Project description:Oncology is currently a sector of medical science with accelerated progress due to rapid technological development, the advancement in molecular biology, and the invention of many innovative therapies. Immunotherapy partially accounts for this advance, since it is increasingly playing an important role in the treatment of cancer patients, bringing on a sense of hope and optimism through a series of clinical studies and cases with spectacular results. Immunotherapy, after the initial successes it experienced in the early 20th century, was forgotten after chemotherapy and radiotherapy prevailed and developed slowly in the background. Today, it is the new hope for cancer treatment, despite the unorthodox path it has followed. In this article, we study the course and key points of the discovery of immune-oncology from the oncologist's point of view. We also record the questions that have been posed about immunotherapy that sometimes lead to confusion or stalemate.
Project description:In terms of human suffering, tuberculosis has a huge impact on global society, making it arguably the most important infectious disease in history. Despite the devastating impact on society, the tools to fight tuberculosis are very limited. Current standard therapy has been used for over 40 years and threats, such as the HIV epidemic and drug-resistant strains, undermine efforts to control the disease. New drugs are needed to address the challenges faced globally.Current therapy is briefly reviewed in this paper and then new doses and combinations of existing drugs are presented. New candidate drugs are also discussed, along with the potential benefits and pitfalls of each of the compounds and approaches to therapy.Despite the need to develop new drugs, the ability of programs to deliver existing therapies must not be neglected. Directly observed therapy and a standard basic level of care for all patients with tuberculosis, regardless of where they reside, is imperative, and will ensure that new drugs and regimens will have the greatest possible impact. New combination regimens, including PA 824 and TMC207, in combination with existing drugs, are very exciting - not only because of their ability to shorten treatment regimens in pan-susceptible cases, but also because they can be used among drug-resistant strains. Although an effective vaccine will probably be necessary to eliminate tuberculosis, new drugs and combination regimens have the potential to save millions of lives before tuberculosis is finally eliminated.
Project description:Analysis of UK blood transcriptional profiles before treatment to indentify changes that occur during (2 weeks, 2 months), at the end of treatment (6 months) and after treatment (12 months) Analysis of South African blood transcriptional profiles before treatment to indentify changes that occur during (2 weeks, 2 months), at the end of treatment (6 months) and after treatment (12 months)
Project description:Analysis of UK blood transcriptional profiles before treatment to indentify changes that occur during (2 weeks, 2 months), at the end of treatment (6 months) and after treatment (12 months) Analysis of South African blood transcriptional profiles before treatment to indentify changes that occur during (2 weeks, 2 months), at the end of treatment (6 months) and after treatment (12 months) Total RNA obtained from active TB patients before, during and after treatment
Project description:Tuberculosis remains the most afflicting infectious disease known by humankind, with one quarter of the population estimated to have it in the latent state. Discovering antituberculosis drugs is a challenging, complex, expensive, and time-consuming task. To overcome the substantial costs and accelerate drug discovery and development, drug repurposing has emerged as an attractive alternative to find new applications for "old" drugs and where computational approaches play an essential role by filtering the chemical space. This work reports the first multi-condition model based on quantitative structure-activity relationships and an ensemble of neural networks (mtc-QSAR-EL) for the virtual screening of potential antituberculosis agents able to act as multi-strain inhibitors. The mtc-QSAR-EL model exhibited an accuracy higher than 85%. A physicochemical and fragment-based structural interpretation of this model was provided, and a large dataset of agency-regulated chemicals was virtually screened, with the mtc-QSAR-EL model identifying already proven antituberculosis drugs while proposing chemicals with great potential to be experimentally repurposed as antituberculosis (multi-strain inhibitors) agents. Some of the most promising molecules identified by the mtc-QSAR-EL model as antituberculosis agents were also confirmed by another computational approach, supporting the capabilities of the mtc-QSAR-EL model as an efficient tool for computational drug repurposing.
Project description:Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have yielded unprecedented efficacy in B cell malignancies, most remarkably in anti-CD19 CAR-T cells for B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate. However, tumor antigen escape has emerged as a main challenge for the long-term disease control of this promising immunotherapy in B cell malignancies. In addition, this success has encountered significant hurdles in translation to solid tumors, and the safety of the on-target/off-tumor recognition of normal tissues is one of the main reasons. In this mini-review, we characterize some of the mechanisms for antigen loss relapse and new strategies to address this issue. In addition, we discuss some novel CAR designs that are being considered to enhance the safety of CAR-T cell therapy in solid tumors.
Project description:BackgroundClear cell RCC (ccRCC) accounts for approximately 75% of the renal cancer cases. Surgery treatment seems to be the best efficacious approach for the majority of patients. However, a consistent fraction (30%) of cases progress after surgery with curative intent. It is currently largely debated the use of adjuvant therapy for high-risk patients and the clinical and molecular parameters for stratifying beneficiary categories. In addition, the treatment of advanced forms lacks reliable driver biomarkers for the appropriated therapeutic choice. Thus, renal cancer patient management urges predictive molecular indicators and models for therapy-decision making.MethodsHere, we developed and optimized new models and tools for ameliorating renal cancer patient management. We isolated from fresh tumor specimens heterogeneous multi-clonal populations showing epithelial and mesenchymal characteristics coupled to stem cell phenotype. These cells retained long lasting-tumor-propagating capacity provided a therapy monitoring approach in vitro and in vivo while being able to form parental tumors when orthotopically injected and serially transplanted in immunocompromised murine hosts.ResultsIn line with recent evidence of multiclonal cancer composition, we optimized in vitro cultures enriched of multiple tumor-propagating populations. Orthotopic xenograft masses recapitulated morphology, grading and malignancy of parental cancers. High-grade but not the low-grade neoplasias, resulted in efficient serial transplantation in mice. Engraftment capacity paralleled grading and recurrence frequency advocating for a prognostic value of our developed model system. Therefore, in search of novel molecular indicators for therapy decision-making, we used Reverse-Phase Protein Arrays (RPPA) to analyze a panel of total and phosphorylated proteins in the isolated populations. Tumor-propagating cells showed several deregulated kinase cascades associated with grading, including angiogenesis and m-TOR pathways.ConclusionsIn the era of personalized therapy, the analysis of tumor propagating cells may help improve prediction of disease progression and therapy assignment. The possibility to test pharmacological response of ccRCC stem-like cells in vitro and in orthotopic models may help define a pharmacological profiling for future development of more effective therapies. Likewise, RPPA screening on patient-derived populations offers innovative approach for possible prediction of therapy response.
Project description:The eukaryotic DNA replication fork is a hub of enzymes that continuously act to synthesize DNA, propagate DNA methylation and other epigenetic marks, perform quality control, repair nascent DNA, and package this DNA into chromatin. Many of the enzymes involved in these spatiotemporally correlated processes perform their functions by binding to proliferating cell nuclear antigen (PCNA). A long-standing question has been how the plethora of PCNA-binding enzymes exert their activities without interfering with each other. As a first step towards deciphering this complex regulation, we studied how Chromatin Assembly Factor 1 (CAF-1) binds to PCNA. We demonstrate that CAF-1 binds to PCNA in a heretofore uncharacterized manner that depends upon a cation-pi (π) interaction. An arginine residue, conserved among CAF-1 homologs but absent from other PCNA-binding proteins, inserts into the hydrophobic pocket normally occupied by proteins that contain canonical PCNA interaction peptides (PIPs). Mutation of this arginine disrupts the ability of CAF-1 to bind PCNA and to assemble chromatin. The PIP of the CAF-1 p150 subunit resides at the extreme C-terminus of an apparent long α-helix (119 amino acids) that has been reported to bind DNA. The length of that helix and the presence of a PIP at the C-terminus are evolutionarily conserved among numerous species, ranging from yeast to humans. This arrangement of a very long DNA-binding coiled-coil that terminates in PIPs may serve to coordinate DNA and PCNA binding by CAF-1.
Project description:BackgroundUveitis presumed to be secondary to Mycobacterium tuberculosis is a rare but potentially blinding condition. Difficulty in making an accurate diagnosis and the low incidence of TB uveitis (TBU) contribute to the lack of evidence regarding the best management of this condition. This systematic review aims to analyse existing research to provide a summary of the literature regarding the utility of TB therapy for the management of TBU.MethodsThis systematic review was prospectively registered on PROSPERO (PROSPERO 2021 CRD42021273379). We searched Medline, Embase and Central databases, and the search was done on 20th June 2023 with an updated literature search.ResultsWe included 55 studies and found that the heterogeneity in the methodology of these studies precluded metanalysis, and a narrative analysis was undertaken. Risk of bias analysis was undertaken using the Newcastle-Ottawa scale.ConclusionsKey findings of this systematic review include multiple systemic biases in the available evidence, and general lack of control for confounding variables. This results in many unanswered questions regarding the utility of TB therapy for TBU and reinforces the need for more data in this area.