduced in peptide residues facing to TCR. Moreover, a MHC-optimized scaffold was designed for improved antigen presentation to TCR by H-2Db allele. The efficacy of such htcPep was assessed in C57BL/6 mice injected with syngeneic melanoma B16F10 or lung TC1 tumor cell lines, in combination with metronomic chemotherapy and immune checkpoint inhibitors. The immunogenicity of htcPep was significantly stronger than the corresponding wt peptide and the modification involving both MHC and TCR binding residues scored the strongest. In particular, the H-2Db-specific scaffold significantly potentiated the peptides' immunogenicity and control of tumor growth was comparable to wt peptide in a therapeutic setting. Overall, we demonstrated that modified TAAs show higher immunogenicity compared to wt peptide. In particular, the MHC-optimized scaffold can present different antigen sequences to TCR, retaining the conformational characteristics of the corresponding wt. Cross-reacting CD8+ T cells are elicited and efficiently kill tumor cells presenting the wild-type antigen. This novel approach can be of high clinical relevance in cancer vaccine development.

Representações sociais: identificando fatores que influenciam as ações de médicos e enfermeiros da Atenção Primária à Saúde no rastreio do câncer de mama / Social representations: identifying factors that influence the actions of physicians and nurses on primary health care in breast cancer screening

O câncer é uma condição patológica e a neoplasia de mama é a mais comum. O objetivo do estudo é identificar as representações sociais que influenciam as ações de médicos e enfermeiros das Unidades Básicas de Saúde de Colatina/ES no rastreio do câncer de mama. Trata-se de um estudo observacional, descritivo e de abordagem qualitativa, realizado entre agosto a novembro de 2019, com médicos e enfermeiros das equipes básicas das Estratégias da Saúde da Família de Colatina, localizado na região noroeste do Espírito Santo. Os dados foram coletados através de um questionário semiestruturado para levantamento das evocações mediante a pergunta norteadora. A análise lexical foi realizada pelo software IRaMuTeQ versão 0.7 Alpha 2 (2014) e posteriormente a elaboração de word cloud e análise de similitude das representações sociais. As evocações dos enfermeiros apontaram o vínculo mais próximo com as mulheres nas atividades de rastreio, já as evocações dos médicos elucidaram que o seu papel está mais atrelado às ações de diagnóstico e pareceres especializados. Diante dos pressupostos, as representações sociais do rastreio do câncer de mama entre médicos e enfermeiros foi "mamografia", sendo que ambos os profissionais assumem papéis importantes nas ações de detecção da neoplasia de mama.

Cancer is a pathological condition and breast cancer is the most common. The objective of the study is to identify the social representations that influence the actions of physicians and nurses from the Basic Health Units units in the city of Colatina/ES in breast cancer screening. This is an observational, descriptive and qualitative approach, conducted between August and November 2019 among physicians and nurses from the basic teams of the Family Health Strategies in Colatina, located in the northwest region of Espírito Santo. Data were collected through a semi- structured questionnaire to survey evocations through the guiding question. The lexical analysis was performed using the IRaMuTeQ software version 0.7 Alpha 2 (2014) and later the development of a word cloud and similarity analysis of social representations. Nurses' evocations pointed to the closest link with women in screening activities, while physicians' evocations elucidated that their role is more linked to diagnostic actions and specialized opinions. Given these assumptions, the social representations of breast cancer screening among physicians and nurses was "mammography", with both professionals playing important roles in breast cancer detection actions.

Shrinkage in the Bayesian analysis of the GGE model: A case study with simulation.

The genotype main effects plus the genotype × environment interaction effects model has been widely used to analyze multi-environmental trials data, especially using a graphical biplot considering the first two principal components of the singular value decomposition of the interaction matrix. Many authors have noted the advantages of applying Bayesian inference in these classes of models to replace the frequentist approach. This results in parsimonious models, and eliminates parameters that would be present in a traditional analysis of bilinear components (frequentist form). This work aims to extend shrinkage methods to estimators of those parameters that composes the multiplicative part of the model, using the maximum entropy principle for prior justification. A Bayesian version (non-shrinkage prior, using conjugacy and large variance) was also used for comparison. The simulated data set had 20 genotypes evaluated across seven environments, in a complete randomized block design with three replications. Cross-validation procedures were conducted to assess the predictive ability of the model and information criteria were used for model selection. A better predictive capacity was found for the model with a shrinkage effect, especially for unorthogonal scenarios in which more genotypes were removed at random. In these cases, however, the best fitted models, as measured by information criteria, were the conjugate flat prior. In addition, the flexibility of the Bayesian method was found, in general, to attribute inference to the parameters of the models which related to the biplot representation. Maximum entropy prior was the more parsimonious, and estimates singular values with a greater contribution to the sum of squares of the genotype + genotype × environmental interaction. Hence, this method enabled the best discrimination of parameters responsible for the existing patterns and the best discarding of the noise than the model assuming non-informative priors for multiplicative parameters.