Highly variable response to cytotoxic chemotherapy in carcinoma-associated fibroblasts (CAFs) from lung and breast

<p>Abstract</p> <p>Background</p> <p>Carcinoma-associated fibroblasts (CAFs) can promote carcinogenesis and tumor progression. Only limited data on the response of CAFs to chemotherapy and their potential impact on therapy outcome are available. This study was undertaken to analyze the influence of chemotherapy on carcinoma-associated fibroblasts (CAFs) <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>The <it>in vivo </it>response of stromal cells to chemotherapy was investigated in 22 neoadjuvant treated breast tumors on tissue sections before and after chemotherapy. Response to chemotherapy was analyzed <it>in vitro </it>in primary cultures of isolated CAFs from 28 human lung and 9 breast cancer tissues. The response was correlated to <it>Mdm2</it>, <it>ERCC1 </it>and <it>TP53 </it>polymorphisms and <it>TP53 </it>mutation status. Additionally, the cytotoxic effects were evaluated in an <it>ex vivo </it>experiment using cultured tissue slices from 16 lung and 17 breast cancer specimens.</p> <p>Results</p> <p>Nine of 22 tumors showed a therapy-dependent reduction of stromal activity. Pathological response of tumor or stroma cells did not correlate with clinical response. Isolated CAFs showed little sensitivity to paclitaxel. In contrast, sensitivity of CAFs to cisplatinum was highly variable with a GI50 ranging from 2.8 to 29.0 μM which is comparable to the range observed in tumor cell lines. No somatic <it>TP53 </it>mutation was detected in any of the 28 CAFs from lung cancer tissue. In addition, response to cisplatinum was not significantly associated with the genotype of <it>TP53 </it>nor <it>Mdm2 </it>and <it>ERCC1 </it>polymorphisms. However, we observed a non-significant trend towards decreased sensitivity in the presence of <it>TP53 </it>variant genotype. In contrast to the results obtained in isolated cell culture, in tissue slice culture breast cancer CAFs responded to paclitaxel within their microenvironment in the majority of cases (9/14). The opposite was observed in lung cancer tissues: only few CAFs were sensitive to cisplatinum within their microenvironment (2/15) whereas a higher proportion responded to cisplatinum in isolated culture.</p> <p>Conclusion</p> <p>Similar to cancer cells, CAF response to chemotherapy is highly variable. Beside significant individual/intrinsic differences the sensitivity of CAFs seems to depend also on the cancer type as well as the microenvironment.</p

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Uses of Intravenous Immunoglobulin: A 13-Year Evaluation of Guillain–Barré Syndrome in Fez, Morocco

Plasma-derived medicines in Morocco have been of great demand, and often on a short supply.Moroccan Intravenous Immunoglobulin (IVIG) formulation is still using sugar as stabilizer, while some other industries are discontinuing sugar and currently using amino acid as stabilizer. This is due to the fact that amino acid is rapidly metabolized/cleared from the blood circulation and has fewer adverse effects. The term Guillain-Barré syndrome (GBS) defi nes a recognizable clinical entity that is characterized by rapidly evolving symmetrical limb weakness, loss of tendon refl exes, absent or mild sensory signs, and variable autonomic dysfunction. Few studies have been conducted to investigate the use of IVIG products for GBS in Morocco. The objective of this study was to evaluate the use of IVIG and its adverse effects in Moroccan hospital. This retrospective study was conducted to evaluate. The demographic(withouts) and clinical features in 74 patients with GBS, and to assess the use of IVIG in these patients at University Hospital Hassan II of Fez - Neurology Department from 2003 to 2015. Forty-seven (64 %) male and 27 (36 %) female cases were studied, among whom nine patients had an infection. Eighty eight 88% of total patients had GBS and 12% had chronic infl ammatory demyelinating polyneuropathy (CIDP). Among the 74 patients, 14 % patients showed spontaneous recovery. Twenty eight % of total patients received corticosteroid therapy, 1% of patients underwent Plasma Exchange (PE), 18% (13 patients) received IVIG. Among the 18% that received IVIG, 1 out of 13 patients developed symptoms of hypersensitivity,including fever and chills. Since the use of IVIG resulted in only 1 out 13 patients developed symptoms of hypersensitivity, we concluded that IVIG therapy had a better outcome. IVIG therapy provides patients with GBS, a safer and effective alternative to standard therapies.</p

Influence du taux d'incorporation de la pulpe de caroube sur la digestibilité et l'utilisation des rations par des ovins à l'engraissement

International audienc

Corrélation entre la perméation électrochimique et la fragilisation par l'hydrogène de l'acier inoxydable 17-4 PH : rôle de la microstructure

Des tests de perméation électrochimique ont permis d'évaluer le coefficient de diffusion de l'hydrogène dans l'acier inoxydable martensitique à durcissement structural 17-4 PH, en fonction de différents traitements de vieillissement. Ces traitements provoquent des variations de la microstructure qui induisent des variations du coefficient de diffusion de l'hydrogène, ainsi que des quantités d'hydrogène piégé et diffusible, qui peuvent affecter la résistance de l'acier à la fragilisation par l'hydrogène. On a pu établir une corrélation entre les résultats de perméation et ceux obtenus par la méthode de traction lente d'éprouvettes à l'air ou sous chargement en hydrogène. L'acier est le plus fragile, comme on pouvait s'y attendre, là où sa résistance mécanique est la plus élevée; cependant, il ne perd pas complètement sa ductilité. Ce résultat est attribué à l'effet bénéfique de la phase durcissante ε riche en cuivre, qui jouerait le rôle de repoussoir pour l'hydrogène, lorsqu'elle est cohérente avec la matrice