DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap , an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NFκB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.

Nonreplicating Adenoviral Vectors: Improving Tropism and Delivery of Cancer Gene Therapy.

Recent preclinical and clinical studies have used viral vectors in gene therapy research, especially nonreplicating adenovirus encoding strategic therapeutic genes for cancer treatment. Adenoviruses were the first DNA viruses to go into therapeutic development, mainly due to well-known biological features: stability in vivo, ease of manufacture, and efficient gene delivery to dividing and nondividing cells. However, there are some limitations for gene therapy using adenoviral vectors, such as nonspecific transduction of normal cells and liver sequestration and neutralization by antibodies, especially when administered systemically. On the other hand, adenoviral vectors are amenable to strategies for the modification of their biological structures, including genetic manipulation of viral proteins, pseudotyping, and conjugation with polymers or biological membranes. Such modifications provide greater specificity to the target cell and better safety in systemic administration; thus, a reduction of antiviral host responses would favor the use of adenoviral vectors in cancer immunotherapy. In this review, we describe the structural and molecular features of nonreplicating adenoviral vectors, the current limitations to their use, and strategies to modify adenoviral tropism, highlighting the approaches that may allow for the systemic administration of gene therapy.

Determinants of Aortic Prosthesis Mismatch in a Brazilian Public Health System Hospital: Big Patients or Small Prosthesis? / Determinantes da Desproporção de Prótese Aórtica em Hospital de Atendimento de Saúde Pública Brasileiro: Pacientes Grandes ou Próteses Pequenas?

Abstract Background: Prosthesis-patient mismatch (PPM) is associated with worse outcomes. Objective: Determine the frequency and evaluate preoperatory variables independently associated with severe PPM in a tertiary hospital focused on Public Health Care. Methods: A total of 316 patients submitted to aortic valve replacement, who had echocardiography performed within the first 30 days after surgery, were retrospectively analyzed. The indexed effective orifice area (iEOA) of the prosthesis was used to classify the patients into three groups, according to PPM, considering body mass index (BMI): severe PPM (iEOA) < 0.65 cm2/m2), mild to moderate PPM (iEOA, 0.65 cm2/m2 - 0.85 cm2/m2) and without PPM (iEOA > 0.85 cm2/m2) for a BMI < 30 kg/m2 and severe PPM (iEOA) < 0.55 cm2/m2), mild to moderate (iEOA, 0.55 cm2/m2- 0.70 cm2/m2) and without PPM (iEOA > 0.7 cm2/m2) for a BMI > 30 kg/m2. Statistical significance was considered when p < 0.05. Results: iEOA was obtained in 176 patients. The frequency of severe and moderate PPM was 33.4% and 36.2%, respectively. Severe PPM patients were younger and had larger BMI, but smaller left ventricular outflow tract diameter (LVOTD). The independent variables used to predict severe PPM were male gender, BMI > 25 kg/m2, age < 60 years, LVOTD < 21 mm, and rheumatic etiology with an area under the ROC curve of 0.82. Conclusion: The frequency of severe PPM is high in a Brazilian population representative of the Public Health System, and it is possible to predict PPM from preoperative variables such as rheumatic valvular disease, gender, BMI, age and LVOTD.

Resumo Fundamento: A desproporção entre o tamanho da prótese aórtica-paciente (DPP) está associada a maior mortalidade. Objetivo: Determinar a frequência e avaliar variáveis ​​pré-operatórias associadas à DPP acentuada no cenário da saúde pública em hospital terciário. Métodos: 316 pacientes submetidos à troca valvar aórtica (TVA), com ecocardiograma realizado nos primeiros 30 dias após cirurgia, foram analisados retrospectivamente. A área de orifício efetivo indexado (AOEi) da prótese foi utilizada para classificar os pacientes em três grupos de acordo com a DPP, considerando o índice de massa corporal (IMC): DPP acentuada (AOEi) < 0,65 cm2/m2, DPP discreta a moderada (AOEi, 0,65 cm2/m2 - 0,85 cm2/m2) e sem DPP (iEOA > 0,85 cm2/m2) para IMC < 30 kg/m2 e DPP acentuada (AOEi) < 0,55 cm2/m2), discreta a moderada (AOEi, 0,55 cm2/m2 - 0,70 cm2/m2) e sem DPP (AOEi > 0,7 cm2/m2) para IMC > 30 kg/m2. Significância estatística foi considerada com p < 0,05. Resultados: A AOEi foi obtida em 176 pacientes. A frequência de DPP acentuada foi de 33,4% e moderada de 36,2%. Pacientes com DPP acentuada foram mais jovens e com maior IMC, mas menor diâmetro da via de saída do ventrículo esquerdo (DVSVE). As variáveis independentes que podem predizer DPP acentuada são: gênero masculino, IMC > 25 kg/m2, idade < 60 anos, DVSVE < 21 mm e etiologia reumática com área sob a curva ROC de 0,82. Conclusão: A frequência de DPP acentuada é alta em uma população brasileira submetida à TVA no Sistema Público de Saúde. Os principais determinantes de DPP acentuada são: valvopatia reumática, gênero masculino, IMC alto, idade < 60 anos e menor DVSVE.

Determinants of Aortic Prosthesis Mismatch in a Brazilian Public Health System Hospital: Big Patients or Small Prosthesis?

BACKGROUND: Prosthesis-patient mismatch (PPM) is associated with worse outcomes. OBJECTIVE: Determine the frequency and evaluate preoperatory variables independently associated with severe PPM in a tertiary hospital focused on Public Health Care. METHODS: A total of 316 patients submitted to aortic valve replacement, who had echocardiography performed within the first 30 days after surgery, were retrospectively analyzed. The indexed effective orifice area (iEOA) of the prosthesis was used to classify the patients into three groups, according to PPM, considering body mass index (BMI): severe PPM (iEOA) < 0.65 cm2/m2), mild to moderate PPM (iEOA, 0.65 cm2/m2 - 0.85 cm2/m2) and without PPM (iEOA > 0.85 cm2/m2) for a BMI < 30 kg/m2 and severe PPM (iEOA) < 0.55 cm2/m2), mild to moderate (iEOA, 0.55 cm2/m2- 0.70 cm2/m2) and without PPM (iEOA > 0.7 cm2/m2) for a BMI > 30 kg/m2. Statistical significance was considered when p < 0.05. RESULTS: iEOA was obtained in 176 patients. The frequency of severe and moderate PPM was 33.4% and 36.2%, respectively. Severe PPM patients were younger and had larger BMI, but smaller left ventricular outflow tract diameter (LVOTD). The independent variables used to predict severe PPM were male gender, BMI > 25 kg/m2, age < 60 years, LVOTD < 21 mm, and rheumatic etiology with an area under the ROC curve of 0.82. CONCLUSION: The frequency of severe PPM is high in a Brazilian population representative of the Public Health System, and it is possible to predict PPM from preoperative variables such as rheumatic valvular disease, gender, BMI, age and LVOTD.

Signature of Aberrantly Expressed microRNAs in the Striatum of Rotenone-Induced Parkinsonian Rats.

Parkinson's disease (PD) is a highly complex brain disorder regarding clinical presentation, pathogenesis, and therapeutics. The cardinal motor signs, i.e., rigidity, bradykinesia, and unilateral tremors, arise in consequence of a progressive neuron death during the prodromal phase. Although multiple transmission systems are involved in disease neurobiology, patients will cross the line between the prodromal and early stage of diagnosed PD when they had lost half of the dopaminergic nigrostriatal cells. As the neurons continue to die ascending the neuroaxis, patients will face a more disabling disease with motor and nonmotor signs. Shedding light on molecular mechanisms of neuron death is an urgent need for understanding PD pathogenesis and projecting therapeutics. This work examined the expression of microRNAs in the striatum of parkinsonian rats chronically exposed to rotenone (2.5 mg/Kg, i.p., daily for 10 days). Rotenone caused motor deficits, the loss of TH(+) cells in the nigrostriatal pathway, and a marked microgliosis. This parkinsonian rat striatum was examined at 26 days after the last rotenone injection, for quantification of microRNAs, miR-7, miR-34a, miR-26a, miR-132, miR-382, and Let7a, by qPCR. Parkinsonian rats presented a significant increase in miR-26a and miR-34a (1.5 and 2.2 fold, respectively, P < 0.05), while miR-7 (0.5 fold, P < 0.05) and Let7a were downregulated. This work reports for first time microRNAs aberrantly expressed in the striatum of rotenone-induced parkinsonian rats, suggesting that this dysregulation may contribute to PD pathogenesis. Beyond revealing new clues of neurodegeneration, our findings might prime further studies targeting miRNAs for neuroprotection or even for diagnosis proposal.