South American perspective of the International Charter "Space and Major Disasters"

International audienceThe International Charter "Space and Major Disasters" is about joint operations and tasking of imaging satellites and other space resources of the member space agencies and operators in the delivery of information products to assist in responding to disasters of natural and technological causes. Authorized Users, who are the civil protection, emergency response or similar organizations of a state that is member of the Charter, can request the data and products. A specialist, called the Project Manager (PM), manages the overall data acquisition and delivery process. Regional initiatives, as for the Latin American countries, are under way to involve PMs from non-member states to have access to satellite data and apply these to disaster coverage in their respective regions. Volcanic eruptions are typical examples of disasters that affect the Latin American countries. A few Charter activations on this disaster type are described to highlight the information products provided under the Charter

Hydrocyclones for single-use perfusion application

Hydrocyclones (HC) are very compact devices that promote solid-liquid separation under the action of a centrifugal field. Despite the small size, HCs have a large processing capacity and do not suffer from clogging. Therefore, several publications explored HCs as a potential cell retention device in perfusion applications in the last 20 years, but limited to non-disposable lab-scale bioreactors and to relatively low cell densities (up to ~10 million cells/mL). Even though the absence of moving parts may streamline the HC manufacturing, the performance of solid-liquid separation is highly dependent on the HC internal geometry. Said that, hydrocyclones can be produced by 3D printing, making them a promising alternative for the integration of cell retention devices in single-use bioreactor bags. The performance of hydrocyclones also depends on the attachment configuration to the bioreactor and cell concentration of the feed suspension. In this work, at first rapid batch tests were carried out to evaluate the impact of: (i) cell concentration; (ii) diameter of connector installed in the recirculation loop; and (iii) controlled harvest flow rate enabled by a peristaltic pump (520U model, Watson Marlow). The main response considered was their effect on HC separation efficiency. The stainless-steel HC2015 designed for mammalian cell separation (Pinto et al., 2008) was selected for the preliminary batch tests, and also used as a benchmark for plastic prototypes produced by 3D-printing techniques. Afterwards, the same HC2015 was installed in a 50-L single-use bag (XDR50 Xcellerex, GE Healthcare) specially customized for a perfusion cultivation with a mAb producer CHO cell line. The stainless-steel HC2015 when operating at 2.3 bar provided a total separation efficiency (Et) up to 96%, and a centrifugal separation efficiency (E´) of 82% for a CHO cell suspension at 24E6 viable cells per mL Concentrated cells recovered by the underflow port did not show decrease in viability compared to the feed suspension. The reduction of a TC connector size from 19.7 to 12.7 mm resulted in the total filling of the recirculation loop with liquid, disrupting the formation of the desirable umbrella-pattern discharge of the underflow and reducing cell retention. The use of a peristaltic pump to control the overflow flow rate equivalent to perfusion rates of 1 and 2 RV (reactor volume) per day in 40-L bioreactor working volume resulted in a reduction of the E´ values and a consequent increase of cell concentration in the harvest stream. The reduction in the separation efficiency was probably due to a disturbance of the liquid flow pattern inside the HC, since it was observed that the typical gas core coming out from the overflow was absent. These features were taken into account in the HC operation in the single-use 50-L perfusion bioreactor, and a cell concentration of 50E6 cells per mL was successfully achieved with a cell-specific perfusion rate (CSPR) as low as 20 pL per cell per day. The harvest stream consisted of a natural cell bleeding leaving the overflow outlet. Moreover, the lower cell viability and average diameter in the overflow evidenced the preferential retention of viable cells returning into the bioreactor, thus providing a healthier culture environment. A 3D-printed hydrocyclone with equivalent geometry to the stainless-steel HC2015 was made and presented slightly lower separation efficiencies. Further studies proposing materials with a smoother surface and investigating further 3D-printing techniques are currently ongoing. Pinto, R. C.V., Medronho, R. A., Castilho, L. R. (2008). Separation of CHO cells using hydrocyclones. Cytotechnology, 56(1), 57–67. doi:10.1007/s10616-007-9108-

A deep learning approach for determining the chiral indices of carbon nanotubes from high-resolution transmission electron microscopy images

Chiral indices determine important properties of carbon nanotubes (CNTs). Unfortunately, their determination from high-resolution transmission electron microscopy (HRTEM) images, the most accurate method for assigning chirality, is a tedious task. We develop a Convolutional Neural Network that automatizes this process. A large and realistic training data set of CNT images is obtained by means of atomistic computer simulations coupled with the multi-slice approach for image generation. In most cases, results of the automated assignment are in excellent agreement with manual classification, and the origin of failures is identified. The current approach, which combines HRTEM imaging and deep learning algorithms allows the analysis of a statistically significant number of HRTEM images of carbon nanotubes, paving the way for robust estimates of experimental chiral distributions.Comment: for use of the discussed computer code, please contact the corresponding autho

Nonclassical binding of formylated peptide in crystal structure of the MHC class lb molecule H2-M3

AbstractH2-M3 is a class Ib MHC molecule of the mouse with a 104-fold preference for binding N-fonmylated peptides. To elucidate the basis of this unusual specificity, we expressed and crystallized a soluble form of M3 with a fonnylated nonamer peptide, fMYFINILTL, and determined the structure by X-ray crystallography. M3, refined at 2.1A˚resolution, resembles class la MHC molecules in its overall structure, but differs in the peptide-binding groove. The A pocket, which usually accommodates the free N-terminus of a bound peptide, is closed, and the peptide Is shifted one residue, such that the P1 side chain is lodged in the B pocket. The formyl group Is coordinated by His-9 and a bound water on the floor of the groove

Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study

Immunoterapia; Pembrolizumab; neoplàsies mamàries triple-negativesInmunoterapia; Pembrolizumab; neoplasias mamarias triple-negativasImmunotherapy; Pembrolizumab; triple-negative breast neoplasmsBackground: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods: Eligible patients had centrally confirmed mTNBC, ?1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ?24 weeks), progression-free survival, and overall survival. Results: All enrolled patients (N¼170) were women, 61.8% had PD-L1–positive tumors, and 43.5% had received ?3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1–positive populations. Disease control rate (95% CI) was 7.6% (4.4–12.7) and 9.5% (5.1–16.8), respectively. Median duration of response was not reached in the total (range, 1.2þ–21.5þ) and in the PD-L1–positive (range, 6.3–21.5þ) populations. Median PFS was 2.0 months (95% CI, 1.9–2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6–11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Economic and Humanistic Burden of Triple-Negative Breast Cancer: A Systematic Literature Review

Triple-Negative Breast Cancer; Economic burdenCáncer de mama triple negativo; Carga económicaCàncer de mama triple negatiu; Càrrega econòmicaBackground Triple-negative breast cancer (TNBC) accounts for 10–20% of all breast cancers (BCs). It is more commonly diagnosed in younger women and often has a less favorable prognosis compared with other BC subtypes. Objective The objective of this study was to provide a literature-based extensive overview of the economic and humanistic burden of TNBC to assist medical decisions for healthcare payers, providers, and patients. Methods A systematic literature review was performed using multiple databases, including EMBASE, MEDLINE, Econlit, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, from database inception to 16 May 2021. In addition, a targeted search was performed in the Northern Light Life Sciences Conference Abstracts database from 2016 through June 2021. The bibliographies of included articles were reviewed to identify other potentially relevant publications. Quality assessment of the included studies was conducted. Results The review identified 19 studies assessing the economic burden and 10 studies assessing the humanistic burden of TNBC. Studies varied widely in study design, settings, patient populations, and time horizons. The estimates of mean per-patient annual direct medical costs ranged from around $20,000 to over$100,000 in stage I–III TNBC and from $100,000 to$300,000 in stage IV TNBC. Healthcare costs and resource utilization increased significantly with disease recurrence, progression, and increased cancer stage or line of therapy. Compared with the costs of systemic anticancer therapy, cancer management costs comprised a larger portion of total direct costs. The estimates of indirect costs due to productivity loss ranged from $207 to$1573 per patient per month (all costs presented above were adjusted to 2021 US dollars). Cancer recurrence led to significantly reduced productivity and greater rates of leaving the workforce. A rapid deterioration of health utility associated with disease progression was observed in TNBC patients. Treatment with pembrolizumab or talazoparib showed significantly greater improvements in health-related quality of life (HRQoL) compared with chemotherapy, as measured by EORTC QLQ-C30, QLQ-BR23, and FACT-B. Conclusion TNBC is associated with a substantial economic burden on healthcare systems and societies and considerably reduced productivity and HRQoL for patients. This study synthesized the published literature on the economic and humanistic burden of TNBC and highlighted the need for continued research due to the rapidly changing landscape of TNBC care

Safety analyses from the phase 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast cancer

Breast cancer; Drug safetyCàncer de mama; Seguretat dels medicamentsCáncer de mama; Seguridad de los medicamentosSacituzumab govitecan (SG) is an anti-Trop-2 antibody-drug conjugate with an SN-38 payload. In the ASCENT study, patients with metastatic triple-negative breast cancer (mTNBC) relapsed/refractory to ≥2 prior chemotherapy regimens (≥1 in the metastatic setting), received SG or single-agent treatment of physician’s choice (eribulin, vinorelbine, capecitabine, or gemcitabine). This ASCENT safety analysis includes the impact of age and UGT1A1 polymorphisms, which hinder SN-38 detoxification. SG demonstrated a manageable safety profile in patients with mTNBC, including those ≥65 years; neutropenia/diarrhea are key adverse events (AE). Patients with UGT1A1 *28/*28 genotype versus those with 1/*28 and *1/*1 genotypes had higher rates of grade ≥3 SG-related neutropenia (59% vs 47% and 53%), febrile neutropenia (18% vs 5% and 3%), anemia (15% vs 6% and 4%), and diarrhea (15% vs 9% and 10%), respectively. Individuals with UGT1A1 *28/*28 genotype should be monitored closely; active monitoring and routine AE management allow optimal therapeutic exposure of SG.This study was sponsored by Immunomedics, Inc., a subsidiary of Gilead Sciences, Inc. We thank the ASCENT patients, their caregivers, study investigators, and team members. We thank William A. Wegener, MD, PhD, Robert M. Sharkey, PhD, and Pius Maliakal, PhD, former employees of Immunomedics, for their contributions to the development of the ASCENT protocol and the clinical development of sacituzumab govitecan. Medical writing and editorial assistance were provided by Robert Rydzewski, MS, CMPP, and Shala Thomas, PhD, CMPP, of Team 9 Science, and funded by Immunomedics, Inc., a subsidiary of Gilead Sciences, Inc

Decreased resistin expression in mice with different sensitivities to a high-fat diet

The regulation of resistin, a new adipose-derived circulating factor, is the subject of controversy. In particular, the question of its modulation in obesity led to opposite results reported by two different groups. In the current study, we assayed adipocyte resistin mRNA using fluorescent real-time RT-PCR. We studied the expression of resistin in mice which are differently sensitive to diet-induced obesity: the FVB/n strain, which poorly responds to high-fat diet and transgenic mice that express human alpha 2A-AR in adipose tissue in the absence of beta 3-adrenergic receptor (AR) under the FVB genetic background which are highly sensitive to high-fat diet and develop hyperplastic obesity. We observed that FVB mice, which have no significant increased body weight after an 8-week high-fat diet period, exhibited no alteration of resistin expression. In contrast, the transgenic mice developing high-fat diet-induced obesity exhibited markedly downregulated adipocyte resistin mRNA. We also showed that obesity induced by gold thioglucose injection in FVB/n mice reduces the expression of resistin in isolated adipocytes. This argues for decreased expression of resistin as a hallmark of obesity. Moreover, our data show that feeding a high-fat diet is not a primary determinant of resistin regulation

Human Microbiota and Breast Cancer—Is There Any Relevant Link?—A Literature Review and New Horizons Toward Personalised Medicine

Breast cancer; Personalized medicine; PharmacomicrobiomicsCáncer de mama; Medicina personalizada; FarmacomicrobiómicaCàncer de mama; Medicina personalitzada; FarmacomicrobiòmicaBreast cancer (BC) is the most common malignancy and the second cause of cancer-specific death in women from high-income countries. Recently, gut microbiota dysbiosis emerged as a key player that may directly and/or indirectly influence development, treatment, and prognosis of BC through diverse biological processes: host cell proliferation and death, immune system function, chronic inflammation, oncogenic signalling, hormonal and detoxification pathways. Gut colonisation occurs during the prenatal period and is later diversified over distinct phases throughout life. In newly diagnosed postmenopausal BC patients, an altered faecal microbiota composition has been observed compared with healthy controls. Particularly, β-glucuronidase bacteria seem to modulate the enterohepatic circulation of oestrogens and their resorption, increasing the risk of hormone-dependent BC. Moreover, active phytoestrogens, short-chain fatty acids, lithocholic acid, and cadaverine have been identified as bacterial metabolites influencing the risk and prognosis of BC. As in gut, links are also being made with local microbiota of tumoural and healthy breast tissues. In breast microbiota, different microbial signatures have been reported, with distinct patterns per stage and biological subtype. Total bacterial DNA load was lower in tumour tissue and advanced-stage BC when compared with healthy tissue and early stage BC, respectively. Hypothetically, these findings reflect local dysbiosis, potentially creating an environment that favours breast tumour carcinogenesis (oncogenic trigger), or the natural selection of microorganisms adapted to a specific microenvironment. In this review, we discuss the origin, composition, and dynamic evolution of human microbiota, the links between gut/breast microbiota and BC, and explore the potential implications of metabolomics and pharmacomicrobiomics that might impact BC development and treatment choices toward a more personalised medicine. Finally, we put in perspective the potential limitations and biases regarding the current microbiota research and provide new horizons for stronger accurate translational and clinical studies that are needed to better elucidate the complex network of interactions between host, microorganisms, and drugs in the field of BC