Electrical properties of strained off-stoichiometric Cu-Cr-O delafossite thin films.

Off-stoichiometric Cu-Cr-O delafossite thin films with different thicknesses were grown by metal organic chemical vapor deposition on substrates with different coefficients of thermal expansion. Seebeck thermoelectric coefficient and resistivity measurements were performed on the range of 300-850 K. A qualitative change in the temperature-dependence of the resistivity is observed at the temperature corresponding to the deposition process, where the transition from tensile to compressive strain takes place. Arrhenius plots reveal different slopes in these two thermal ranges. The fact that the shift is more pronounced for the thinner films might indicate the induced strain plays a role in changing electrical behaviour. Furthermore, changes below 0.1% in electrical mobility were measured when the strain is induced by mechanical bending.

Multicellular tumor spheroid model to study the multifaceted role of tumor-associated macrophages in PDAC.

While considerable efforts have been made to develop new therapies, progress in the treatment of pancreatic cancer has so far fallen short of patients' expectations. This is due in part to the lack of predictive in vitro models capable of accounting for the heterogeneity of this tumor and its low immunogenicity. To address this point, we have established and characterized a 3D spheroid model of pancreatic cancer composed of tumor cells, cancer-associated fibroblasts, and blood-derived monocytes. The fate of the latter has been followed from their recruitment into the tumor spheroid to their polarization into a tumor-associated macrophage (TAM)-like population, providing evidence for the formation of an immunosuppressive microenvironment.This 3D model well reproduced the multiple roles of TAMs and their influence on drug sensitivity and cell migration. Furthermore, we observed that lipid-based nanosystems consisting of sphingomyelin and vitamin E could affect the phenotype of macrophages, causing a reduction of characteristic markers of TAMs. Overall, this optimized triple coculture model gives a valuable tool that could find useful application for a more comprehensive understanding of TAM plasticity as well as for more predictive drug screening. This could increase the relevance of preclinical studies and help identify effective treatments.

iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer.

Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain1. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues2-6. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development7-10. However, current approaches do not incorporate microglia or address their role in organoid maturation11-21. Here we generated microglia-sufficient brain organoids by coculturing brain organoids with primitive-like macrophages generated from the same human induced pluripotent stem cells (iMac)22. In organoid cocultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro) and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PLIN2+ lipid droplets that exported cholesterol and its esters, which were taken up by NPCs in the organoids. We also detected PLIN2+ lipid droplet-loaded microglia in mouse and human embryonic brains. Overall, our approach substantially advances current human brain organoid approaches by incorporating microglial cells, as illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and NPCs that leads to improved neurogenesis.

Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial.

BACKGROUND: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. METHODS: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. FINDINGS: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. INTERPRETATION: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. FUNDING: Bristol Myers Squibb, ARTIC.

Immune-Desert Tumor Microenvironment in Thoracic SMARCA4-Deficient Undifferentiated Tumors with Limited Efficacy of Immune Checkpoint Inhibitors.

BACKGROUND: Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. MATERIALS AND METHODS: Patients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non-small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma. RESULTS: Nine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line. CONCLUSION: SMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.

Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC).

Renal cell carcinoma (RCC) is the seventh most frequently diagnosed malignancy with an increasing incidence in developed countries. Despite a greater understanding of the cancer biology, which has led to an increase of therapeutic options, metastatic clear cell renal cell carcinoma (mccRCC) still have a poor prognosis with a median five-years survival rate lower than 10%. The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies. In the face of these rising therapeutic options, the question of the therapeutic sequences is crucial. Predictive biomarkers are urgently required to provide a personalized treatment for each patient. Disappointingly, the usual ICI biomarkers, PD-L1 expression and Tumor Mutational Burden, approved in melanoma or non-small cell lung cancer (NSCLC) have failed to distinguish good and poor mccRCC responders to ICI. The tumor microenvironment is known to be involved in ICI response. Innovative technologies can be used to explore the immune contexture of tumors and to find predictive and prognostic biomarkers. Recent comprehensive molecular characterization of RCC has led to the development of robust genomic signatures, which could be used as predictive biomarkers. This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures.

Tertiary Lymphoid Structures and B cells: Clinical impact and therapeutic modulation in cancer.

Tumors progression is under the control of a heterogeneous microenvironment composed of immune cells, fibroblasts, blood and lymphatic vessels, in which T cells have been demonstrated to be major actors, through their cytotoxic and cytokine producing effector functions and their long term memory that protects against metastasis. In this scenario, lessons from mouse models taught that B cells exert a protumoral role, via macrophage-dependent activation of inflammation. However, it became progressively evident from studies in patients with human cancers that the anti-tumor responses can be generated and controlled in tertiary lymphoid structures (TLS) that concentrate most of the intratumoral B cells and where B cells can differentiate into plasma cells and memory cells. Furthermore, recent studies demonstrated that the presence in tumors of B cells and TLS are associated with favorable outcome in patients treated by immunotherapy, unraveling TLS as a new predictive marker of anti-tumor response human cancers. This review encompasses the characteristics and functions of TLS and of B cells in human tumors, their prognostic and theranostic impact and summarizes the mouse models used to induce TLS neogenesis in tumors.

[Impact of molecular signatures on the choice of systemic treatment for metastatic kidney cancer]. / Impact des signatures moléculaires sur le choix du traitement systémique du cancer du rein métastatique.

The standard of care for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the past decades thanks to the increasing number of treatments: anti-VEGFR tyrosine kinase inhibitors (TKI), mTOR inhibitors and immune checkpoint inhibitors (ICI): anti PD(L)-1 used as monotherapy or in combination with anti CTLA-4 or anti angiogenic therapies. In the face of rising therapeutic options, the question of the therapeutic sequences arises: which treatment for which patient? Actually, there is a lack of predictive biomarkers. A greater understanding of the cancer biology and its interaction with the microenvironment has allowed the development of genomic signatures which could perhaps be used as predictive biomarker. This review will give an insight on some robust genomic signatures assessed in mccRCC and will have a closer look at BIONIKK phase II trial, which is the first trial to adapt treatments according to the molecular characteristics of the tumor in the context of mccRCC.

BIONIKK: A phase 2 biomarker driven trial with nivolumab and ipilimumab or VEGFR tyrosine kinase inhibitor (TKI) in naïve metastatic kidney cancer.

BACKGROUND: The nivolumab-ipilimumab combination provides an overall response rate of 42% in first-line metastatic treatment of clear cell renal carcinoma (mccRCC). To date, there is no robust predictive biomarker of response to immune checkpoint inhibitor (ICI). In addition, severe autoimmune disorders occur more frequently with ICI combination than with ICI alone. The objective of this study is to compare the efficacy of ICI alone or in combination in patients according to tumor molecular characteristics. METHODS: Using a 35-gene expression mRNA signature, patients were divided into 4 molecular groups (1 to 4). Patients in groups 1 and 4 were randomized to receive nivolumab alone (arms 1A and 4A) or nivolumab plus ipilimumab for 4 injections followed by nivolumab alone (arms 1B and 4B). Patients in groups 2 and 3 were randomized to receive nivolumab plus ipilimumab followed by nivolumab alone (arms 2B and 3B) or a tyrosine kinase inhibitor (sunitinib or pazopanib at the investigator's choice (arms 2C and 3C)). The main objective is the overall response rate by treatment and molecular group. DISCUSSION: BIONIKK is the first trial in mccRCC to study the personalization of treatment with ICI or TKI according to tumor molecular characteristics in mccRCC. This trial is the most appropriate to prospectively identify biomarkers of response to nivolumab used alone or in combination or TKI monotherapy in patients with mccRCC. NCT02960906.

B cells are associated with survival and immunotherapy response in sarcoma.

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.

Resistance to cancer immunotherapy in metastatic renal cell carcinoma.

The prognosis of metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the years with the emergence of immune checkpoint inhibitors (ICI) used alone, or in combination with another ICI, or with vascular endothelial growth factor receptor tyrosine kinase inhibitor. Although major response rates have been observed with ICI, many patients do not respond, reflecting primary resistance, and durable responses remain exceptional, reflecting secondary resistance. Factors contributing to primary and acquired resistance are manifold, including patient-intrinsic factors, tumor cell-intrinsic factors and factors associated with the tumoral microenvironment (TME). While some mechanisms of resistance are common to several tumor types, others are specific to mccRCC. Predictive biomarkers and alternative strategies are needed to overcome this resistance. This review provides an overview of the major ICI resistance mechanisms, highlights the potential of the TME to induce resistance to ICI, and discusses the predictive biomarkers available to guide therapeutic choice.

Tailoring IGZO Composition for Enhanced Fully Solution-Based Thin Film Transistors.

Solution-processed metal oxides have been investigated as an alternative to vacuum-based oxides to implement low-cost, high-performance electronic devices on flexible transparent substrates. However, their electrical properties need to be enhanced to apply at industrial scale. Amorphous indium-gallium-zinc oxide (a-IGZO) is the most-used transparent semiconductor metal oxide as an active channel layer in thin-film transistors (TFTs), due to its superior electrical properties. The present work evaluates the influence of composition, thickness and ageing on the electrical properties of solution a-IGZO TFTs, using solution combustion synthesis method, with urea as fuel. After optimizing the semiconductor properties, low-voltage TFTs were obtained by implementing a back-surface passivated 3-layer In:Ga:Zn 3:1:1 with a solution-processed high-к dielectric; AlOx. The devices show saturation mobility of 3.2 cm2 V-1 s-1, IOn/IOff of 106, SS of 73 mV dec-1 and VOn of 0.18 V, thus demonstrating promising features for low-cost circuit applications.

Transferência de tecnologia no Brasil — duas décadas de incorporações tecnológicas e lições aprendidas com os produtos biológicos / Technology transfer in Brazil — Two decades of technological incorporations and lessons learned with biological products

A partir de discussões que visavam estruturar as políticas públicas para o desenvolvimento nacional de produção de vacinas, percebeu–se que o modelo poderia ser reproduzido para outros insumos em toda a cadeia da saúde que também careciam de incentivo ao seu desenvolvimento e à incorporação de produção nacional. Foi com focona premissa de expansão e possível consolidação de mercado, bem como no atual déficit da balança comercial do setor da saúde, que o Ministério da Saúde (MS), a partir do poder de compra do Estado, apostou em um modelo competitivo e saudável de parcerias entre laboratórios públicos e privados, para acelerar a incorporação e a produção nacional de insumos e equipamentos.

With the goal of structuring public policies for the national development of vaccine production, it was found that this model could be replicated for other inputs throughout the chain of health, which also lacked incentive to its development and incorporation in national production. It was focused on the premise of expansion and possible market consolidation, as well as in the current trade deficit of the health sector, that the Ministry of Health (MS), fromthe purchasing power of the State, bet on a competitive and healthy model of partnerships between public and private laboratories to accelerate the incorporation and national productionof inputs and equipments.

Análise comparativa entre duas escalas de avaliação clínica na esclerose múltipla: revisão de 302 casos / Comparative analysis of two clinical scales for multiple sclerosis: review of 302 cases

Muitas escalas neurológicas têm sido utilizadas para avaliar evolutivamente portadores da esclerose múltipla. O Expanded Disability Status Scale (EDSS) de Kurtzke ainda é a mais utilizada. Analisamos comparativamente a aplicação do EDSS e Neurologic Rating Scale (NRS), de Sipe e col. em 302 pacientes com forma definida de esclerose múltipla. Os resultados demonstram que o NRS foi mais sensível que o EDSS na detecção de alterações clínicas em 22,1 por cento dos casos, sendo possivelmente mais sensível na caracterização de um novo surto. As variações do EDSS ocorrereram mais nos pacientes com EDSS de 36,0 e 3,5. Fazemos considerações sobre estes achados, sugerindo a aplicação de mais de uma escala clínica para avaliação dos pacientes nos estudos com novas drogas para tratamento da doença.

Características interpessoais, estrutura e desempenho das equipes em um jogo de empresas estudo de caso

O presente estudo pretendeu identificar características da dinâmica de funcionamento de equipes, bem como atributos pessoais de seus componentes, no contexto de uma simulação empresarial. Utilizando instrumento de auto – avaliação e entrevista dirigida, foram identificados auto – estima, conhecimentos anteriores e participação como determinantes do bom desempenho empresarial...(AU)

O uso da associaçäo Tinidazol/Tioconazol no tratamento de infecçöes vaginais por Trichomonas vaginalis, Candida albicans e/ou Gardnerella vaginalis / The use of association tinidazole/tioconazole in the treatment of vaginal infections due to Trichomonas vaginalis, Candida albicans and/or Gardnerella vaginalis

Foram estudas a eficácia da associaçäo Tinidazol/Tioconazol no tratamento de 62 pacientes com vulvovaginites devidas à T. vaginalis, G. vaginalis ou C. albicans. A associaçäo foi administrada duas vezes ao dia durante três dias na formulaçäo creme vaginal, contendo cada dose 150 mg de tinidazol e 100 mg de tioconazol. A avaliaçäo clínico-laboratorial foi realizada à inclusäo de pacientes, no 7§ e no 30§ dia após início de tratamento. Em todos os pacientes foi observada remissäo progressiva dos sinais e sintomas desde o início do tratamento até o 30§ dia de seguimento. A avaliaçäo clíinica global mostrou resultados exelentes e bons em 69,5 por cento das pacientes no 7§ dia pós-tratamento e 86 por cento, no 30§ dia. Reaçöes adversas foram observadas em quetro pacientes: alergia em duas, calor local em uma e irritaçäo locol em uma. Conclui-se que o uso da associaçäo tinidazol/tioconazol creme vaginal é eficaz e bem tolerado no tratamento das vaginites causadas por T. vaginalis, C. albicans, e/ou G. vaginalis, além de apresentar comodidade de administraçäo

Síndrome de hipoperistaler intestinal com microcólon e megacistis / Megacystis-microcolon-intestinal hypoperistalsis syndrome: a case report

Os autores relatam um caso raro de dismotilidade intestinal conhecido como Síndrome de Hippoperistalse Intestinal com microcólon e Megacistis (SHIMM). Esta se manifesta no período neonatal com sintomas de pseudo-obstruçäo intestinal. Recém-nascido com 3.110 g, do sexo feminino, protando pequena onfalocele, com clínica de vômitos biliosos e raios-X mostrando velamento abdominal total. Durante correçäo cirúrgica da onfalocele, constatou-se um intestino curto, hipodesenvolvido e mal-rodado, associado a grande distensäo vesical. Foi realizada gastrostomia, vesicostomia e colostomia, além de biópsias seriadas que demonstraram presença normal de gânglios e filetes nervosos preservados. A hipotonia intestinal difusa impossibilitou a aceitaçäo de dieta enteral, permanecendo, deste modo, sob nutriçäo parenteral exclusiva. Evoluiu para óbito no 51§ dia, com a autópsia comprovando o diagnóstico. A SHMM caracteriza-se por um quadro de obstruçäo intestinal crônica, decorrente da falta de contratilidade intestinal, acompanhado de grande distensäo vesical. Näo existe tratamento estabelecido e o prognóstico é bem reservado.

Torçäo primária do epiplon: apresentacao de um caso / Primary torsion of the greater omentum: report of a case

Os autores apresentam um caso de torcao primaria do epiplon por ser esta uma patologia rara e poucas vezes relatada na literatura. Sua patogenese e pouco conhecida,seu quadro clinico e indistinguivel da apendicite aguda e o unico exame complementar de real valor a tomografia computadorizada. E causa de dor e bridas de fossa iliaca direita de etiologia indeterminada,e deve permanecer como um dos diagnosticos diferenciais da apendicite aguda.Assim o exame do epiplon durante uma exploracao abdominal negativa por suspeita de apendicite e mandatoria