Individualized neoantigen peptide immunization of a metastatic pancreatic cancer patient: a case report of combined tumor and liquid biopsy.

This report details a case of pancreatic cancer with liver metastasis that exhibited a positive immune response to personalized immunization therapy. Our study involved the identification of neoantigens and their corresponding immunogenic peptides using an in-house bioinformatic pipeline. This process included the identification of somatic mutations through DNA/RNA sequencing of solid tumor tissue and blood liquid biopsy. Computational prediction techniques were then employed to identify novel epitopes, followed by the design and manufacture of patient-specific immunization peptides. In combination with standard-of-care chemotherapy, the patient received a sequence of 5 biweekly prime injections followed by 2 boost injections 2 and 5 months later. The peptides were emulsified in Montanide and the injection-site was conditioned with nivolumab and imiquimod. The combined regimen of peptide immunization and chemotherapy resulted in a notable decline in CA19-9 tumor marker levels following both prime and boost applications. Subsequent MRI assessments revealed a reduction in the size of liver metastases several months post-immunization initiation. Importantly, the patient showed and improved overall survival and reported an improved quality of life without experiencing significant treatment-related adverse effects. This case underscores the potential benefits of personalized peptide-based immunization as an adjunctive therapy in the treatment of advanced pancreatic cancer, showcasing promising outcomes in tumor marker reduction, tumor shrinkage, and enhanced patient well-being.

Improved Survival of a HER2-Positive Metastatic Breast Cancer Patient Following a Personalized Peptide Immunization.

Cancer neoantigens that arise from somatic mutations have emerged as important targets for personalized immunization. Here, we report an improved overall survival of a HER2-positive metastatic breast cancer patient using a bioinformatic-based personalized peptide immunization called BITAP (BioInformatic Tumor Address Peptides). The epitopes were predicted using our in-house bioinformatic pipeline, and the immunogenicity was tested by IFN-γ ELISPOT and intracellular cytokine staining assays. In total, a significant peptide-specific T-cell response was detected against 18 out of the 76 (≈24%) tested peptides. The patient's follow-up by measuring serologic markers showed a significant reduction in the tumor marker levels following BITAP immunization. Along with standard treatment, the patient treated with the BITAP showed stable disease with a remarkably improved overall survival, and no serious treatment-related adverse effects. In conclusion, our findings suggest that BITAP immunization is feasible, and safe, and may induce tumor regressions in patients with HER2-positive subsets of breast cancer.

Terá cor a pandemia?: O impacto da covid-19 nos pequenos empreendedores negros

O objetivo deste trabalho foi problematizar a política empreendedora, tão difundida pelo Estado nos últimos anos, e tentar evidenciar a vulnerabilidade do negro empreendedor a partir da análise do maior impacto sofrido, na pandemia, por esse estrato social. E, nesse sentido, alertar para o fato de que a transformação desse discurso, apresentado muitas vezes como panaceia para a superação de desigualdades, em políticas públicas que não levem em conta desigualdades "de origem", pode acabar por retroalimentar e aprofundar essas mesmas desigualdades. A compreensão da posição do negro no mercado de trabalho permite identificar questões estruturais e desigualdades nos processos produtivos e reprodutivos que vão, com o passar do tempo, explicando com cada vez mais força a subalternização dos segmentos identificados por sua cor/raça e, por conseguinte, sua posição social (Almeida, 2018). As desigualdades, por assim dizer, são o desaguadouro da combinação complexa de desvantagens materiais e de uma hegemonia estrutural branca que afeta as capacidades pessoais e a autoconfiança de grupos sociais estigmatizados.

Da virose biológica à virose econômica: uma vacina para microempresas no Brasil / De la virosis biológica a la virosis económica: una vacuna para microempresas en Brasil / From biological viruses to economic viruses: a vaccine for microenterprises in Brazil

Resumo Diante da ameaça de desestruturação do tecido produtivo como consequência do isolamento social imposto no Brasil, e tendo em vista que as micro e pequenas empresas são aquelas mais duramente atingidas, o presente trabalho tem por objetivo formular uma proposta de auxílio emergencial governamental para este segmento econômico. Para tanto, apresenta uma breve análise das medidas já adotadas pelo Governo Federal, propõe uma medida capaz de preencher suas lacunas e, por fim, estima os custos da medida proposta para o Tesouro Nacional.

Resumen Ante la amenaza de desestructuración del tejido productivo como consecuencia del aislamiento social impuesto en Brasil y considerando que las micro y pequeñas empresas son las más afectadas, el presente trabajo tiene como objetivo formular una propuesta de asistencia gubernamental de emergencia a este segmento económico. Para ello, presenta un breve análisis de las medidas ya adoptadas por el Gobierno Federal, propone una medida capaz de llenar sus lagunas y, finalmente, estima los costos de la medida propuesta para el Tesoro Nacional.

Abstract Facing the threat of disruption to the productive sector as a result of social distancing measures imposed in Brazil, and considering that micro and small enterprises are those hardest struck, this study aims to formulate a government emergency aid proposal for this segment. It presents a brief analysis of the federal government's current actions and proposes a measure capable of filling the gaps observed. Finally, the study offers an estimation of costs for the National Treasury if adopting the proposed measure.

Socorro governamental às pequenas unidades produtivas frente à atual pandemia / Nota Técnica n. 63 (Diset): Socorro governamental às pequenas unidades produtivas frente à atual pandemia / Português

Este trabalho tem por objetivo avaliar as principais ações do governo federal brasileiro, no sentido de socorrer os segmentos mais vulneráveis do aparato produtivo nacional. Como será possível observar ao longo do texto, entendemos que as medidas apresentadas até o momento não se conectam em uma perspectiva sistêmica, mas, sim, compõem uma miríade cujo entendimento está escapando à grande parte dos micro e pequenos empresários e dos trabalhadores autônomos, alvos principais das ações aqui destacadas.

Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated.

The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.

The Development of Target-Specific Machine Learning Models as Scoring Functions for Docking-Based Target Prediction.

The identification of possible targets for a known bioactive compound is of the utmost importance for drug design and development. Molecular docking is one possible approach for in-silico protein target prediction, whereas a molecule is docked into several different protein structures to identify potential targets. This reverse docking approach is hampered by the limitation of current scoring functions to correctly discriminate between targets and nontargets. In this work, a development of target-specific scoring functions is described that showed improved prediction performances for the correct target prediction of both actives and decoys on three validation data sets. In contrast to pure ligand-based approaches, that are in general faster and include a greater target space, docking-based approaches can cover also unknown chemical space that lies outside the known bioactivity data. These target-specific scoring functions are based on known bioactivity data retrieved from ChEMBL and supervised machine learning approaches. Neural Networks and Support Vector Machines (SVMs) models were trained for 20 different protein targets. Our protein-ligand interaction fingerprint PADIF (Protein Atom Score Contributions Derived Interaction Fingerprint) represents the input for training, whereas the PADIFs are calculated based on docking poses of active and inactive compounds. Different data sets of previously unseen molecules were used for the final evaluation and analysis of the prediction performance of the created models. For a single-target selectivity data set, the correct target model returns in most of the cases the highest probabilities scores for their active molecules and with statistically significant differences from the other targets. These probability scores were also predicted and successfully used to rank the targets for molecules of a multitarget data set with activity data described simultaneously for two, three, and four to seven protein targets.

Complementary Quantitative Structure⁻Activity Relationship Models for the Antitrypanosomal Activity of Sesquiterpene Lactones.

Three complementary quantitative structure⁻activity relationship (QSAR) methodologies, namely, regression modeling based on (i) "classical" molecular descriptors, (ii) 3D pharmacophore features, and (iii) 2D molecular holograms (HQSAR) were employed on the antitrypanosomal activity of sesquiterpene lactones (STLs) toward Trypanosoma brucei rhodesiense (Tbr), the causative agent of the East African form of human African trypanosomiasis. In this study, an extension of a previous QSAR study on 69 STLs, models for a much larger and more diverse set of such natural products, now comprising 130 STLs of various structural subclasses, were established. The extended data set comprises a variety of STLs isolated and tested for antitrypanosomal activity within our group and is furthermore enhanced by 12 compounds obtained from literature, which have been tested in the same laboratory under identical conditions. Detailed QSAR analyses yielded models with comparable and good internal and external predictive ability. For a set of compounds as chemically diverse as the one under study, the models exhibited good coefficients of determination (R²) ranging from 0.71 to 0.85, as well as internal (leave-one-out Q2 values ranging from 0.62 to 0.72) and external validation coefficients (P² values ranging from 0.54 to 0.73). The contributions of the various tested descriptors to the generated models are in good agreement with the results of previous QSAR studies and corroborate the fact that the antitrypanosomal activity of STLs is very much dependent on the presence and relative position of reactive enone groups within the molecular structure but is influenced by their hydrophilic/hydrophobic properties and molecular shape.

ent-Pimarane and ent-Kaurane Diterpenes from Aldama discolor (Asteraceae) and Their Antiprotozoal Activity.

Aldama discolor (syn.Viguiera discolor) is an endemic Asteraceae from the Brazilian "Cerrado", which has not previously been investigated for its chemical constituents and biological activity. Diterpenes are common secondary metabolites found in Aldama species, some of which have been reported to present potential antiprotozoal and antimicrobial activities. In this study, the known ent-3-α-hydroxy-kaur-16-en-18-ol (1), as well as three new diterpenes, namely, ent-7-oxo-pimara-8,15-diene-18-ol (2), ent-2S,4S-2-19-epoxy-pimara-8(3),15-diene-7ß-ol (3) and ent-7-oxo-pimara-8,15-diene-3ß-ol (4), were isolated from the dichloromethane extract of A. discolor leaves and identified by means of MS and NMR. The compounds were assayed in vitro against Trypanosoma brucei rhodesiense, T. cruzi and Leishmania donovani, Plasmodium falciparum and also tested for cytotoxicity against mammalian cells (L6 cell line). The ent-kaurane 1 showed significant in vitro activity against both P. falciparum (IC 50 = 3.5 µ M) and L. donovani (IC 50 = 2.5 µ M) and ent-pimarane 2 against P. falciparum (IC 50 = 3.8 µ M). Both compounds returned high selectivity indices (SI >10) in comparison with L6 cells, which makes them interesting candidates for in vivo tests. In addition to the diterpenes, the sesquiterpene lactone budlein A (5), which has been reported to possess a strong anti-T. b. rhodesiense activity, was identified as major compound in the A. discolor extract and explains its high activity against this parasite (100% growth inhibition at 2 µ g/mL).

Flavonoids and Methoxy-galloylquinic Acid Derivatives from the Leaf Extract of Copaifera langsdorffii Desf.

Despite reports on the pharmacological potential of Copaifera langsdorffii Desf. (Leguminosae-Caesalpinioideae) leaf extract, little is known about its chemical composition. In this work, a phytochemical study from the C. langsdorffii ethanol/H2O 7:3 (v/v) extract was undertaken. Separation was performed by high-speed counter-current (HSCCC) and Sephadex LH-20 column chromatographies, followed by preparative HPLC. The EtOAc- and H2O-soluble fractions of the extract furnished the flavonoids quercitrin (1) and afzelin (2) and 3-O-(3-O-methyl-galloyl)quinic acid (3), respectively. The H2O-soluble fraction furnished 3,4-di-O-(3-O-methyl-galloyl)quinic acid (4), 3,5-di-O-(galloyl)-4-O-(3-O-methyl-galloyl)quinic acid (5), and 3,5-di-O-(3-O-methyl-galloyl)-4-O-(galloyl)quinic acid (6). Their chemical structures were elucidated by NMR means.

Atividades antimicrobiana e antioxidante da Chamomilla recutita L / Antimicrobial and antioxidant activity of Chamomilla recutita L

A espécie Chamomilla recutita L., conhecida popularmente por camomila, camomila-dos-alemães ou matricária, é uma planta herbácea anual, aromática, pertencente à família Asteraceae. Neste trabalho, o extrato metanólico de camomila teve sua atividade antioxidante determinada pelo método do sequestro do radical 2,2'-difenil-1-picrilhidrazilo (DPPH·), apresentando CI50 de 13,7 ± 1,0µg/mL. A atividade antimicrobiana foi avaliada pelo teste de microdiluição em caldo para determinação da concentração inibitória mínima (CIM) contra sete cepas de microorganismos. Os microorganismos mais sensíveis ao extrato foram Bacillus cereus (CIM = 0,625 mg/mL), Pseudomonas aeruginosa (CIM = 1,25mg/mL) e Cryptococcus neoformans (CIM = 0,156mg/mL). A concentração bactericida mínima (CBM) foi de 0,625mg/mL para B. cereuse de 5,0mg/mL para P. aeruginosa. Este trabalho relata, pela primeira vez, a atividade anticriptocócica do extrato metanólico de camomila e mostra que, apesar de extensivamente estudada, ainda existem novas propriedades biológicas que podem ser identificadas para a camomila.

Identification of antioxidant and antimicrobial compounds of Lippia species by bioautography.

The methanolic extracts of the leaves of Lippia species (L. pseudo-thea, L. hermannioides, L. alba, L. rubella, and L. sidoides) were tested for their antibacterial, antifungal, and antioxidant activity. Cytotoxicity was determined by using brine shrimp lethality bioassay. Phytochemical screening was also performed. The extracts showed a minimum inhibitory concentration (MIC) ranging from 78 to 5000 µg/mL for antibacterial activity against at least 2 species of bacteria, although none was active against Escherichia coli. Antifungal activity was found only for L. pseudo-thea (MIC, 625 µg/mL for Candida albicans) and L. sidoides (MIC, 625 µg/mL for both C. albicans and C. neoformans). The bioautography showed that flavonoids and coumarins are responsible for the antioxidant activity of the extracts and that the antimicrobial properties are due to flavonoids and terpenoids. The cytotoxic activity was stronger for L rubella extract. To our knowledge, this is the first report of the biological and chemical constituents of L. pseudo-thea, L. hermannioides, and L. rubella.