In silico and in vivo analysis reveal impact of c-Myc tag in FMC63 scFv-CD19 protein interface and CAR-T cell efficacy.

Anti-CD19 CAR-T cell therapy represents a breakthrough in the treatment of B-cell malignancies, and it is expected that this therapy modality will soon cover a range of solid tumors as well. Therefore, a universal cheap and sensitive method to detect CAR expression is of foremost importance. One possibility is the use of epitope tags such as c-Myc, HA or FLAG tags attached to the CAR extracellular domain, however, it is important to determine whether these tags can influence binding of the CAR with its target molecule. Here, we conducted in-silico structural modelling of an FMC63-based anti-CD19 single-chain variable fragment (scFv) with and without a c-Myc peptide tag added to the N-terminus portion and performed molecular dynamics simulation of the scFv with the CD19 target. We show that the c-Myc tag presence in the N-terminus portion does not affect the scFv's structural equilibrium and grants more stability to the scFv. However, intermolecular interaction potential (IIP) analysis reveals that the tag can approximate the complementarity-determining regions (CDRs) present in the scFv and cause steric impediment, potentially disturbing interaction with the CD19 protein. We then tested this possibility with CAR-T cells generated from human donors in a Nalm-6 leukemia model, showing that CAR-T cells with the c-Myc tag have overall worse antitumor activity, which was also observed when the tag was added to the C-terminus position. Ultimately, our results suggest that tag addition is an important aspect of CAR design and can influence CAR-T cell function, therefore its use should be carefully considered.

Emerging and anticipated innovations in prostate cancer MRI and their impact on patient care.

Prostate cancer (PCa) remains the leading malignancy affecting men, with over 3 million men living with the disease in the US, and an estimated 288,000 new cases and almost 35,000 deaths in 2023 in the United States alone. Over the last few decades, imaging has been a cornerstone in PCa care, with a crucial role in the detection, staging, and assessment of PCa recurrence or by guiding diagnostic or therapeutic interventions. To improve diagnostic accuracy and outcomes in PCa care, remarkable advancements have been made to different imaging modalities in recent years. This paper focuses on reviewing the main innovations in the field of PCa magnetic resonance imaging, including MRI protocols, MRI-guided procedural interventions, artificial intelligence algorithms and positron emission tomography, which may impact PCa care in the future.

Porto-sinusoidal Vascular Disease and Portal Hypertension.

Porto-sinusoidal vascular disease (PSVD) is the medical diagnosis for a patient who has portal hypertension in the absence of cirrhosis on liver biopsy. There are several specific histologic findings for PSVD, including obliterative portal venopathy, nodular regenerative hyperplasia, and incomplete septal fibrosis. Epidemiologic reports vary widely among regions; PSVD comprises less than 10% of causes of portal hypertension in Western countries but incidence has been found to be as high as 48% in India. There is an expansive list of etiologies that have been reported to cause PSVD.

Multispecies comparative prostate anatomy by imaging: Implications for experimental models of prostatic disease.

BACKGROUND: There is an increasing interest in using preclinical models for development and assessment of medical devices and imaging techniques for prostatic disease care. Still, a comprehensive assessment of the prostate's radiological anatomy in primary preclinical models such as dogs, rabbits, and mice utilizing human anatomy as a reference point remains necessary with no optimal model for each purpose being clearly defined in the literature. Therefore, this study compares the anatomical characteristics of different animal models to the human prostatic gland from the imaging perspective. METHODS: We imaged five Beagle laboratory dogs, five New Zealand White rabbits, and five mice, all sexually mature males, under Institutional Animal Care and Use Committee (IACUC) approval. Ultrasonography (US) was performed using the Vevo® F2 for mice (57 MHz probe). Rabbits and dogs were imaged using the Siemens® Acuson S3000 (17 MHz probe) and endocavitary (8 MHz) probes, respectively. Magnetic resonance imaging (MRI) was also conducted with a 7T scanner in mice and 3T scanner in rabbits and dogs. RESULTS: Canine transrectal US emerged as the optimal method for US imaging, depicting a morphologically similar gland to humans but lacking echoic zonal differentiation. MRI findings in canines indicated a homogeneously structured gland similar to the human peripheral zone on T2-weighted images (T2W) and apparent diffusion coefficient (ADC). In rabbits, US imaging faced challenges due to the pubic symphysis, whereas MRI effectively visualized all structures with the prostate presenting a similar aspect to the human peripheral gland on T2W and ADC maps. Murine prostate assessment revealed poor visualization of the prostate glands in ultrasound due to its small size, while 7T MRI delineated the distinct prostates and its lobes, with the lateral and dorsal prostate resembling the peripheral zone and the anterior prostate the central zone of the human gland. CONCLUSION: Dogs stand out as superior models for advanced preclinical studies in prostatic disease research. However, mice present as a good model for early stage studies and rabbits are a cost-effective alternative and serve as valuable tools in specific research domains when canine research is not feasible.

PI-RADS Upgrading Rules: Impact on Prostate Cancer Detection and Biopsy Avoidance of MRI-Directed Diagnostic Pathways.

BACKGROUND. PI-RADS incorporates rules by which ancillary sequence findings upgrade a dominant score to a higher final category. Evidence on the upgrading rules' impact on diagnostic pathways remains scarce. OBJECTIVE. The purpose of this article was to evaluate the clinical net benefit of the PI-RADS upgrading rules in MRI-directed diagnostic pathways. METHODS. This study was a retrospective analysis of a prospectively maintained clinical registry. The study included patients without known prostate cancer who underwent prostate MRI followed by prostate biopsy from January 2016 to May 2020. Clinically significant prostate cancer (csPCa) was defined as International Society of Urological Pathology (ISUP) grade group 2 and higher. csPCa detection was compared between dominant (i.e., no upgrade rule applied) and upgraded lesions. Decision-curve analysis was used to compare the net benefit, considering the trade-off of csPCa detection and biopsy avoidance, of MRI-directed pathways in scenarios considering and disregarding PI-RADS upgrading rules. These included a biopsy-all pathway, MRI-focused pathway (no biopsy for PI-RADS ≤ 2), and risk-based pathway (use of PSA density ≥ 0.15 ng/mL2 to select patients with PI-RADS ≤ 3 for biopsy). RESULTS. The sample comprised 716 patients (mean age, 64.9 years; 93 with a PI-RADS ≤ 2 examination, 623 with total of 780 PI-RADS ≥ 3 lesions). Frequencies of csPCa were not significantly different between dominant and upgraded PI-RADS 3 transition zone lesions (20% vs 19%, respectively), dominant and upgraded PI-RADS 4 transition zone lesions (33% vs 26%), and dominant and upgraded PI-RADS 4 peripheral zone lesions (58% vs 45%) (p > .05). In the biopsy-all, per-guideline MRI-focused, MRI-focused disregarding upgrading rules, per-guideline risk-based, and risk-based disregarding upgrading rules pathways, csPCa frequency was 53%, 52%, 51%, 52%, and 48% and biopsy avoidance was 0%, 13%, 16%, 19%, and 25%, respectively. Disregarding upgrading rules yielded 5.5 and 1.9 biopsies avoided per missed csPCa for MRI-focused and risk-based pathways, respectively. At probability thresholds for biopsy selection of 7.5-30.0%, net benefit was highest for the per-guideline risk-based pathway. CONCLUSION. Disregarding PI-RADS upgrading rules reduced net clinical bene fit of the risk-based MRI-directed diagnostic pathway when considering trade-offs between csPCa detection and biopsy avoidance. CLINICAL IMPACT. This study supports the application of PI-RADS upgrading rules to optimize biopsy selection, particularly in risk-based pathways.

The hypertension-based chronic disease model in a primary care setting.

Background: Driver-based chronic disease models address the public health challenge of cardiometabolic risk. However, there is no data available about the novel Hypertension-Based Chronic Disease (HBCD) model. This study investigates the prevalence, characteristics, and prognostic significance of HBCD Stages in a primary care cohort. Methods: This study included participants aged ≥45 years, randomly selected from the primary care program of a Brazilian medium-sized city. Participants underwent electrocardiogram, tissue Doppler echocardiogram and were followed for a median of 6 years. Participants were classified into HBCD Stages as follows: Stage 1: hypertension risk factors; Stage 2: pre-hypertension; Stage 3: hypertension; and Stage 4: hypertension complications. Results: Overall, 633 participants were included in the cross-sectional analysis and 560 that had follow-up data were included in the prognostic analysis. From 633 participants, 1.3% had no identifiable risk factors for HBCD, 10.0% were Stage 1, 14.7% Stage 2, 51.5% Stage 3, and 22.5% Stage 4. Increasing HBCD stages had worse glomerular filtration rates, echocardiographic markers, and higher body mass index, waist circumference, blood glucose levels, and prevalence of type 2 diabetes. Rates of all-cause mortality or cardiovascular hospitalization increased across HBCD Stages: Stage 1: 3.6%; Stage 2: 4.8%, Stage 3: 7.6%; and Stage 4: 39.5%. Kaplan-Meier curves showed composite outcome worsened across HBCD Stages 1-4 (p < 0.001). Conclusions: HBCD is a conceptually and prognostically valid model. Remarkably, HBCD stages were associated with progressively worsening markers of heart disease, declining kidney function and higher rates of all-cause mortality or cardiovascular hospitalization.

The CRISPR/Cas System in Human Cancer.

The use of CRISPR as a genetic editing tool modified the oncology field from its basic to applied research for opening a simple, fast, and cheaper way to manipulate the genome. This chapter reviews some of the major uses of this technique for in vitro- and in vivo-based biological screenings, for cellular and animal model generation, and new derivative tools applied to cancer research. CRISPR has opened new frontiers increasing the knowledge about cancer, pointing to new solutions to overcome several challenges to better understand the disease and design better treatments.

Magnetic resonance fingerprinting based comprehensive quantification of T1 and T2 values of the background prostatic peripheral zone: Correlation with clinical and demographic features.

PURPOSE: To quantify and assess the distribution of MR fingerprinting (MRF)-derived T1 and T2 values of the whole prostatic peripheral zone (PZ), and perform subgroup analyses according to clinical and demographic features. METHOD: One hundred and twenty-four patients with prostate MR exams and MRF-based T1 and T2 maps of the prostatic apex, mid gland, and base were identified from our database and included. Regions of interest encompassing the right and left lobes of the PZ were drawn for each axial slice on the T2 map and copied to the T1 map. Clinical data were obtained from medical records. Kruskal-Wallis test was used for assessing differences between subgroups and the Spearman coefficient was used for assessing any correlations. RESULTS: Mean T1 and T2 values were 1941 and 88 ms, respectively, for the whole-gland, 1884 and 83 ms for the apex, 1974 and 92 ms for the mid-gland, 1966 and 88 ms for the base. T1 values were weakly negatively correlated with PSA values, while T1 and T2 values were weakly positively correlated with prostate weight and moderately positively correlated with PZ width. Finally, patients with PI-RADS 1 scores had higher T1 and T2 values of the whole PZ, compared with those with scores 2-5. CONCLUSION: Mean T1 and T2 values of the background PZ of the whole gland were 1941 ± 313 and 88 ± 39 ms, respectively. Among clinical and demographic factors, there was a significant positive correlation between T1 and T2 values and PZ width.

Influenza Vaccination as Prevention Therapy for Stable Coronary Artery Disease and Acute Coronary Syndrome: A Meta-Analysis of Randomized Trials.

BACKGROUND: Influenza can cause a significant burden on patients with coronary artery disease. This meta-analysis assessed the effectiveness of influenza vaccination in patients with acute coronary syndrome and stable coronary artery disease. METHODS: We searched the Cochrane Controlled Register of Trials (CENTRAL), Embase, MEDLINE, www. CLINICALTRIALS: gov, and the World Health Organization International Clinical Trials Registry Platform from inception to September 2021. Estimates were summarized using the Mantel-Haenzel method and a random-effects model. To assess heterogeneity the I² statistic was used. RESULTS: Five randomized trials, comprising 4187 patients, were included, 2 of which included patients with acute coronary syndrome and 3 that included patients with stable coronary artery disease and acute coronary syndrome. Influenza vaccination significantly reduced the risk for all-cause mortality (relative risk [RR] = 0.56; 95% confidence interval [CI], 0.38-0.84), cardiovascular mortality (RR = 0.54; 95% CI, 0.37-0.80), major acute cardiovascular events (RR = 0.66; 95% CI, 0.49-0.88), and acute coronary syndrome (RR = 0.63; 95% CI, 0.44-0.89). On subgroup analysis, influenza vaccination remained effective for these outcomes in acute coronary syndrome but did not meet statistical significance in coronary artery disease. Furthermore, influenza vaccination did not reduce the risk for revascularization (RR = 0.89; 95% CI, 0.54-1.45), stroke or transient ischemic attack (RR = 0.85; 95% CI, 0.31-2.32), or heart failure hospitalization (RR = 0.91; 95% CI, 0.21-4.00). CONCLUSIONS: Influenza vaccine is a cheap and effective intervention to reduce the risk for all-cause mortality, cardiovascular mortality, major acute cardiovascular events, and acute coronary syndrome among coronary artery disease patients, especially in those with acute coronary syndrome.

Cardiometabolic-based chronic disease: adiposity and dysglycemia drivers of heart failure.

Heart failure (HF) is a complex clinical syndrome, associated with high rates of mortality, hospitalization, and impairment of quality of life. Obesity and type 2 diabetes are major cardiometabolic drivers, represented as distinct stages of adiposity- and dysglycemia-based chronic disease (ABCD, DBCD), respectively, and leading to cardiometabolic-based chronic disease (CMBCD). This review focuses on one aspect of the CMBCD model: how ABCD and DBCD influence genesis and progression of HF phenotypes. Specifically, the relationships of ABCD and DBCD stages with structural and functional heart disease, HF risk, and outcomes in overt HF are detailed. Also, evidence-based lifestyle, pharmacological, and procedural interventions that promote or reverse cardiac remodeling and outcomes in individuals at risk or with HF are discussed. In summary, driver-based chronic disease models for individuals at risk or with HF can expose prevention targets for more comprehensive interventions to improve clinical outcomes. Future randomized trials that investigate structured lifestyle, pharmacological, and procedural therapies specifically tailored for the CMBCD model are needed to develop personalized care plans to decrease HF susceptibility and improve outcomes.

Raciocínio Clínico em Cardiologia: Passado, Presente e Futuro / Clinical Reasoning in Cardiology: Past, Present and Future

Resumo O raciocínio clínico nasceu 2500 anos atrás com Hipócrates, tendo evoluído ao longo dos séculos, e se tornado uma mistura de arte e ciência. Várias personalidades ao longo da história contribuíram para melhorar a acurácia diagnóstica. Contudo, o erro diagnóstico é ainda comum e causa um grande impacto nos sistemas de saúde. Para lidar com esse desafio, vários modelos de raciocínio clínico surgiram para sistematizar o processo de pensamento clínico. Este artigo descreve a história do raciocínio clínico e os métodos atuais de raciocínio diagnóstico, propõe um novo modelo de raciocínio clínico chamado Raciocínio Integrativo, e traz perspectivas sobre o futuro do raciocínio clínico.

Abstract Clinical reasoning was born 2,500 years ago with Hippocrates, having evolved over the centuries, becoming a mixture of art and science. Several personalities throughout history have contributed to improving diagnostic accuracy. Nonetheless, diagnostic error is still common and causes a severe impact on healthcare systems. To face this challenge, several clinical reasoning models have emerged to systematize the clinical thinking process. This paper describes the history of clinical reasoning and current diagnostic reasoning methods, proposes a new clinical reasoning model, called Integrative Reasoning, and brings perspectives about the future of clinical reasoning.

Clinical Reasoning in Cardiology: Past, Present and Future. / Raciocínio Clínico em Cardiologia: Passado, Presente e Futuro.

Clinical reasoning was born 2,500 years ago with Hippocrates, having evolved over the centuries, becoming a mixture of art and science. Several personalities throughout history have contributed to improving diagnostic accuracy. Nonetheless, diagnostic error is still common and causes a severe impact on healthcare systems. To face this challenge, several clinical reasoning models have emerged to systematize the clinical thinking process. This paper describes the history of clinical reasoning and current diagnostic reasoning methods, proposes a new clinical reasoning model, called Integrative Reasoning, and brings perspectives about the future of clinical reasoning.

O raciocínio clínico nasceu 2500 anos atrás com Hipócrates, tendo evoluído ao longo dos séculos, e se tornado uma mistura de arte e ciência. Várias personalidades ao longo da história contribuíram para melhorar a acurácia diagnóstica. Contudo, o erro diagnóstico é ainda comum e causa um grande impacto nos sistemas de saúde. Para lidar com esse desafio, vários modelos de raciocínio clínico surgiram para sistematizar o processo de pensamento clínico. Este artigo descreve a história do raciocínio clínico e os métodos atuais de raciocínio diagnóstico, propõe um novo modelo de raciocínio clínico chamado Raciocínio Integrativo, e traz perspectivas sobre o futuro do raciocínio clínico.

Tecido Adiposo Epicárdico nos Fenótipos de Insuficiência Cardíaca - Uma Metanálise / Epicardial Adipose Tissue in Heart Failure Phenotypes - A Meta-Analysis

Resumo Fundamento O tecido adiposo epicárdico (TAE) é aumentado em comorbidades comuns na insuficiência cardíaca (IC). Dessa forma, o TAE teria o potencial de mediar efeitos que levam à deterioração da função cardíaca. Objetivos Esta metanálise tem o objetivo de investigar se a quantidade de TAE em todos os tipos de IC e cada tipo de IC são significativamente diferentes dos pacientes de controle. Métodos Esta metanálise seguiu as diretrizes da Meta-analysis of Observational Studies in Epidemiology (Metanálise de estudos observacionais em epidemiologia). A pesquisa foi realizada nos bancos de dados MEDLINE, Embase e Lilacs até novembro de 2020. Dois autores realizaram a triagem, a extração de dados e a avaliação de qualidade. Um p-valor <0,05 foi definido como estatisticamente significativo. Resultados Foram incluídos oito estudos observacionais, compreendendo 1248 pacientes no total, dos quais 574 eram de controle, 415 tinham IC com fração de ejeção reduzida (ICFER) e 259 tinham IC com fração de ejeção de faixa média ou preservada (ICFEfm ou ICFEP). A quantidade de TAE não era diferente entre todos os tipos de IC e o grupo de controle (DMP = -0,66, IC 95%: -1,54 a 0,23, p =0,14) . Analisando cada fenótipo de IC separadamente, pacientes com ICFER tinham TAE reduzido em comparação aos pacientes de controle (DMP = 1,27, IC 95%: - 1,87 a -0,67, p <0,0001), enquanto os pacientes com ICFEfm ou ICFEP tiveram TAE aumentado em comparação aos pacientes de controle (DMP = 1,24, IC 95%: 0,99 a 1,50, p <0,0001). Conclusão A quantidade de TAE não era significativamente diferente entre todos os tipos de IC e o grupo de controle. Em pacientes com ICFER o volume de TAE era reduzido, enquanto em pacientes com ICFEP e ICFEfm, a quantidade de TAE era significativamente aumentada. Número de registro PROSPERO: CRD42019134441.

Abstract Background Epicardial adipose tissue (EAT) is increased in comorbidities common in heart failure (HF). In this sense, EAT could potentially mediate effects that lead to an impaired cardiac function. Objectives This meta-analysis aims to investigate if the amount of EAT in all-types of HF and each HF phenotype is significantly different from control patients. Methods This meta-analysis followed the Meta-analysis Of Observational Studies in Epidemiology guidelines. The search was performed in the MEDLINE, Embase, and Lilacs databases until November 2020. Two authors performed screening, data extraction, and quality assessment. A p-value <0.05 was defined as statistically significant. Results Eight observational studies were included, comprehending 1,248 patients in total, from which 574 were controls, 415 had HF with reduced ejection fraction (HFrEF) and 259 had HF with mid-range or preserved ejection fraction (HFmrEF or HFpEF). The amount of EAT was not different between all types of HF and the control group (SMD = -0.66, 95% CI: -1.54 to 0.23, p =0.14). Analyzing each HF phenotype separately, patients with HFrEF had a reduced EAT when compared to the controls (SMD= -1.27, 95% CI: - 1.87 to -0.67, p <0.0001), while patients with HFmrEF or HFpEF showed an increased EAT when compared to controls (SMD= 1.24, 95% CI: 0.99 to 1.50, p <0.0001). Conclusion The amount of EAT was not significantly different between all types of HF and the control group. In patients with HFrEF, the EAT volume was reduced, whereas in HFpEF and HFmrEF, the amount of EAT was significantly increased. PROSPERO registration number: CRD42019134441.