Anti-PD-1 checkpoint blockade monotherapy in the orthotopic GL261 glioma model: the devil is in the detail

The GL261 cell line, syngeneic on the C57BL/6 background, has, since its establishment half a century ago in 1970, become the most commonly used immunocompetent murine model of glioblastoma. As immunotherapy has entered the mainstream of clinical discourse in the past decade, this model has proved its worth as a formidable opponent against various immunotherapeutic combinations. Although advances in surgical, radiological, and chemotherapeutic interventions have extended mean glioblastoma patient survival by several months, five year survival post-diagnosis remains under 5%. Immunotherapeutic interventions, such as the ones explored in the murine GL261 model, may prove beneficial for patients with glioblastoma. However, even common immunotherapeutic interventions in the GL261 model still have unclear efficacy, with wildly discrepant conclusions being made in the literature regarding this topic. Here, we focus on anti-PD-1 checkpoint blockade monotherapy as an example of this pattern. We contend that a fine-grained analysis of how biological variables (age, sex, tumor location, etc…) predict treatment responsiveness in this pre-clinical model will better enable researchers to identify glioblastoma patients most likely to benefit from checkpoint blockade immunotherapy moving forward.

Genomewide Analysis of Mode of Action of the S-Adenosylmethionine Analogue Sinefungin in Leishmania infantum

The two main cellular metabolic one-carbon donors are reduced folates and S-adenosylmethionine, whose biosynthetic pathways have proven highly effective in chemotherapeutic interventions in various cell types. Sinefungin, a nucleoside analogue of S-adenosylmethionine, was shown to have potent activity against the protozoan parasite Leishmania. Here, we studied resistance to sinefungin using whole-genome approaches as a way to further our understanding of the role of S-adenosylmethionine in this parasite and to reveal novel potential drug targets. These approaches allowed the characterization of novel features related to S-adenosylmethionine function in Leishmania which could further help in the development of sinefungin-like compounds against this pathogenic parasite.

Oxidative Stress-Driven Autophagy acROSs Onset and Therapeutic Outcome in Hepatocellular Carcinoma

Reactive oxygen species- (ROS-) mediated autophagy physiologically contributes to management of cell homeostasis in response to mild oxidative stress. Cancer cells typically engage autophagy downstream of ROS signaling derived from hypoxia and starvation, which are harsh environmental conditions that need to be faced for cancer development and progression. Hepatocellular carcinoma (HCC) is a solid tumor for which several environmental risk factors, particularly viral infections and alcohol abuse, have been shown to promote carcinogenesis via augmentation of oxidative stress. In addition, ROS burst in HCC cells frequently takes place after administration of therapeutic compounds that promote apoptotic cell death or even autophagic cell death. The interplay between ROS and autophagy (i) in the disposal of dysfunctional mitochondria via mitophagy, as a tumor suppressor mechanism, or (ii) in the cell survival adaptive response elicited by chemotherapeutic interventions, as a tumor-promoting event, will be depicted in this review in relation to HCC development and progression.

Deletion of a dehydratase important for intracellular growth and cording renders roughMycobacterium abscessusavirulent

Mycobacterium abscessus(Mabs) is a rapidly growingMycobacteriumand an emerging pathogen in humans. Transitioning from a smooth (S) high-glycopeptidolipid (GPL) producer to a rough (R) low-GPL producer is associated with increased virulence in zebrafish, which involves the formation of massive serpentine cords, abscesses, and rapid larval death. Generating a cord-deficientMabsmutant would allow us to address the contribution of cording in the physiopathological signs of the R variant. Herein, a deletion mutant ofMAB_4780, encoding a dehydratase, distinct from the β-hydroxyacyl-ACP dehydratase HadABC complex, was constructed in the R morphotype. This mutant exhibited an alteration of the mycolic acid composition and a pronounced defect in cording. This correlated with an extremely attenuated phenotype not only in wild-type but also in immunocompromised zebrafish embryos lacking either macrophages or neutrophils. The abolition of granuloma formation in embryos infected with the dehydratase mutant was associated with a failure to replicate in macrophages, presumably due to limited inhibition of the phagolysosomal fusion. Overall, these results indicate that MAB_4780 is required forMabsto successfully establish acute and lethal infections. Therefore, targeting MAB_4780 may represent an attractive antivirulence strategy to controlMabsinfections, refractory to most standard chemotherapeutic interventions. The combination of a dehydratase assay with a high-resolution crystal structure of MAB_4780 opens the way to identify such specific inhibitors.

Antimicrobial susceptibility testing guidelines as a necessary tool to guide chemotherapeutic interventions in aquaculture

The selection of chemotherapy in aquatic animal medicine is not as straightforward as one might believe. A multitude of factors can impact effectiveness in situ. Some of these factors include the pathogen(s) present and their antimicrobial susceptibility, site(s) of infection, timing of treatment, host health/disease status, dose and regimen, water salinity, and water temperature. This article will focus on the first of these factors, and how susceptibility testing of target pathogen(s) can be used to both inform therapy decisions and assist in compliance with principles of prudent and judicious use.

Advances in Development of New Treatment for Leishmaniasis

Leishmaniasis is a neglected infectious disease caused by several different species of protozoan parasites of the genusLeishmania. Current strategies to control this disease are mainly based on chemotherapy. Despite being available for the last 70 years, leishmanial chemotherapy has lack of efficiency, since its route of administration is difficult and it can cause serious side effects, which results in the emergence of resistant cases. The medical-scientific community is facing difficulties to overcome these problems with new suitable and efficient drugs, as well as the identification of new drug targets. The availability of the complete genome sequence ofLeishmaniahas given the scientific community the possibility of large-scale analysis, which may lead to better understanding of parasite biology and consequent identification of novel drug targets. In this review we focus on how high-throughput analysis is helping us and other groups to identify novel targets for chemotherapeutic interventions. We further discuss recent data produced by our group regarding the use of the high-throughput techniques and how this helped us to identify and assess the potential of new identified targets.