Influence of the morphogranulometry and hydrophobicity of talc on its antisticking power in the production of tablets

International audienceAntisticking power varies according to the talc considered. It is difficult to define the physical properties of talc implicated in its antisticking power. In this work, different talcs were characterized and an evaluation made of their performance in reducing sticking in tablet manufacturing. Determination of the specific surface area was made by permeametry, morphogranulometric analysis by laser diffractometry using a method, which made it possible to assess the mean thickness of talc particles, and measurement of water absorption kinetics was taken to assess hydrophobicity. The relationship between the characteristics of talcs and their antisticking power was then considered. There is a correlation between the particle size of talc and surface hydrophobicity. The detaching force of tablets appears to be dependent on the basal dimension of talc

A human factors perspective on automated driving.

Automated driving can fundamentally change road transportation and improve quality of life. However, at present, the role of humans in automated vehicles (AVs) is not clearly established. Interviews were conducted in April and May 2015 with 12 expert researchers in the field of human factors (HFs) of automated driving to identify commonalities and distinctive perspectives regarding HF challenges in the development of AVs. The experts indicated that an AV up to SAE Level 4 should inform its driver about the AV's capabilities and operational status, and ensure safety while changing between automated and manual modes. HF research should particularly address interactions between AVs, human drivers and vulnerable road users. Additionally, driver-training programmes may have to be modified to ensure that humans are capable of using AVs. Finally, a reflection on the interviews is provided, showing discordance between the interviewees’ statements – which appear to be in line with a long history of HFs research – and the rapid development of automation technology. We expect our perspective to be instrumental for stakeholders involved in AV development and instructive to other parties. (Author/publisher

Ethionamide boosters. 2. Combining bioisosteric replacement and structure-based drug design to solve pharmacokinetic issues in a series of potent 1,2,4-oxadiazole EthR inhibitors31058

Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters. Despite high metabolic stability, pharmacokinetic evaluation revealed poor mice exposure; therefore, a second phase of optimization was required. Herein a structure-property relationship study is reported according to the replacement of the two aromatic heterocycles: 2-thienyl and 1,2,4-oxadiazolyl moieties. This work was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906), which displays improved efficacy in addition to high exposure to mice after oral administration</p

T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for MHC class I loss variants.

Tumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancer (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy. We analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes [metastatic lymph nodes (mLN)] in early BC (EBC) after exposure to T-cell bispecific antibodies (TCB) bridging CD3ε and human epidermal growth factor receptor 2 (HER2) or Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5), before and after chemotherapy. Human leukocyte antigen (HLA) class I loss was assessed by whole exome sequencing and immunohistochemistry. One hundred primary BC, 64 surrounding 'healthy tissue' and 24 mLN-related parameters were analyzed. HLA loss of heterozygosity was observed in EBC, at a clonal and subclonal level and was associated with regulatory T cells and T-cell immunoglobulin and mucin-domain-3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3ε and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN. TCB should be developed in BC to circumvent low MHC/peptide complexes

Predictors of responses to immune checkpoint blockade in advanced melanoma

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8 T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel

Predictors of responses to immune checkpoint blockade in advanced melanoma

International audienceImmune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma

Clinical significance of blood-device interaction in hemodialysis

The syndrome of dialysis-associated leukopenia and complement activation by cellulosic membranes, including the so-called "first use syndrome", is reviewed and the pathophysiology of these phenomena is discussed. Subsequently the clinical side effects of hemodialysis, including dialysis-associated hypoxemia, are discussed. The hypoxemia, according to the authors, is mainly related to the loss of carbon dioxide through the dialyser. A minor role may be played by complement activation causing temporary sequestration of leukocytes in the pulmonary capillaries with (asymptomatic) peripheral leukopenia on the one hand and plugging of the pulmonary capillary bed with transient pulmonary hypertension and hypoxemia on the other. The question of dialysis-associated eosinophilia and ethylene oxide hypersensitivity is addressed as also contributing to the first use syndrome. The effects of interleukin release from monocytes and of contamination of the dialysis fluid are briefly discussed. The rare syndrome of silicone rubber spallation with hepato-and splenomegaly is also mentioned and finally the pathogenesis and symptomatology of the beta 2 microglobulin amyloidosis syndrome in long-term dialysis patients is presented.Journal ArticleReviewinfo:eu-repo/semantics/publishe