Sodium-glucose cotranspor ter 2 (SGLT2) inhibitors in nephrolithiasis: should we "gliflozin" patients with kidney stone disease? / Inibidores de cotransportadores sódio-glicose-2 (SGLT2) na nefrolitíase - devemos "gliflozinar" os litiásicos?

ABSTRACT The prevalence of nephrolithiasis is increasing worldwide. Despite advances in understanding the pathogenesis of lithiasis, few studies have demonstrated that specific clinical interventions reduce the recurrence of nephrolithiasis. The aim of this review is to analyze the current data and potential effects of iSGLT2 in lithogenesis and try to answer the question: Should we also "gliflozin" our patients with kidney stone disease?

RESUMO A prevalência da nefrolitíase está aumentando em todo o mundo. Apesar dos avanços na compreensão da patogênese da doença litiásica, poucos estudos demonstraram que intervenções clínicas específicas diminuem a recorrência da nefrolitíase. O objetivo desta revisão é analisar os dados atuais e efeitos potenciais dos iSGLT2 na doença litiásica e tentar responder à pergunta: devemos também "gliflozinar" os litiásicos?

Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know / Complexo da Esclerose Tuberosa e rins: o que os nefrologistas devem saber

Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability. The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism. Consequently, the hyperactivation of the mTOR pathway leads to abnormal tissue proliferation and the development of solid tumors. Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function. Over the past years, there has been a notable shift in the therapeutic approach to TSC, particularly in addressing renal manifestations. mTOR inhibitors have emerged as the primary therapeutic option, whereas surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage. This review focuses on the main clinical characteristics of TSC, the mechanisms underlying kidney involvement, the recent advances in therapy for kidney lesions, and the future perspectives.

Resumo O complexo da esclerose tuberosa (CET) é uma doença autossômica dominante caracterizada pelo desenvolvimento de hamartomas no sistema nervoso central, coração, pele, pulmões e rins e outras manifestações, incluindo convulsões, tubérculos corticais, linhas de migração radial, autismo e deficiência cognitiva. A doença está associada a variantes patogênicas nos genes TSC1 ou TSC2, resultando na hiperativação da via mTOR, um importante regulador do crescimento e metabolismo celular. Consequentemente, a hiperativação da via mTOR leva à proliferação anormal do tecido e ao desenvolvimento de tumores sólidos. O envolvimento renal no CET é caracterizado pelo desenvolvimento de lesões císticas, carcinoma de células renais e angiomiolipomas renais, que podem progredir e causar dor, sangramento e perda da função renal. Nos últimos anos, houve uma mudança notável na abordagem terapêutica do CET, especialmente no tratamento das manifestações renais. Os inibidores de mTOR surgiram como a principal opção terapêutica, enquanto intervenções cirúrgicas como nefrectomia e embolização são reservadas principalmente para complicações que não respondem ao tratamento clínico, como hemorragia renal grave. Esta revisão se concentra nas principais características clínicas do CET, nos mecanismos subjacentes ao envolvimento renal, nos recentes avanços na terapia para lesões renais e nas perspectivas futuras.

Targeted therapy for immune mediated skin diseases. What should a dermatologist know?

Abstract Background Molecularly targeted therapies, such as monoclonal antibodies (mAbs) and Janus Kinase inhibitors (JAKis), have emerged as essential tools in the treatment of dermatological diseases. These therapies modulate the immune system through specific signaling pathways, providing effective alternatives to traditional systemic immunosuppressive agents. This review aims to provide an updated summary of targeted immune therapies for inflammatory skin diseases, considering their pathophysiology, efficacy, dosage, and safety profiles. Methods The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic search was conducted on PubMed over the past 10 years, focusing on randomized clinical trials, case reports, and case series related to targeted immune therapies in dermatology. Eligibility criteria were applied, and data were extracted from each study, including citation data, study design, and results. Results We identified 1360 non-duplicate articles with the initial search strategy. Title and abstract review excluded 1150, while a full-text review excluded an additional 50 articles. The review included 143 studies published between 2012 and 2022, highlighting 39 drugs currently under investigation or in use for managing inflammatory skin diseases. Study limitations The heterogeneity of summarized information limits this review. Some recommendations originated from data from clinical trials, while others relied on retrospective analyses and small case series. Recommendations will likely be updated as new results emerge. Conclusion Targeted therapies have revolutionized the treatment of chronic skin diseases, offering new options for patients unresponsive to standard treatments. Paradoxical reactions are rarely observed. Further studies are needed to fully understand the mechanisms and nature of these therapies. Overall, targeted immune therapies in dermatology represent a promising development, significantly improving the quality of life for patients with chronic inflammatory skin diseases.

Anticoagulantes Orais Diretos versus Antagonistas da Vitamina K para Trombo Ventricular Esquerdo: Uma Metanálise com Análise Sequencial de Ensaios / Direct Oral Anticoagulants versus Vitamin K Antagonists for Left Ventricular Thrombus: A Meta-Analysis with Trial Sequential Analysis

Resumo Fundamento Os antagonistas da vitamina K (AVKs) são o tratamento de primeira linha recomendado para trombo ventricular esquerdo (TVE); entretanto, os anticoagulantes orais diretos (AODs) têm sido considerados uma terapia alternativa. Objetivos Avaliar a eficácia e a segurança dos AODs em comparação com a terapia com AVKs em pacientes com TVE. Métodos PubMed, Embase e Cochrane foram sistematicamente pesquisados em busca de ensaios clínicos randomizados ou estudos de coorte que comparassem AODs versus AVKs para TVE. As razões de risco (RR) foram calculadas para desfechos binários, com intervalos de confiança (IC) de 95%. A significância estatística foi definida como valor de p < 0,05. Resultados Foram incluídos um total de 4 ensaios clínicos randomizados e 29 estudos de coorte, com 4.450 pacientes designados para AODs ou AVKs. Não houve diferença significativa entre os grupos para acidente vascular cerebral ou eventos embólicos sistêmicos (AVC/EES) (RR 0,84; IC 95% 0,65 a 1,07; p = 0,157), acidente vascular cerebral (RR 0,73; IC 95% 0,48 a 1,11; p = 0,140), eventos embólicos sistêmicos (EES) (RR 0,69; IC 95% 0,40 a 1,17; p = 0,166), resolução do trombo (RR 1,05; IC 95% 0,99 a 1,11; p = 0,077), qualquer sangramento (RR 0,78; IC 95% 0,60 a 1,00; p = 0,054), sangramento clinicamente relevante (RR 0,69; IC 95% 0,46 a 1,03; p = 0,066), sangramento menor (RR 0,73; IC 95% 0,43 a 1,23; p = 0,234), sangramento maior (RR 0,87; IC 95% 0,42 a 1,80; p = 0,705) e mortalidade por todas as causas (RR 1,05; IC 95% 0,79 a 1,39; p = 0,752). Em comparação com AVKs, a rivaroxabana reduziu significativamente AVC/EES (RR 0,35; IC 95% 0,16 a 0,91; p = 0,029) e EES (RR 0,39; IC 95% 0,16 a 0,95; p = 0,037). Conclusões Os AODs tiveram uma taxa semelhante de eventos tromboembólicos e hemorrágicos, bem como de resolução do trombo, em comparação com os AVKs no tratamento de TVE. A terapia com rivaroxabana teve uma redução significativa nos eventos tromboembólicos, em comparação com os AVKs.

Abstract Background Vitamin K antagonists (VKAs) are the recommended first-line treatment for left ventricular thrombus (LVT); however, direct oral anticoagulants (DOACs) have been considered an alternative therapy. Objectives To evaluate the efficacy and safety of DOACs compared with VKAs therapy in patients with LVT. Methods PubMed, Embase, and Cochrane were systematically searched for randomized clinical trials or cohort studies that compared DOACs versus VKAs for LVT. Risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (95% CIs). Statistical significance was defined as p value < 0.05. Results A total of 4 randomized clinical trials and 29 cohort studies were included, with 4,450 patients assigned to either DOACs or VKAs. There was no significant difference between groups for stroke or systemic embolic (SSE) events (RR 0.84; 95% CI 0.65 to 1.07; p = 0.157), stroke (RR 0.73; 95% CI 0.48 to 1.11; p = 0.140), systemic embolic (SE) events (RR 0.69; 95% CI 0.40 to 1.17; p = 0.166), thrombus resolution (RR 1.05; 95% CI 0.99 to 1.11; p = 0.077), any bleeding (RR 0.78; 95% CI 0.60 to 1.00; p = 0.054), clinically relevant bleeding (RR 0.69; 95% CI 0.46 to 1.03; p = 0.066), minor bleeding (RR 0.73; 95% CI 0.43 to 1.23; p = 0.234), major bleeding (RR 0.87; 95% CI 0.42 to 1.80; p = 0.705), and all-cause mortality (RR 1.05; 95% CI 0.79 to 1.39; p = 0.752). Compared with VKAs, rivaroxaban significantly reduced SSE events (RR 0.35; 95% CI 0.16 to 0.91; p = 0.029) and SE events (RR 0.39; 95% CI 0.16 to 0.95; p = 0.037). Conclusions DOACs had a similar rate of thromboembolic and hemorrhagic events, as well as thrombus resolution, compared to VKAs in the treatment of LVTs. Rivaroxaban therapy had a significant reduction in thromboembolic events, compared to VKAs.

Control metabólico de pacientes diabéticos tipo 2 tratados con empagliflozina: serie de casos / Metabolic control in type 2 diabetic patients treated with empagliflozin: A case series

Introducción La diabetes mellitus tipo 2 es una enfermedad de alta prevalencia y está asociada a mayor morbimortalidad. Debido al bajo porcentaje de compensación, se han buscado nuevas estrategias de tratamiento farmacológico, como los inhibidores del cotransportador sodio-glucosa tipo 2. Objetivo Describir la evolución de pacientes diabéticos tipo 2 insulino-requirentes tratados con empagliflozina en el Hospital Peñaflor, ubicado en el sector poniente de la Región Metropolitana, Chile. El objetivo primario fue evaluar la eficacia del medicamento respecto a hemoglobina glicosilada A1c. Los objetivos secundarios fueron registrar el logro de hemoglobina glicosilada A1c igual o menor a 7,5% según análisis de supervivencia. Luego, consignar el cambio en la velocidad de filtración glomerular y en la excreción urinaria de albúmina post tratamiento. Métodos Revisión de ficha clínica de todos los pacientes tratados con empagliflozina desde noviembre de 2019 a junio de 2023. Media de seguimiento de 19 (de 16,3 a 40) meses. Para comparación entre valores de hemoglobina glicosilada A1c según rangos de seguimiento, se utilizó prueba T de Student de términos pareados o prueba de Wilcoxon. Resultados Se estudió a 58 pacientes, 15 hombres y 43 mujeres (74,1%). Edad 58,5 ± 9,2 años, rango de 35 a 75 años. Hemoglobina glicosilada A1c basal de 10,3 ± 1,6% y 8,98% ± 2,2 en un rango de seguimiento de 18 a 24 meses post tratamiento, resultando en un descenso de 1,27% (p = 0,002; intervalo de confianza 95%: 0,5 a 2,03). El efecto adverso más frecuente fue infección del tracto urinario. Conclusiones Los pacientes diabéticos tipo 2 insulino-requirentes tratados con empagliflozina en el Hospital Peñaflor lograron un mejor control glicémico con pocos efectos adversos.

Background Type 2 diabetes mellitus is a highly prevalent disease and is associated with increased morbidity and mortality. Due to the low percentage of adequate glycemic control, new strategies for the treatment of type 2 diabetes mellitus have been sought, including sodium-glucose cotransporter type 2 inhibitorss. Objective To describe the evolution of patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital. The primary objective was to evaluate the efficacy of the medication regarding glycosylated hemoglobin A1c (HbA1c). The secondary objectives were: 1) achievement of HbA1c equal to or less than 7.5% according to survival analysis. 2) Change in glomerular filtration rate and urinary albumin excretion post treatment. Methods Review of clinical records of all patients treated with empagliflozin from November 2019 to June 2023. Average follow-up of 19 (16.3 to 40) months. To compare HbA1c values according to follow-up ranges, the paired T test or Wilcoxon test was used. Results We included 58 patients, 15 men and 43 women (74.1%), with an average age of 58.5 ± 9.2 years, ranging from 35 to 75 years. Baseline HbA1c of 10.3 ± 1.6% and 8.98% ± 2.2 in a follow-up of 18 to 24 months post-treatment, resulted in a decrease of 1.27% (p = 0.002; confidence interval 95%: 0.5 to 2.03). The most common adverse effect was urinary tract infection. Conclusions Patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital achieved better glycemic control with few adverse effects.

Do statins decrease testosterone in men? Systematic review and meta-analysis

ABSTRACT Purpose: Statins are one of the most prescribed classes of drugs worldwide to treat hypercholesterolemia and dyslipidemia. By lowering the level of cholesterol, the use of statin could cause a reduction in testosterone levels. The objective was to evaluate whether the continued use of statins in patients with hypercholesterolemia causes a deficiency in testosterone and other sex hormones. Materials and Methods: Systematic Review with Meta-analysis, performed in Embase, Medline and Cochrane databases, until May 2023; PROSPERO CRD42021270424protocol. Selection performed by two independent authors with subsequent conference in stages. Methodology based on PRISMA statement. There were selected comparative studies, prospective cohorts (CP), randomized clinical trials (RCT) and cross-sectional studies (CSS) with comparison of testosterone levels before and after statin administration and between groups. Bias analysis were evaluated with Cochrane Tool, The Newcastle-Ottawa Scale (NOS), and using the Assess the Quality of Cross-sectional studies (AXIS) tool. Results: There were found on MedLine, Embase and Cochrane, after selected comparative studies, 10CP and 6RCT and 6CSS for the meta-analysis. In the Forrest plot with 6CSS, a correlation between patients with continuous use of statins and a reduction in total testosterone was evidenced with a statistically significant reduction of 55.02ng/dL (95%CI=[39.40,70.64],I²=91%,p<0.00001). In the analysis with 5RCT, a reduction in the mean total testosterone in patients who started continuous statin use was evidenced, with a statistical significance of 13.12ng/dL (95%CI=[1.16,25.08],I²=0%,p=0.03). Furthermore, the analysis of all prospective studies with 15 articles showed a statistically significant reduction in the mean total testosterone of 9.11 ng/dL (95%CI=[0.16,18.06],I²=37%,p=0.04). A reduction in total testosterone has been shown in most studies and in its accumulated analysis after statin use. However, this decrease was not enough to reach levels below normal. Conclusion: Statins use causes a decrease in total testosterone, not enough to cause a drop below the normal range and also determines increase in FSH levels. No differences were found in LH, Estradiol, SHBG and Free Testosterone analysis.

Retos y avances del cáncer de pulmón de células no pequeñas metastásico EGFR mutado / Challenges and advances in metastatic non-small cell lung cancer with EGFR mutation

RESUMEN Los inhibidores de la tirosina quinasa han cambiado drásticamente la perspectiva clínica de los pacientes con cáncer de pulmón de células no pequeñas avanzado con mutaciones del receptor del factor de crecimiento epidérmico. Sin embargo, existen aún retos en el manejo de los pacientes con esta mutación en un escenario metastásico, como es la resistencia intrínseca y adquirida a inhibidores de tirosina quinasa. Se discutirán los últimos avances y nuevas estrategias en primera línea de tratamiento, resistencia a osimertinib y tratamiento en mutación, en el exón 20.

ABSTRACT Tyrosine kinase inhibitors have dramatically changed the clinical outcomes for patients with advanced non-small cell lung cancer with epidermal growth factor receptor mutations. However, there are still challenges in the management of patients with this mutation in a metastatic setting, such as intrinsic and acquired resistance to tyrosine kinase inhibitors. We will discuss the latest advances and new strategies in first-line treatment, osimertinib resistance, and exon 20 mutation treatment.

Papel da Rigidez Aórtica na Previsão da Resposta aos Inibidores da Fosfodiesterase-5 no Tratamento da Disfunção Erétil / Role of Aortic Stiffness in Predicting Response to Phosphodiesterase-5 Inhibitors in the Treatment of Erectile Dysfunction

Resumo Fundamento: Sabe-se que a rigidez aórtica (RA) aumenta em pacientes com disfunção erétil (DE). Os inibidores da enzima fosfodiesterase tipo 5 (PDE-5) são usados no tratamento da DE, e as respostas dos pacientes a esse tratamento podem variar. Objetivos: Nosso objetivo foi investigar o papel da RA na previsão da resposta de pacientes planejados para tomar inibidores da enzima PDE-5 devido à DE. Métodos: Um total de 96 pacientes do sexo masculino com DE foram incluídos no estudo. O questionário do Índice Internacional de Função Erétil (IIEF) foi utilizado para avaliar a presença e gravidade da DE e a resposta ao tratamento. A ecocardiografia transtorácica foi utilizada para avaliar RA. Resultados: Houve diferença estatisticamente significativa entre os valores de deformação aórtica e distensibilidade aórtica dos grupos de estudo (p<0,001). O escore delta IIEF apresentou alto nível de correlação positiva com a deformação aórtica (p<0,01, r=0,758) e um nível moderado de correlação positiva com a distensibilidade aórtica (p<0,01, r=0,574). Conclusão: Determinamos que em pacientes com DE, a deformação aórtica e a distensibilidade aórtica medidas de forma não invasiva por meio de ecocardiografia transtorácica são parâmetros importantes na previsão da resposta dos pacientes à terapia com inibidores da PDE-5.

Abstract Background: It is known that aortic stiffness (AS) increases in patients with erectile dysfunction (ED). Phosphodiesterase type-5 (PDE-5) enzyme inhibitors are used in the treatment of ED, and patients' responses to this treatment may vary. Objectives: We aimed to investigate the role of AS in predicting the response of patients planned to take PDE-5 enzyme inhibitors due to ED. Methods: A total of 96 male patients with ED were included in the study. The International Index of Erectile Function (IIEF) questionnaire was used to evaluate the presence and severity of ED and the response to treatment. Transthoracic echocardiography was used to evaluate AS. Results: There was a statistically significant difference between the aortic strain and aortic distensibility values of the study groups (p<0.001). The delta IIEF score had a high level of positive correlation with aortic strain (p<0.01, r=0.758) and a moderate level of positive correlation with aortic distensibility (p<0.01, r=0.574). Conclusion: We determined that in patients with ED, aortic strain and aortic distensibility measured non-invasively using transthoracic echocardiography are important parameters in predicting patients' response to PDE-5 inhibitor therapy.

Anticoagulação Crônica em Pacientes com Fibrilação Atrial e COVID-19: Uma Revisão Sistemática e Metanálise / Chronic Anticoagulation in Patients with Atrial Fibrillation and COVID-19: A Systematic Review and Meta-Analysis

Resumo Fundamento: A doença por coronavírus 2019 (COVID-19) está associada à hipercoagulabilidade. Permanece incerto se a anticoagulação contínua para fibrilação atrial (FA) em pacientes que posteriormente contraem COVID-19 melhora os desfechos clínicos. Objetivos: Comparar a anticoagulação oral crônica com ausência de anticoagulação prévia em pacientes com FA que contraíram uma infecção por COVID-19 em relação aos desfechos de mortalidade por todas as causas, mortalidade por COVID-19, admissão em unidade de terapia intensiva (UTI) e hospitalização. Métodos: Buscamos sistematicamente no PubMed, Embase e Cochrane Library estudos elegíveis desde o início até dezembro de 2022. Incluímos estudos que compararam desfechos de COVID-19 em pacientes com e sem anticoagulação crônica prévia para FA. Foram agrupadas razões de risco (RR) com intervalos de confiança (IC) de 95% por meio de um modelo de efeitos aleatórios. O nível de significância foi estabelecido em p < 0,05. As avaliações da qualidade e do risco de viés foram realizadas de acordo com as recomendações da Cochrane. Resultados: Foram identificados 10 estudos abrangendo 1.177.858 pacientes com COVID-19 e FA, dos quais 893.772 (75,9%) estavam em anticoagulação crônica prévia para FA. Em pacientes com COVID-19, a anticoagulação crônica para FA reduziu significativamente a mortalidade por todas as causas (RR 0,75; IC 95% 0,57 a 0,99; p = 0,048; I2 = 89%) e a mortalidade relacionada à COVID-19 (RR 0,76; IC 95% 0,72 a 0,79; p < 0,001; I2 = 0%) quando comparada com a ausência de anticoagulação prévia. Em contrapartida, não houve diferença entre os grupos em relação à hospitalização (RR 1,08; IC 95% 0,82 a 1,41; p = 0,587; I2 = 95%) ou internação em UTI (RR 0,86; IC 95% 0,68 a 1,09; p = 0,216; I2 = 69%). Conclusões: Nesta metanálise, a anticoagulação crônica para pacientes com FA que contraíram COVID-19 foi associada a taxas significativamente mais baixas de mortalidade por todas as causas e mortalidade relacionada à COVID-19 em comparação com a ausência de anticoagulação anterior.

Abstract Background: Coronavirus disease 2019 (COVID-19) is associated with hypercoagulability. It remains uncertain whether ongoing anticoagulation for atrial fibrillation (AF) in patients who later contract COVID-19 improves clinical outcomes. Objectives: To compare chronic oral anticoagulation with no previous anticoagulation in patients with AF who contracted a COVID-19 infection concerning the outcomes of all-cause mortality, COVID-19 mortality, intensive care unit (ICU) admission, and hospitalization. Methods: We systematically searched PubMed, Embase, and Cochrane Library for eligible studies from inception to December 2022. We included studies comparing COVID-19 outcomes in patients with versus without prior chronic anticoagulation for AF. Risk ratios (RR) with 95% confidence intervals (CI) were pooled with a random-effects model. The level of significance was set at p < 0.05. Quality assessment and risk of bias were performed according to Cochrane recommendations. Results: Ten studies comprising 1,177,858 patients with COVID-19 and AF were identified, of whom 893,772 (75.9%) were on prior chronic anticoagulation for AF. In patients with COVID-19, being on chronic anticoagulation for AF significantly reduced all-cause mortality (RR 0.75; 95% CI 0.57 to 0.99; p = 0.048; I2 = 89%) and COVID-19-related mortality (RR 0.76; 95% CI 0.72 to 0.79; p < 0.001; I2 = 0%) when compared with no prior anticoagulation. In contrast, there was no difference between groups regarding hospitalization (RR 1.08; 95% CI 0.82 to 1.41; p = 0.587; I2 = 95%) or ICU admission (RR 0.86; 95% CI 0.68 to 1.09; p = 0.216; I2 = 69%). Conclusions: In this meta-analysis, chronic anticoagulation for patients with AF who contracted COVID-19 was associated with significantly lower rates of all-cause mortality and COVID-19-related mortality as compared with no previous anticoagulation.

Abordaje de la enfermedad por reflujo gastroesofágico refractaria / Approach to refractory gastroesophageal reflux disease

RESUMEN Un adecuado abordaje de la enfermedad por reflujo gastroesofágico refractaria (rERGE) es imprescindible para lograr el éxito terapéutico. Desde la definición precisa de rERGE hasta la detallada caracterización de sus fenotipos, establecerá el camino hacia la personalización de la terapia óptima para cada paciente. En esta revisión narrativa de la literatura, se busca proporcionar una síntesis actualizada de la utilidad de las diversas herramientas diagnósticas y explorar el amplio espectro de opciones terapéuticas, tanto médicas como invasivas disponibles para esta condición.

ABSTRACT An adequate approach to refractory gastroesophageal reflux disease (rGERD) is essential for achieving therapeutic success. From the precise definition of rGERD to the detailed characterization of its phenotypes, it will pave the way for the customization of optimal therapy for each patient. In this narrative literature review, the aim is to provide an updated synthesis of the utility of various diagnostic tools and explore the wide range of therapeutic options, both medical and invasive, available for this condition.

Research progress on targeted protein S-palmitoylation modification in T cell immunotherapy / 中国药科大学学报

@#Abstract: S-palmitoylation, a reversible and dynamic post-translational modification in cells, is involved in regulating the transcription and expression of downstream target genes as well as signal transduction, thereby affecting cell life activities. Studies have shown that thousands of human proteins undergo S-palmitoylation modification, suggesting that S-palmitoylation is closely related to the progression and treatment of diseases. T cells play central roles in anti-tumor immune responses. A variety of T cell immune-related proteins are regulated by S-palmitoylation. In the present study, we focus on the impact of S-palmitoylation on T cell signal transduction and its application in T cell immunotherapy, aiming to provide new ideas for the development of new targets and peptide inhibitors for T cell immunotherapy.

Design, synthesis and biological study of BTK/JAK3 dual-target inhibitors / 中国药科大学学报

@#Abstract: In the present study, the compound XL-12 from our previous work was utilized as a lead compound. Through the optimization of the terminal phenyl ring, 12 target compounds were designed and synthesized. The structures of all target compounds were confirmed by 1H NMR, 13C NMR, and H RMS. In vitro enzyme activity assay showed that most compounds demonstrated significant inhibitory activity toward Bruton’s tyrosine kinase (BTK) and Janus kinase 3 (JAK3). Among them, compound I-3 exhibited moderate cell proliferation inhibitory activity toward Daudi cells and BaF3-JAK3 cells. In the evaluation of anti-inflammatory activity in vitro, compound I-3 could effectively inhibit the production of inflammatory factors IL-6; besides, it exhibited superior anti-inflammatory activity compared to ibrutinib in xylene-induced ear swelling model in mice.

Research progress of KRAS inhibitors / 中国药科大学学报

@#Abstract: KRAS protein, a small GTPase encoded by the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene, is involved in cell proliferation, differentiation, migration and cell survival, and is known as a regulatory switch for the cell life cycle. However, KRAS gene is prone to mutation, leading to hyperactivation of its downstream signaling pathways, and has a vital role in driving tumorigenesis. KRAS mutations predominantly take place at residue G12, G13 or Q61, and different mutants have varying effects on protein physiological functions and tumor types. Due to its smooth surface and high affinity for nucleotides, KRAS had been considered to be “undruggable” until the launch of selective KRAS G12C inhibitors sotorasib and adagrasib, which broke the dogma. This review introduces the structure and functions of KRAS, as well as the status and progress of inhibitors directly targeting KRAS mutants (G12C, G12D, G12R, G12S) and pan-KRAS inhibitors, aiming to provide some insightful reference for the development of KRAS inhibitors.

Analysis of mutation characteristics in TKI-resistant chronic myeloid leukemia patients based on next-generation sequencing technology / 白血病·淋巴瘤

Objective:To explore the characteristics and patterns of gene mutations in tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) patients and their relationship with TKI-resistant CML.Methods:A retrospective case series study was performed. Clinical data and next-generation sequencing results from TKI-resistant CML patients in Nanfang Hospital of Southern Medical University and Yuebei People's Hospital of Shantou University Medical College from August 2018 to November 2022 were retrospectively analyzed, and the gene mutations of the patients in general and at different disease stages were analyzed.Results:Sixty patients were enrolled, with the age [ M ( Q1, Q3)] of 41.5 years old (32 years old, 53 years old); 38 cases (63.33%) were male and 22 cases (36.67%) were female; 43 cases were in the chronic stage, and 17 cases were in the progression stage (3 cases were in the accelerated stage and 14 cases were in the blast stage). non-ABL1 mutations were detected in 30 patients (50.00%) including 45 times of 15 non-ABL1 genes. The number of non-ABL1 mutation gene was 1 (0, 2) in 60 patients. Of the 60 patients, 21 (35.00%) had ASXL1 mutations, 5 (8.33%) had DNMT3A mutations, 5 (8.33%) had RUNX1 mutations, and 3 (5.00%) had SETBP1 mutations; the proportions of patients with 1 and ≥2 non-ABL1 mutations were 33.33% (20/60) and 16.67% (10/60), respectively. The total detection rates of non-ABL1 mutations were 52.94% (9/17) and 48.84% (21/43), and the detection rates of ≥2 non-ABL1 mutations were 23.53% (4/17) and 13.95% (6/43) in patients with progression and patients with chronic disease, and the differences were not statistically significant ( χ2 = 0.08, P = 0.774; χ2 = 0.80, P = 0.370). Seventeen of 60 patients (28.33%) had mutations in the ABL1 kinase region, of which 14 (82.35%) had non-ABL1 mutations; of these 17 cases, 6 patients with progressive disease all had non-ABL1 mutations, in 11 patients with chronic disease, 8 patients had non-ABL1 mutations, and the difference was not statistically significant ( P = 0.452). Conclusions:Patients with TKI-resistant CML have high frequencies of non-ABL1 mutations, and there is a trend for higher mutation rates in patients with progressive disease than in patients with chronic disease, and these may be related to the abnormal activation of ABL1 kinase by BCR-ABL1 fusion gene in patients with drug-resistant CML, which leads to the genome-level and epigenome-level mutations, and driving disease progression from chronic phase to accelerated or blast phase.

Serological index PAI-1 as risk factor of complications of femoral head necrosis after internal fixation of femoral neck fracture / 国际检验医学杂志

Objective To investigate the risk factors of femoral head necrosis after internal fixation of fem-oral neck fracture,and to clarify the predictive role of serological index plasminogen activator inhibitors-1(PAI-1)on femoral head necrosis.Methods A total of 95 patients undergoing internal fixation for femoral neck fracture were included in the study.Relevant clinical information of patients was obtained and the serum PAI-1 levels of the patients before surgery,1,2,and 3 days after surgery were detected.After 1-year follow-up,patients were divided into necrosis group and non-necrosis group according to the occurrence of femoral head necrosis.Visual Analog Scale(VAS),Western Ontario McMaster University Osteoarthritis Index(WOMAC),and Harris Hip Score(HHS)were conducted in all patients one year after the surgery.The differences of basic clinical information and serum PAI-1 levels before and after the surgery between necrosis group and non-necrosis group were compared,and Logistic regression analysis was performed to identify the relevant risk factors for femoral head necrosis.The relationships between the PAI-1 level after operation and the VAS,WOMAC,and HHS scores of patients were figured out.The receiver operating characteristic(ROC)curve of serum PAI-1 as a predictive indicator for femoral head necrosis was drawn to clarify its predictive val-ue.Results Garden classification and reduction quality between the necrosis group and the non-necrosis group were risk factors for femoral head necrosis(P＜0.05).The serum PAI-1 at 1 day and 2 days after surgery in the necrosis group were significantly higher than that in the non-necrosis group(P＜0.05).The level of PAI-1 at 1 day and 2 days after surgery was positively correlated with VAS and WOMAC(P＜0.05),and negative-ly correlated with HHS(P＜0.05).Logistic regression analysis showed that the increase of serum PAI-1 level at 1 day and 2 days after surgery were risk factors for femoral head necrosis(P＜0.05).The ROC curve showed that serum PAI-1 level at 2 days after surgery had higher predictive value than that at 1 day after sur-gery,and the cut-off value was 44.8 ng/L,the sensitivity was 68.49％,the specificity was 86.36％,and the ar-ea under the curve(AUC)was 0.807.Conclusion The serum PAI-1 level at 1 day and 2 days after internal fixation of femoral neck fracture could be used to predict the occurrence of femoral head necrosis,especially the serum PAI-1 levels at 2 days after surgery.

Bioinformatics-based screening for ferroptosis-related DEGs of EGFR-TKIs resistance in non-small cell lung cancer / 国际检验医学杂志

Objective To screen for ferroptosis-related differentially expressed genes(DEGs)of epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)resistance in non-small cell lung cancer(NSCLC).Methods The gene sequencing dataset GSE117846 of NSCLC EGFR-TKIs resistant cells was se-lected from the Gene Expression Omnibus data base(GEO)and screened for DEGs with P＜0.05 and | log2 FC |1.Ferroptosis-related genes were collected using the FerrDb database and jvenn was used to intersected the DEGs screened from GSE117846 dataset with the ferroptosis-related genes obtained from FerrDb database.GO function and KEGG pathway enrichment analysis of intersection genes were performed,and protein-pro-tein interaction(PPI)network was drawn.The score of intersection genes was calculated by using Cytohubba plug-in in Cytoscape software,and the top 10 genes were used for Hub genes screening.ULCAN and GEPIA2 databases were used to analyze the expression of Hub genes in NSCLC and its effect on the survival prognosis of patients.Real-time fluorescence quantitative PCR(qPCR)was used to detect the relative expression levels of Hub gene mRNA in NSCLC patients'cancer tissues,adjacent tissues and in vitro cells to verify the results of bioinformatics analysis.Results A total of 60 ferroptosis-related DEGs of EGFR-TKIs resistance in NSCLC were screened out,including 30 up-regulated genes and 30 down-regulated genes.The 60 genes were mainly enriched in P53 signaling pathway,ferroptosis pathway and FoxO signaling pathway.There were 57 nodes and 99 edges in the PPI network,with an average clustering coefficient of 0.377 and PPI enrichment P＜0.01.The Hub gene screened out by Cytohubba plug-in was tumor protein P63(TP63).ULCAN and GE-PIA2 database analysis showed that the expression of TP63 in lung adenocarcinoma tissue was significantly lower than that in normal tissue,while the expression of TP63 in lung squamous cell carcinoma tissue was sig-nificantly higher than that in normal tissue,and the differences were statistically significant(P＜0.05).In pa-tients with lung adenocarcinoma,there was no significant difference in the survival prognosis between TP63 high and low expression groups(P＞0.05),while in patients with lung squamous cell carcinoma,the survival prognosis of TP63 low expression group was better,and the difference was statistically significant(P＜0.05).QPCR showed that TP63 mRNA highly expressed in lung squamous cell carcinoma tissue and lowly expressed in lung adenocarcinoma tissue compared with adjacent tissues(P＜0.05).The expression of TP63 mRNA was down-regulated in gefitinib-resistant PC9/GR cells(P＜0.05),which was consistent with the re-sults of bioinformatics analysis.Conclusion TP63 may be an important gene linking NSCLC EGFR-TKIs re-sistance to ferroptosis.

Intravenous thrombolysis in patients with stroke warning syndrome: comparison with antiplatelet therapy / 国际脑血管病杂志

Objective:To investigate the efficacy and safety of intravenous thrombolysis and antiplatelet therapy in patients with stroke warning syndrome (SWS), as well as influencing factors of the outcome in patients with SWS.Method:Patients with SWS admitted to the 521 st Hospital of Ordnance Group from June 1, 2018 to December 31, 2023 were retrospectively included. Some patients were treated with ateplase intravenous thrombolysis, followed by oral antiplatelet therapy; some patients only received antiplatelet therapy. The main outcome measure was the modified Rankin Scale score at 90 days after onset, with a score of 0-2 defined as good outcome. Results:A total of 35 patients with SWS were included, including 26 males (74.3%) with an age of 58.29±11.06 years. Nineteen patients (54.3%) received intravenous thrombolysis, and 27 (77.1%) had good outcome at 90 days. There was no statistically significant difference in demographic, baseline data, and good outcome between the intravenous thrombolysis group and the antiplatelet therapy group. One patient had new stroke and one had transient ischemic attack in the intravenous thrombolysis group. There were statistically significant differences in ABCD2 score, systolic blood pressure, low-density lipoprotein cholesterol, fasting blood glucose, highest National Institutes of Health Stroke Scale (NIHSS) score at onset, and symptom duration between the good outcome group and the poor outcome group (all P<0.05). Conclusions:The efficacy of intravenous thrombolysis is similar to that of antiplatelet drugs alone in treating SWS. ABCD2 score, systolic blood pressure, low-density lipoprotein cholesterol, fasting blood glucose, highest NIHSS score at onset, and duration of symptoms may be influencing factors for the outcome of patients with SWS.

A real-world clinical study of immunocheckpoint inhibitor maintenance therapy after radical radiotherapy and chemotherapy in stage Ⅲ-ⅣA esophageal squamous cell carcinoma / 国际肿瘤学杂志

Objective:To investigate the efficacy of immune checkpoint inhibitor maintenance therapy after radical radiotherapy and chemotherapy for stage Ⅲ-ⅣA esophageal squamous cell carcinoma (ESCC) in the real world.Methods:The clinical data of 65 patients with stage Ⅲ-ⅣA ESCC treated by radical radiotherapy and chemotherapy from January 1, 2018 to December 31, 2022 in Hefei Cancer Hospital, Chinese Academy of Sciences were retrospectively analyzed. According to whether to undergo immune checkpoint inhibitor maintenance therapy after radical radiotherapy and chemotherapy, the patients were divided into a control group ( n=29) and an immune maintenance therapy group ( n=36) . The objective response rate (ORR) , progression-free survival (PFS) , and overall survival (OS) between the two groups were compared. Kaplan-Meier method was used to draw the survival curve accompanied with log-rank test. Cox regression model was used to conduct both univariate and multivariate analyses. Results:The ORR was 34.5% (10/29) in the control group and 61.1% (22/36) in the immune maintenance therapy group, with a statistically significant difference ( χ2=4.56, P=0.032) . The median PFS of control group and immune maintenance therapy group were 7.2 and 17.9 months, respectively, with a statistically significant difference ( χ2=7.86, P=0.005) . The median OS was 14.1 and 27.8 months, respectively, with a statistically significant difference ( χ2=5.40, P=0.020) . Univariate analysis showed that, objective response ( HR=0.09, 95% CI: 0.03-0.28, P<0.001) and immune maintenance therapy ( HR=0.38, 95% CI: 0.17-0.88, P=0.024) were the influential factors of OS in ESCC patients treaded by radical chemoradiotherapy in stage Ⅲ-ⅣA. Multivariate analysis showed that, objective response ( HR=0.09, 95% CI: 0.03-0.29, P<0.001) and immune maintenance therapy ( HR=0.40, 95% CI: 0.17-0.92, P=0.032) were the independent influencing factors for OS in ESCC patients treaded by radical chemoracial therapy in stage Ⅲ-ⅣA. The incidence of adverse reactions was 22.22% (8/36) in the immune maintenance therapy group and 10.34% (3/29) in the control group, with no statistically significant difference ( χ2=1.61, P=0.204) . All the adverse reactions were grade 1-2, and the symptoms were relieved after symptomatic treatment. Conclusion:Maintenance therapy with immune checkpoint inhibitors after radical chemoradiotherapy of stage Ⅲ-ⅣA ESCC can significantly improve the prognosis of patients with good safety.