Effects of rosmarinic acid and doxorubicine on an ovarian adenocarsinoma cell line (OVCAR3) via the EGFR pathway

Purpose: We aimed to reveal the effects of rosmarinic acid (RA), which has come to the forefront with its antitumor and antioxidant properties in many studies recently in the ovarian adenocarcinoma cell line, on the epidermal growth factor receptor (EFGR) signaling pathway in the presence of doxorubicin (DOX). Methods: Ovarian adenocarcinoma cell line (OVCAR3) and human skin keratinocyte cell line human skin keratinocyte cell line (HaCaT) were used as control. (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was applied to determine the effect of RA and DOX on the proliferation of OVCAR3 and HaCaT cells. Bcl2 expression and epidermal growth factor receptor (EGFR) and western blot analysis were performed to determine the expression levels of the markers. Results: It was determined that RA (IC50 = 437.6 µM) and DOX (IC50 = 0.08 µM) have the ability to inhibit the proliferation of OVCAR3 cells and induce apoptosis in a 72-hour time and dose-dependent manner. Western blot showed that the expression level of Bcl-2 and EGFR in OVCAR3 cells was down-regulated by RA and DOX. Conclusions: Apoptosis in OVCAR3 cells can potentially be induced by RA via the EGFR pathway, and RA may be a potent agent for cancer therapy.

Recidiva de los cánceres superficiales de vejiga posterior a quimioterapia intravesical con doxorrubicina / Recurrence of superficial bladder cancers after in-travesical chemotherapy with doxorubicin

Introducción: El cáncer de vejiga es una enfermedad de gran prevalencia, siendo su mayor problema la tendencia a la recidiva y a la progresión. Para disminuir en lo posible esta recidiva y progresión se han utilizado muchos quimioterapéuticos intravesicales aplicados a lo largo de meses tras la resección transuretral de vejiga con resultados desiguales. La doxorrubicina es un antibiótico antraciclino con actividad antitumoral producido por Streptococcus peucetius var. caesius. Tiene la capacidad de intercalarse con el DNA, afecta muchas de sus funciones e inhibe la síntesis de DNA y RNA, que por vía intravesical actúa evitando la implantación de células tumorales circulantes. Metodología: El estudio será de tipo observacional descriptivo, retrospectivo de corte transversal, comprendido entre el 1 de enero de 2018 y el 31 de enero de 2021 y desarrollado en el Servicio de Urología del Hospital Teodoro Maldonado Carbo. Resultados: Fueron 148 casos analizados. La especificidad del índice fue de 81 %, con un valor predictivo (VP) positivo del 77 % y VP negativo de 68 %. La sensibilidad de la ascitis 85 % y la masa abdominal palpable del 79 %. En las pacientes que presentaron valores de antígeno CA-125 menor a 1000 U/ml, el riesgo de obtener una citorreducción óptima fue OR: 0.15 (IC95% 0.069 ­ 0.307; P: 0.0001); las pacientes que presentaron valores del índice de irresecabilidad entre 1 y 2 puntos versus 3 y 4 fue de OR: 7.04 (IC95% 3.33 -14.87, P: 0.0001). Conclusiones: el cáncer de vejiga es una enfermedad prevalente que presenta desafíos significativos debido a su propensión a la recidiva y progresión. Para abordar este problema, se han utilizado diversos quimioterapéuticos intravesicales después de la resección transuretral de vejiga, aunque con resultados variables. La doxorrubicina, un antibiótico antraciclino con propiedades antitumorales, ha demostrado la capacidad de interferir con el ADN y el ARN, lo que la convierte en una opción valiosa para prevenir la implantación de células tumorales circulantes cuando se administra por vía intravesical.

Introduction: Bladder cancer is a highly prevalent disease; its most significant problem is its tendency to recur and progress. To reduce this recurrence and progression as much as possible, many intravesical chemotherapeutics applied over months after transurethral resection of the bladder have been used with mixed results. Doxorubicin is an anthracycline antibiotic with antitumor activity produced by Streptococcus peucetius var. cesius. It can intercalate with DNA, affects many of its functions, and inhibits the synthesis of DNA and RNA, which acts intravesically to prevent the implantation of circulating tumor cells. Methodology: The study will be of an observational, descriptive, retrospective, cross-sectional type between January 1, 2018, and January 31, 2021, and developed in the Urology Service of the Teodoro Maldonado Carbo Hospital. Results: A total of 148 cases were analyzed. The specificity of the index was 81%, with a positive predictive value (PV) of 77% and a negative PV of 68%. The sensitivity of ascites was 85%, and that of the palpable abdominal mass was 79%. In patients who presented CA-125 antigen values less than 1000 U/ml, the risk of obtaining optimal cytoreduction was OR: 0.15 (95% CI 0.069 - 0.307; P: 0.0001). The patients who presented unresectability index values between 1 and 2 points versus 3 and 4 points were OR: 7.04 (95% CI 3.33 -14.87, P: 0.0001). Conclusions: Bladder cancer is a prevalent disease that presents significant challenges due to its propensity for recurrence and progression. To address this problem, various intravesical chemotherapeutics have been used after transurethral resection of the bladder, although with variable results. Doxorubicin, an anthracycline antibiotic with antitumor properties, has demonstrated the ability to interfere with DNA and RNA, making it a valuable option to prevent the implantation of circulating tumor cells when administered intravesically.

Medição automática de valva mitral a partir de ecocardiograma utilizando processamento digital de imagens / Automatic measurement of the mitral valve based on echocardiography using digital image processing

Fundamento: A avaliação da área valvar mitral por meio da reconstrução multiplano na ecocardiografia tridimensional é restrita a softwares específicos e à experiência dos ecocardiografistas. Eles precisam selecionar manualmente o frame do vídeo que contenha a área de abertura máxima da valva mitral, dimensão fundamental para a identificação de estenose mitral. Objetivo: Automatizar o processo de determinação da área de abertura máxima da valva mitral, por meio da aplicação de Processamento Digital de Imagens (PDI) em exames de ecocardiograma, desenvolvendo um algoritmo aberto com leitura de vídeo no formato avi. Método: Este estudo piloto observacional transversal foi realizado com vinte e cinco exames diferentes de ecocardiograma, sendo quinze com abertura normal e dez com estenose mitral reumática. Todos os exames foram realizados e disponibilizados por dois especialistas, com autorização do Comitê de Ética em Pesquisa, que utilizaram dois modelos de aparelhos ecocardiográficos: Vivid E95 (GE Healthcare) e Epiq 7 (Philips), com sondas multiplanares transesofágicas. Todos os vídeos em formato avi foram submetidos ao PDI através da técnica de segmentação de imagens. Resultados: As medidas obtidas manualmente por ecocardiografistas experientes e os valores calculados pelo sistema desenvolvido foram comparados utilizando o diagrama de Bland-Altman. Observou-se maior concordância entre valores no intervalo de 0,4 a 2,7 cm². Conclusão: Foi possível determinar automaticamente a área de máxima abertura das valvas mitrais, tanto para os casos advindos da GE quanto da Philips, utilizando apenas um vídeo como dado de entrada. O algoritmo demonstrou economizar tempo nas medições quando comparado com a mensuração habitual. (AU)

Background: The evaluation of mitral valve area through multiplanar reconstruction in 3-dimensional echocardiography is restricted to specific software and to the experience of echocardiographers. They need to manually select the video frame that contains the maximum mitral valve opening area, as this dimension is fundamental to identification of mitral stenosis. Objective: To automate the process of determining the maximum mitral valve opening area, through the application of digital image processing (DIP) in echocardiography tests, developing an open algorithm with video reading in avi format. Method: This cross-sectional observational pilot study was conducted with 25 different echocardiography exams, 15 with normal aperture and 10 with rheumatic mitral stenosis. With the authorization of the Research Ethics Committee, all exams were performed and made available by 2 specialists who used 2 models of echocardiographic devices: Vivid E95 (GE Healthcare) and Epiq 7 (Philips), with multiplanar transesophageal probes. All videos in avi format were submitted to DIP using the image segmentation technique. Results: The measurements obtained manually by experienced echocardiographers and the values calculated by the developed system were compared using a Bland-Altman diagram. There was greater agreement between values in the range from 0.4 to 2.7 cm². Conclusion: It was possible to automatically determine the maximum mitral valve opening area, for cases from both GE and Philips, using only 1 video as input data. The algorithm has been demonstrated to save time on measurements when compared to the usual method. (AU)

Can pumpkin save us of doxorubicin induced cardiotoxicity? / ¿Puede la calabaza salvarnos de la cardiotoxicidad inducida por doxorrubicina?

SUMMARY: Doxorubicin (DOX) is one of the drugs necessary for the treatment of the 10 most common types of cancer. The leading adverse effect limiting clinical use of DOX is cardiotoxicity. Given that literature data indicate a protective role of carotenoids in doxorubicin-induced toxicity, in our study we compared the cardioprotective effect of a mixture of pumpkin carotenoids and a commercially available antioxidant preparation. Animals were distributed in 8 groups (Control - S; NADES - N; Doxorubicin - Dox; Carotenoids - Car; CardiofortIN - CF; NADES-Doxorubicin - N-Dox; Carotenoids-Doxorubicin - Car-Dox; CardiofortIN-Doxorubicin - CF-Dox). Histological sections were stained with the hematoxylin-eosin (HE) and analyzed for the presence of myocardial damage by doxorubicin damage score (DDS). From the heart tissue homogenate were determined the intensity of lipid peroxidation and specific antioxidative enzyme activity (superoxide dismutase; catalase; glutathione S-transferase; glutathione peroxidase). In Car-DOX and CF-DOX groups, lipid peroxidation is significantly reduced compared to DOX group. Pretreatment of animals with carotenoids and in lesser extent with CardiofortIN led to higher antioxidative enzymes activity, compared to DOX group. Pretreated with carotenoids, only 50 % of animals had some degree of myocardial damage, and no animals had extensive damage. CardiofortIN pretreatment showed less protective effect. Pretreatment with carotenoid extract, reduced DDS significantly, so Car-DOX group has changes equivalent to mild myocardial damage. Although CardiofortIN pretreatment lowered DDS score values, animals still had moderate level of myocardium damage. This in vivo study and its findings indicate that carotenoids extracted from pumpkin may be a promising cardioprotective agent against doxorubicin induced cardiotoxicity, at least in part mediated through inhibition of DOX-induced oxidative stress.

La doxorrubicina (DOX) es uno de los fármacos necesarios para el tratamiento de los 10 tipos más comunes de cáncer. El principal efecto adverso que limita el uso clínico de DOX es la cardiotoxicidad. Debido a que los datos de la literatura indican un papel protector de los carotenoides en la toxicidad inducida por doxorrubicina, en nuestro estudio comparamos el efecto cardioprotector de una mezcla de carotenoides de calabaza y una preparación antioxidante disponible comercialmente. Los animales se distribuyeron en 8 grupos (Control - S; NADES - N; Doxorrubicina - Dox; Carotenoides - Car; CardiofortIN - CF; NADES-Doxorrubicina - N-Dox; Carotenoides-Doxorrubicina - Car-Dox; CardiofortIN- Doxorrubicina - CF-Dox). Las secciones histológicas se tiñeron con hematoxilina-eosina (HE) y se analizaron para detectar la presencia de daño miocárdico mediante la puntuación de daño por doxorrubicina (DDS). A partir del homogeneizado de tejido cardíaco se determinó la intensidad de la peroxidación lipídica y la actividad enzimática antioxidante específica (superóxido dismutasa, catalasa, glutatión S-transferasa, glutatión peroxidasa). En los grupos Car-DOX y CF-DOX, la peroxidación lipídica se redujo significativamente en comparación con el grupo DOX. El pre tratamiento de los animales con carotenoides y, en menor medida, con CardiofortlN condujo a una mayor actividad de las enzimas antioxidantes, en comparación con el grupo DOX. Al ser pre tratados con carotenoides, solo el 50 % de los animales tenían algún grado de daño miocárdico y ningún animal tenía daño extenso. El pre tratamiento con CardiofortIN mostró un efecto protector menor. El pre tratamiento con extracto de carotenoides redujo significativamente el DDS, por lo que el grupo Car-DOX mostró cambios equivalentes a un daño miocárdico leve. Aunque el pre tratamiento con CardiofortIN redujo los valores de la puntuación DDS, los animales aún tenían un nivel moderado de daño al miocardio. Este estudio in vivo y sus hallazgos indican que los carotenoides extraídos de la calabaza pueden ser un agente cardioprotector prometedor contra la cardiotoxicidad inducida por doxorrubicina, al menos en parte mediada por la inhibición del estrés oxidativo inducido por DOX.

Ephedra Herb extract ameliorates adriamycin-induced nephrotic syndrome in rats via the CAMKK2/AMPK/mTOR signaling pathway / 中国天然药物

This study aimed to investigate the effect and mechanisms of Ephedra Herb (EH) extract on adriamycin-induced nephrotic syndrome (NS), providing an experimental basis for the clinical treatment of NS. Hematoxylin and eosin staining, creatinine, urea nitrogen, and kidn injury molecule-1 were used to evaluate the activities of EH extract on renal function. The levels of inflammatory factors and oxidative stress were detected by kits. The levels of reactive oxygen species, immune cells, and apoptosis were measured by flow cytometry. A network pharmacological approach was used to predict the potential targets and mechanisms of EH extract in the treatment of NS. The protein levels of apoptosis-related proteins and CAMKK2, p-CAMKK2, AMPK, p-AMPK, mTOR and p-mTOR in the kidneys were detected by Western blot. The effective material basis of EH extract was screened by MTT assay. The AMPK pathway inhibitor (compound C, CC) was added to investigate the effect of the potent material basis on adriamycin-induced cell injury. EH extract significantly improved renal injury and relieve inflammation, oxidative stress, and apoptosis in rats. Network pharmacology and Western blot results showed that the effect of EH extract on NS may be associated with the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine significantly ameliorated adriamycin-induced NRK-52e cell injury. Methylephedrine also significantly improved the phosphorylation of AMPK and mTOR, which were blocked by CC. In sum, EH extract may ameliorate renal injury via the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine may be one of the material bases of EH extract.

Effect of Nucleolin on Lymphoma Proliferation by Regulating Thymidine Kinase 1 / 中国实验血液学杂志

OBJECTIVE@#To investigate the mechanism of nucleolin (NCL) involved in lymphoma proliferation by regulating thymidine kinase 1 (TK1).@*METHODS@#Twenty-three patients with diffuse large B-cell lymphoma (DLBCL) were selected and divided into initial treatment group (14 cases) and relapsed/refractory group (9 cases). Serum TK1 and C23 protein in peripheral blood mononuclear cells were detected. Cell models of CA46-NCL-KD (CA46-NCL-knockdown) and CA46-NCL-KNC (CA46-NCL-knockdown negative control) were established by lentivirus vector mediated transfection in Burkitt lymphoma cell line CA46. The half maximal inhibitory concentration (IC50) of CA46-NCL-KD, CA46-NCL-KNC, and CA46 to adriamycin were detected by cell proliferation assay (MTS). The expression of NCL mRNA and protein in CA46-NCL-KD and CA46-NCL-KNC cells were dectected by Q-PCR and Western blot, respectively. The cell cycle of CA46-NCL-KD, CA46-NCL-KNC, and CA46 cells were detected by flow cytometry. The expression of TK1 protein in CA46-NCL-KD and CA46-NCL-KNC cells was detected by an enhanced chemiluminescence (ECL) dot blot assay.@*RESULTS@#The level of serum TK1 in the initial treatment group was 0.43(0-30-1.01) pmol/L, which was lower than 10.56(2.19-14.99) pmol/L in the relapsed/refractory group (P<0-01), and the relative expression level of NCL protein in peripheral blood was also significantly lower. The IC50 of CA46-C23-KD cells to adriamycin was (0.147±0.02) μg/ml, which was significantly lower than (0.301±0.04) μg/ml of CA46-C23-KNC cells and (0.338±0.05) μg/ml of CA46 cells (P<0.05). Compared with CA46-NCL-KNC cells, the expression of NCL mRNA and protein, TK1 protein decreased in CA46-NCL-KD cells, and the proportion of S phase and G2/M phase also decreased, while G0/G1 phase increased in cell cycle.@*CONCLUSION@#The increased expression of NCL in DLBCL and CA46 cells indicates low sensitivity to drug. NCL may participate in regulation of lymphoma proliferation by affecting TK1 expression, thereby affecting the drug sensitivity.

The Role and Mechanism of MiR-451 in Multidrug Resistance of Leukemia Cell Line K562/A02 / 中国实验血液学杂志

OBJECTIVE@#To detect the differential expressions of miR-451, ABCB1 and ABCC2 in drug-sensitive leukemia cell line K562 and drug-resistant cell line K562/A02, and explore the regulatory relationship between miR-451 and the expressions of ABCB1 and ABCC2 , and the mechanism of miR-451 involved in drug resistance in leukemia.@*METHODS@#CCK-8 assay was used to detect the drug resistance of K562/A02 and K562 cells. Quantitative Real-time PCR (qRT-PCR) was used to verify the differential expressions of miR-451 in K562 and K562/A02 cells. MiR-451 mimic and negative control (miR-NC), miR-451 inhibitor and negative control (miR-inNC) were transfected into K562 and K562/A02 cells respectively, then qRT-PCR and Western blot were used to detect the expression levels of mRNA and protein of ABCB1 and ABCC2 in K562 and K562/A02 cells and the transfected groups.@*RESULTS@#The drug resistance of K562/A02 cells to adriamycin was 177 times higher than that of its parent cell line K562. Compared with K562 cells, the expression of miR-451 in K562/A02 cells was significantly higher (P <0.001), and the mRNA and protein expression levels of ABCB1 and ABCC2 in K562/A02 cells were significantly higher than those in K562 cells (P <0.001). After transfected with miR-451 inhibitor, the expression of miR-451 was significantly down-regulated in K562/A02 cells (P <0.001), the sensitivity to chemotherapy drugs was significantly enhanced (P <0.05), and the mRNA and protein expressions of ABCB1 and ABCC2 were significantly decreased (P <0.01). After transfected with miR-451 mimic, the expression of miR-451 was significantly upregulated in K562 cells (P <0.001), and the mRNA and protein expressions of ABCB1 and ABCC2 were significantly increased (P <0.01).@*CONCLUSION@#There are significant differences in the expressions of miR-451, ABCB1 and ABCC2 between the drug-sensitive leukemia cell line K562 and drug-resistant cell line K562/A02, which suggests that miR-451 may affect the drug resistance of leukemia cells by regulating the expression of ABCB1 and ABCC2.

Effect and Mechanism of Atorvastatin on Reversing Drug Resistance in Leukemia by Regulating Glycolysis through PTEN/mTOR Pathway / 中国实验血液学杂志

OBJECTIVE@#To investigate the influence and mechanism of atorvastatin on glycolysis of adriamycin resistant acute promyelocytic leukemia (APL) cell line HL-60/ADM.@*METHODS@#HL-60/ADM cells in logarithmic growth phase were treated with different concentrations of atorvastatin, then the cell proliferation activity was measured by CCK-8 assay, the apoptosis was detected by flow cytometry, the glycolytic activity was checked by glucose consumption test, and the protein expressions of PTEN, p-mTOR, PKM2, HK2, P-gp and MRP1 were detected by Western blot. After transfection of PTEN-siRNA into HL-60/ADM cells, the effects of low expression of PTEN on atorvastatin regulating the behaviors of apoptosis and glycolytic metabolism in HL-60/ADM cells were further detected.@*RESULTS@#CCK-8 results showed that atorvastatin could inhibit the proliferation of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.872, r=0.936), and the proliferation activity was inhibited most significantly when treated with 10 μmol/L atorvastatin for 24 h, which was decreased to (32.3±2.18)%. Flow cytometry results showed that atorvastatin induced the apoptosis of HL-60/ADM cells in a concentration-dependent manner (r=0.796), and the apoptosis was induced most notably when treated with 10 μmol/L atorvastatin for 24 h, which reached to (48.78±2.95)%. The results of glucose consumption test showed that atorvastatin significantly inhibited the glycolytic activity of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.915, r=0.748), and this inhibition was most strikingly when treated with 10 μmol/L atorvastatin for 24 h, reducing the relative glucose consumption to (46.53±1.71)%. Western blot indicated that the expressions of p-mTOR, PKM2, HK2, P-gp and MRP1 protein were decreased in a concentration-dependent manner (r=0.737, r=0.695, r=0.829, r=0.781, r=0.632), while the expression of PTEN protein was increased in a concentration-dependent manner (r=0.531), when treated with different concentrations of atorvastatin for 24 h. After PTEN-siRNA transfected into HL-60/ADM cells, it showed that low expression of PTEN had weakened the promoting effect of atorvastatin on apoptosis and inhibitory effect on glycolysis and multidrug resistance.@*CONCLUSION@#Atorvastatin can inhibit the proliferation, glycolysis, and induce apoptosis of HL-60/ADM cells. It may be related to the mechanism of increasing the expression of PTEN, inhibiting mTOR activation, and decreasing the expressions of PKM2 and HK2, thus reverse drug resistance.

Dose-adjusted EPOCH-R vs. R-CHOP in frontline management of Waldeyer's ring diffuse large B-cell lymphoma: a retrospective study from a single institution / 中华医学杂志(英文版)

BACKGROUND@#To compare the efficacy and safety of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL) at a single institution.@*METHODS@#This retrospective study included 115 newly diagnosed patients with WR-DLBCL, of whom 68 patients received R-CHOP, and 47 patients received DA-EPOCH-R as their first-line treatment. The baseline features of the two groups were well balanced using a 1:1 propensity score matching method, and a total of 84 cases were obtained, including respective 42 cases in the R-CHOP and DA-EPOCH-R groups, for further survival and prognosis analysis. The primary objectives included progression-free survival (PFS) and overall survival (OS).@*RESULTS@#During a median follow-up of 45 months, there were nine (21.4%) deaths in the R-CHOP group and two (4.8%) in the DA-EPOCH-R group. Kaplan-Meier analysis showed statistically significant improvements in PFS and OS in patients with DA-EPOCH-R compared with those treated with R-CHOP (log-rank test, P  = 0.025 and P  = 0.035, respectively). The 2-year PFS and OS rates in the DA-EPOCH-R group were 90.1% (95% confidence interval [CI]: 81.4-99.8%) and 95.2% (95% CI: 89.0-100.0%), respectively, and 80.5% (95% CI: 69.3-93.6%) and 90.5% (95% CI: 52.8-99.8%) in the R-CHOP group. Patients without B symptoms and elevated lactate dehydrogenase levels had a higher PFS in the DA-EPOCH-R group, with P values of 0.038 (hazard ratio [HR]: 0.11; 95% CI: 0.01-0.88) and 0.042 (HR: 0.19; 95% CI: 0.04-0.94), respectively. There were no statistically significant differences in clinical responses and treatment-related toxicities between the two groups.@*CONCLUSION@#Compared with patients received R-CHOP, those treated by DA-EPOCH-R had superior PFS, OS, and controlled toxicity in patients with WR-DLBCL.

Single-center study of different treatment for advanced or unresectable angiosarcoma patients / 中华肿瘤杂志

Objective: To evaluate the efficacy and safety of different medical treatment in advanced or unresectable angiosarcoma. Methods: This study was a single-center retrospective clinical study. Fifty-five advanced or unresectable angiosarcoma patients treated in Sun-Yat Sen University Cancer Center from January 2005 to August 2020 were enrolled. There were 34 patients who received first-line doxorubicin-based chemotherapy (doxorubicin group), 12 patients received first-line doxorubicin or liposome doxorubicin plus paclitaxel or albumin bound paclitaxel chemotherapy (combination therapy group), and 4 patients received first-line paclitaxel-based treatment (paclitaxel group). There were 6 patients who received anti-angiogenesis targeted therapy, another 2 patients received anti-PD-1 antibody plus anti-angiogenesis targeted therapy. Targeted therapy and immunotherapy plus targeted therapy included 5 cases of first-line therapy and 3 cases of second-line therapy. The therapeutic effect was evaluated by RECIST 1.1 standard. The adverse reactions were evaluated by CTCAE4.0 standard. Kaplan-Meier survival analysis was evaluated with Log rank test. Cox proportional hazard model was used to analyze the influencing factors. Results: There were 18 patients achieved partial response (PR) in 34 patients in the doxorubicin group, median progression-free survival (mPFS) was 4.5 months, and median overall survival (mOS) was 15 months. Four patients achieved PR in 12 patients in the combination therapy group, mPFS and mOS were 4 months and 19 months. Two patients achieved PR in 4 patients in the paclitaxel group, mPFS and mOS were 3 months and 9 months. However, only 1 in 6 patients achieved PR for anti-angiogenesis targeted therapy, mPFS and mOS were 3 months and 16 months. Two patients who received anti-PD-1 immunotherapy combined with anti-angiogenesis targeted therapy acquired PR for 17 months and more than 16 months. Median PFS (7.5 months) were longer in those with primary liver, lung and spleen angiosarcoma than in those with other primary site (3.0 months, P=0.028). The mOS (20 months) was longer in females than that in males (12 months, P=0.045). Primary tumor site, sex, age and treatment were not independent prognostic factors for angiosarcoma patients (P>0.05). Grade 3-4 cardiac toxicity was found in 2 patients in the combination therapy group. Conclusions: Doxorubicin-based and paclitaxel-based chemotherapy are the most important treatment for advanced angiosarcoma. Potential efficacy for targeted therapy combined with anti-PD-1 immunotherapy are showed in some patients with long duration of response and moderate adverse event.

Clinicopathologic characteristics and prognostic analysis of testicular diffuse large B-cell lymphoma / 中华血液学杂志

Objective: To analyze the clinicopathologic characteristics and prognosis of testicular diffuse large B-cell lymphoma (DLBCL) . Methods: A retrospective analysis was performed on 68 patients with testicular DLBCL admitted to Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine from October 2001 to April 2020. The gene mutation profile was evaluated by targeted sequencing (55 lymphoma-related genes) , and prognostic factors were analyzed. Results: A total of 68 patients were included, of whom 45 (66.2% ) had primary testicular DLBCL and 23 (33.8% ) had secondary testicular DLBCL. The proportion of secondary testicular DLBCL patients with Ann Arbor stage Ⅲ-Ⅳ (P<0.001) , elevated LDH (P<0.001) , ECOG score ≥ 2 points (P=0.005) , and IPI score 3-5 points (P<0.001) is higher than that of primary testicular DLBCL patients. Sixty-two (91% ) patients received rituximab in combination with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) -based first-line regimen, whereas 54 cases (79% ) underwent orchiectomy prior to chemotherapy. Patients with secondary testicular DLBCL had a lower estimated 5-year progression-free survival (PFS) rate (16.5% vs 68.1% , P<0.001) and 5-year overall survival (OS) rate (63.4% vs 74.9% , P=0.008) than those with primary testicular DLBCL, and their complete remission rate (57% vs 91% , P=0.003) was also lower than that of primary testicular DLBCL. The ECOG scores of ≥2 (PFS: P=0.018; OS: P<0.001) , Ann Arbor stages Ⅲ-Ⅳ (PFS: P<0.001; OS: P=0.018) , increased LDH levels (PFS: P=0.015; OS: P=0.006) , and multiple extra-nodal involvements (PFS: P<0.001; OS: P=0.013) were poor prognostic factors in testicular DLBCL. Targeted sequencing data in 20 patients with testicular DLBCL showed that the mutation frequencies of ≥20% were PIM1 (12 cases, 60% ) , MYD88 (11 cases, 55% ) , CD79B (9 cases, 45% ) , CREBBP (5 cases, 25% ) , KMT2D (5 cases, 25% ) , ATM (4 cases, 20% ) , and BTG2 (4 cases, 20% ) . The frequency of mutations in KMT2D in patients with secondary testicular DLBCL was higher than that in patients with primary testicular DLBCL (66.7% vs 7.1% , P=0.014) and was associated with a lower 5-year PFS rate in patients with testicular DLBCL (P=0.019) . Conclusion: Patients with secondary testicular DLBCL had worse PFS and OS than those with primary testicular DLBCL. The ECOG scores of ≥2, Ann Arbor stages Ⅲ-Ⅳ, increased LDH levels, and multiple extra-nodal involvements were poor prognostic factors in testicular DLBCL. PIM1, MYD88, CD79B, CREBBP, KMT2D, ATM, and BTG2 were commonly mutated genes in testicular DLBCL, and the prognosis of patients with KMT2D mutations was poor.

Doxorubicin cardiotoxicity and Camellia sinensis cardioprotection determined by speckle-tracking echocardiography

Abstract Doxorubicin (Dox) is a medication used in the treatment of cancerous tumors and hematologic malignancies with potentially serious side effects, including the risk of cardiotoxicity. Flavonoids are plant metabolites with antioxidant properties and can be extracted from Camellia sinensis (CS). The aim of this study is to evaluate the possible cardioprotective effect of CS against injuries induced by Dox in rats. A total of 32 animals were distributed into four groups: (1) control - intraperitoneal injection (I.P.) of 0.5 mL saline weekly and 1.0 mL water by gavage daily; (2) CS - 0.5 mL saline I.P. weekly and 200 mg/kg CS by gavage daily; (3) Dox - 5.0 mg/kg Dox I.P. weekly and 1.0 mL water by gavage daily; and (4) Dox+CS -5.0 mg/kg Dox I.P. weekly and 200 mg/kg CS by gavage daily. Clinical examinations, blood profiles, electrocardiograms, echocardiograms, and histological analyses of hearts were performed over 25 days. The animals in the Dox group showed changes in body weight and in erythrogram, leukogram, electrocardiography, and echocardiography readings. However, animals from the dox+CS group had significantly less change in body weight, improved cardiac function, and showed more preserved cardiac tissue. This study demonstrated that CS prevents dox-induced cardiotoxicity, despite enhancing the cytotoxic effect on blood cells

Biochemical and histopathological evaluations of chronic renal failure rats treated with pluripotent human stem cells

Abstract Regeneration of damaged kidney cells using stem cells is the current research approach in the treatment of chronic renal failure (CRF). In the present study, the histopathological and biochemical techniques were used to evaluate stem cells' (SCs) role in treatment of CRF. Sixty-four rats were divided into eight groups. Group I (GI): rats were injected with doxorubicin (15 mg/kg) to initiate CRF. GII-GVII: rats were injected with doxorubicin and treated with SCs (1x106 MSCs or/and 2x104 HSCs/rat) with/without growth factors extract (200 µL/rat) and/or immunosuppressor (cyclosporine A, 5 mg/kg/day). GVIII: rats treated with PBS (100 µL/kg/day). Levels of creatinine, urea and uric acid were increased in rats sera after injection with doxorubicin, while blood electrolyte levels of Na, K, P and Mg were decreased. Also, histopathological abnormalities such as hyalinized blood vessels, degenerated hyalinized glomerulus tubules and cell debris in the lumen and degeneration of renal tissues were observed in these rats. After treatment with SCs, all these parameters restore their normal values with regeneration of the damaged cells as demonstrated in histopathology of the treated groups. It can be concluded that, the use of SCs in treatment of kidney diseases is a promising approach and needs more efforts.

Sarcoma de Kaposi anoperineal: uma rara apresentação / Perineal Kaposi's Sarcoma: a rare presentation

O sarcoma de Kaposi é uma neoplasia maligna associada à infecção pelo herpes vírus humano 8 em doentes imunossupressos. O sarcoma de Kaposi Epidêmico é o tipo epidemiológico mais frequente e afeta indivíduos VIH-positivos. A região anoperineal é raramente envolvida e as lesões suspeitas devem ser biopsiadas para confirmação histológica. A base do tratamento é a restauração imune do doente. Relatamos o caso de um jovem, com diagnóstico recente de infeção pelo VIH, sem tratamento, que foi admitido no serviço de infectologia apresentando sintomas constitucionais, adenomegalias inguinais e extensa lesão verrucosa e ulcerada na região anoperineal. As biópsias confirmaram o diagnóstico de sarcoma de Kaposi e o doente iniciou terapia antirretroviral e quimioterapia. Houve recuperação clínica, regressão das lesões e desaparecimento das adenomegalias. Este relato objetiva alertar as equipes médicas no sentido de se incluir o sarcoma de Kaposi no diagnóstico diferencial das lesões que afetam a região anoperineal.

Kaposi's sarcoma is a malignant neoplasm associated with human herpesvirus 8 infection in immunocompromised patients. Epidemic Kaposi's sarcoma is the most common epidemiological type and affects HIV-positive patients. Perineal involvement is rare, and suspicious lesions should be biopsied to confirm histological diagnosis. Treatment consists of restoring the patient's immune system. We report the case of a young patient recently diagnosed with HIV, without treatment, who was admitted to the Department of Infectious Diseases with nonspecific symptoms, inguinal lymphadenopathy, and an extensive verrucous ulcerated lesion in the perineal region. Biopsy confirmed the diagnosis of Kaposi's sarcoma, and the patient was started on antiretroviral therapy and chemotherapy. Clinical recovery was achieved, with lesion reduction and inguinal adenopathy resolution. This case report aims to encourage physicians to include Kaposi's sarcoma in the differential diagnosis of perineal lesions.

Protective effects of psoralen polymer lipid nanoparticles on doxorubicin - induced myocardial toxicity

Abstract Doxorubicin (DOX) induced myocardial toxicity may limit its therapeutic use in clinic. Psoralen (PSO), a major active tricyclic furocoumarin extracted from Psoralea corylifolia, is widely used as an antineoplastic agent in treatment of leukemia and other cancers. This study is aim to find the protective effect of psoralen polymer lipid nanoparticles (PSO-PLN) on doxorubicin-induced myocardial toxicity in mice. The model of myocardial toxicity induced by DOX was established. The experiment was divided into 6 groups: normal saline group, DOX + Sulfotanshinone Sodium, DOX + PSO-PLN (3 mg/kg), DOX + PSO-PLN (6 mg/kg), DOX + PSO-PLN (9 mg/ kg), DOX group. DOX alone treated mice lead to a significant decrease in the body weight, heart weight, and increase in the serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and malondialdehyde (MDA) markers of cardiotoxicity. However, DOX reduced glutathione (GSH) content and activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPX), were recovered by PSO-PLN. And PSO-PLN also decreased markers of cardiotoxicity in the serum. Western blotting data showed that the protective effects of PSO-PLN might be mediated via regulation of protein kinase A (PKA) and p38. Our study suggest that PSO-PLN possesses antioxidant activities, inactivating PKA and p38 effect, which in turn protect the heart from the DOX-induced cardiotoxicity.

Effects of photobiomodulation (660 nm laser) on anthracycline extravasation: An experimental study / Efeitos da fotobiomodulação (laser 660 nm) no extravasamento de antraciclina: estudo experimental / Efectos de la fotobiomodulación (láser de 660 nm) sobre la extravasación de antraciclinas: estudio experimental

Abstract Objective: to investigate the effect of using different agents (topical hyaluronidase, photobiomodulation, and the association of photobiomodulation with topical hyaluronidase) in preventing the formation of lesions caused by doxorubicin extravasation, as well as in the reduction of lesions formed by extravasation of this drug. Method: a quasi-experimental study conducted with 60 Wistar rats, randomized into four groups with 15 animals each. Group 1 (Control); Group 2 (Hyaluronidase); Group 3 (Photobiomodulation); and Group 4 (Hyaluronidase + Photobiomodulation). A wound was induced by applying 1 mg of doxorubicin to the subcutaneous tissue of the back of the animals. The concentration of topical hyaluronidase was 65 turbidity units/g and the energy employed was 1 joule of 100 mW red laser per square centimeter. With macroscopic evaluation every two days for 28 days, the following variables were observed: skin integrity, presence of blisters, hyperemia, exudate, bleeding, edema, crust, peeling and granulation tissue. Results: the animals from the groups subjected to photobiomodulation obtained better results in the assessment of the following variables: bleeding, hyperemia, exudate, intact skin and edema. Conclusion: it was evidenced that the association of photobiomodulation with topical hyaluronidase was effective in reducing the local effects and assisted in the wound healing process, and that PBM alone was able to prevent appearance of lesions.

Resumo Objetivo: investigar o efeito do uso de diferentes agentes (hialuronidase tópica, fotobiomodulação e da associação da fotobiomodulação com a hialuronidase tópica) na prevenção de formação de lesões causadas por extravasamento de doxorrubicina bem como na diminuição de lesões formadas pelo extravasamento desta droga. Método: estudo experimental com 60 ratos Wistar, randomizados em quatro grupos de 15 animais. Grupo 1 (Controle); Grupo 2 (Hialuronidase); Grupo 3 (Fotobiomodulação) e Grupo 4 (Hialuronidase + Fotobiomodulação). Induziu-se ferida aplicando 1 mg de doxorrubicina no subcutâneo do dorso dos animais. A concentração da hialuronidase tópica foi de 65 unidades de turbidez/g, a energia empregada foi de 1 joule de laser vermelho 100 mW por centímetro quadrado. Com avaliação macroscópica a cada dois dias por 28 dias, observou-se as variáveis: integridade da pele, presença de flictema, hiperemia, exsudato, sangramento, edema, crosta, descamação e tecido de granulação. Resultados: os animais dos grupos com fotobiomodulação obtiveram melhores resultados na avaliação das variáveis: sangramento, hiperemia, exsudato, pele íntegra e edema. Conclusão: evidenciou-se que a associação da fotobiomodulação com a hialuronidase tópica foi eficaz na diminuição dos efeitos locais e auxiliou no processo de cicatrização da ferida e que a FBM isolada foi capaz de prevenir o aparecimento de lesões.

Resumen Objetivo: investigar el efecto del uso de diferentes agentes (hialuronidasa tópica, fotobiomodulación y la combinación de fotobiomodulación y hialuronidasa tópica) en la prevención de la formación de lesiones causadas por la extravasación de doxorrubicina y en la reducción de las lesiones formadas por la extravasación de ese fármaco. Método: estudio experimental con 60 ratas Wistar, distribuidos aleatoriamente en cuatro grupos de 15 animales. Grupo 1 (Control); Grupo 2 (Hialuronidasa); Grupo 3 (Fotobiomodulación) y Grupo 4 (Hialuronidasa + Fotobiomodulación). La herida se indujo aplicando 1 mg de doxorrubicina por vía subcutánea en el lomo de los animales. La concentración de hialuronidasa tópica fue de 65 unidades de turbidez/g, la energía utilizada fue de 1 joule de láser rojo de 100 mW por centímetro cuadrado. En la evaluación macroscópica cada dos días durante 28 días se observaron las siguientes variables: piel intacta, presencia de flictena, hiperemia, exudado, sangrado, edema, costra, descamación y tejido de granulación. Resultados: los animales de los grupos con fotobiomodulación obtuvieron mejores resultados en la evaluación de las variables: sangrado, hiperemia, exudado, piel intacta y edema. Conclusión: se demostró que la combinación de fotobiomodulación y hialuronidasa tópica fue eficaz para reducir los efectos locales y ayudó en el proceso de cicatrización de heridas y que la FBM por sí sola previno la aparición de lesiones.

Strain longitudinal global como preditor de cardiotoxicidade induzida por quimioterapia / Global longitudinal strain as predictor of chemotherapy-induced cardiotoxicity

Fundamento: A cardiotoxicidade induzida por quimioterapia (CiC) é uma complicação importante entre os pacientes que recebem antraciclinas. Biomarcadores e parâmetros de imagem têm sido estudados por sua capacidade de identificar pacientes com risco de desenvolver essa complicação. O strain longitudinal global do ventrículo esquerdo (SLG-VE) tem sido descrito como um parâmetro sensível para detectar disfunção sistólica, mesmo na presença de fração de ejeção do ventrículo esquerdo (FEVE) preservada. Objetivo: avaliar o papel do SLG-VE como preditor de CiC. Métodos: O presente estudo consiste em uma análise post-hoc do estudo CECCY (Carvedilol for Prevention of ChemotherapyRelated Cardiotoxicity [Carvedilol para Prevenção da Cardiotoxicidade Relacionada à Quimioterapia]), que avaliou a prevenção primária de cardiotoxicidade com carvedilol durante quimioterapia com doxorrubicina em uma população com câncer de mama. Definiu-se cardiotoxicidade como uma redução >10% na FEVE. O SLG-VE foi obtido antes da quimioterapia em pacientes sem doença cardiovascular prévia ou anormalidades no ecocardiograma. Resultados: Trinta e um pacientes submetidos a estudo ecocardiográfico completo incluindo avaliação de SLG-VE antes da quimioterapia foram incluídos nesta análise. Um SLG-VE absoluto <16,9% antes da quimioterapia mostrou 100% de sensibilidade e 73% de especificidade para predizer cardiotoxicidade (AUC=0,85; IC 95% 0,680­0,959, p<0,001). Nesta população, os valores de FEVE antes da quimioterapia não foram preditores de CiC (IC 95% 0,478 a -0,842, p=0,17). A associação de baixos níveis séricos de SLG-VE (<17%) e BNP (>17 pg/mL) dois meses após a quimioterapia aumentou a precisão para detectar CiC de início precoce (100% de sensibilidade, 88% de especificidade, AUC=0,94; IC 95% 0,7810,995, p<0,0001). Conclusões: Nossos dados sugerem que o SLG-VE é um possível preditor de cardiotoxicidade induzida por quimioterapia. São necessários estudos maiores para confirmar a relevância clínica desse parâmetro ecocardiográfico nesse cenário clínico. (AU)

Background: Chemotherapy-induced cardiotoxicity (ChC) is an important complication among patients receiving anthracyclines. Biomarkers and imaging parameters have been studied for their ability to identify patients at risk of developing ChC. Left ventricular global longitudinal strain (LV-GLS) is a sensitive parameter for detecting systolic dysfunction despite the presence of preserved left ventricular ejection fraction (LVEF). Objective: To evaluate the role of the LV-GLS as a predictor of ChC. Methods: This was a post-hoc analysis of the Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity trial, which evaluated the primary prevention of cardiotoxicity with carvedilol during doxorubicin chemotherapy in a population of patients with breast cancer. Cardiotoxicity was defined as a reduction ≥10% in LVEF. LV-GLS was determined before chemotherapy in patients with no prior cardiovascular disease or echocardiogram abnormalities. Results: Thirty-one patients for whom a complete echocardiography study including measurement of LV-GLS was performed before chemotherapy were included in this analysis. An absolute LV-GLS<16.9% before chemotherapy showed 100% sensitivity and 73% specificity for predicting cardiotoxicity (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.680­0.959; p<0.001). In this population, LVEF values before chemotherapy did not predict ChC (95% CI, 0.478 to -0.842; p=0.17). The association of low LV-GLS (<17%) and brain-type natriuretic peptide serum levels (>17 pg/mL) at 2 months after chemotherapy increased the accuracy for detecting early-onset ChC (100% sensitivity, 88% specificity; AUC, 0.94; 95% CI, 0.781­0.995; p<0.0001). Conclusions: Our data suggest that LV-GLS is a potential predictor of ChC. Larger studies are needed to confirm its clinical relevance in this clinical setting. (AU)

Is paclitaxel less cardiotoxic in the treatment of breast cancer before or after doxorubicin? / Qual estratégia terapêutica é menos cardiotóxica no tratamento do câncer de mama: uso de paclitaxel antes ou depois da doxorrubicina?

Background: The combination of doxorubicin (DOX) with paclitaxel (PTX) effectively treats breast cancer (BC). However, DOX-associated cardiotoxicity (CTX) is aggravated by the use of PTX. Consensus is lacking about which drug sequence involves the most CTX. Objectives: To evaluate whether DOX followed by PXT or the reverse sequence has the greatest cardiotoxic potential in the treatment of BC. Methods: Prospective study of women with primary BC who received four cycles of DOX and 12 infusions of PTX. Participants were divided into Group 1 (G1; PXT before DOX) and Group 2 (G2; DOX before PXT) at the discretion of the oncologist. CTX was defined as an absolute reduction in left ventricular ejection fraction (LVEF) > 10% to a value <53%. Patients underwentclinical evaluations and echocardiography before treatment (Phase 1) and one year after treatment (Phase 2). Results: Sixty-nine women were evaluated: 19 in G1 and 50 in G2. The groups had similar clinical characteristics. The doses of radiation, DOX, and PTX used were similar. Eight (11.6%) patients developed CTX: two (10.5%) in G1 and six (12.0%) in G2 (p=0.62). The mean LVEF was similar between groups in Phase 1 (G1=65.1±3.5%; G2=65.2±3.9%; p=0.96), with a significant reduction noted after one year in both groups: G1=61.4±8.1% (p=0.021) and G2=60.8±7.6% (p<0,001). Although lower, mean LVEF remained similar between groups after Phase 2 (p=0.79). Conclusions: In women with BC who underwent chemotherapy, the incidence of CTX at the end of the first year of treatment was similar regardless of whether DOX was used before or after PTX. (AU)

Pathological characteristics and clinical prognosis of nodular sclerosis grade 2 of classic Hodgkin's lymphoma / 中华肿瘤杂志

Objective: To investigate the pathological characteristics and clinical prognosis of nodular sclerosis grade 2 of classic Hodgkin's lymphoma (cHL-NS2) in our cancer center. Methods: A retrospective collection of 23 cases of cHL-NS2 admitted in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from July 2008 to April 2019 was performed. Fifty-five cases of nodular sclerosis grade 1 of classical Hodgkin's lymphoma (cHL-NS1) during the same period were selected as control group. Survival curves were plotted using the Kaplan-Meier method, and Cox regression model was used to analyze the influencing factors for survival. Results: The median age of 23 cases of cHL-NS2 was 30 years old. Five cases had extra nodal invasion, and 19 cases were Ⅰ-Ⅱ stage based on Ann Arbor system. The pathological morphology of cHL-NS2 showed that the lymph node structure was completely destroyed and was divided into nodules by thick collagen. The tumor cells in the nodules were abundant and proliferated in sheets. The boundaries between the tumor cells were not clear. The incidence of tumor necrosis in cHL-NS2 was 43.5% (10/23), which was significantly higher than 18.2% (10/55) in cHL-NS1 (P=0.040). The 3-year progression-free survival (PFS) rate of patients in the cHL-NS2 group was 58.1%, which was significantly lower than 89.7% in the cHL-NS1 group (P=0.002). In all of 78 cases, the 3-year PFS rate of patients who did not obtain complete response (CR) was 67.1%, which was significantly lower than 92.2% in patients who achieved CR (P=0.030). Multivariate Cox regression analysis demonstrated that both cHL-NS2 and failure to obtain CR by first-line treatment were independent indicators for short PFS time (P<0.05). Conclusions: In cHL-NS2, the morphology of tumor cells are diverse, and tumor necrosis can be easily found. Under the current first-line treatments of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), cHL-NS2 is an independent indicator for worse PFS.

Sacubitril/valsartan attenuates left ventricular remodeling and improve cardiac function by upregulating apelin/APJ pathway in rats with heart failure / 中华心血管病杂志

Objective: To investigate the effect and mechanism of sacubitril/valsartan on left ventricular remodeling and cardiac function in rats with heart failure. Methods: A total of 46 SPF-grade male Wistar rats weighed 300-350 g were acclimatized to the laboratory for 7 days. Rats were then divided into 4 groups: the heart failure group (n=12, intraperitoneal injection of adriamycin hydrochloride 2.5 mg/kg once a week for 6 consecutive weeks, establishing a model of heart failure); heart failure+sacubitril/valsartan group (treatment group, n=12, intragastric administration with sacubitril/valsartan 1 week before the first injection of adriamycin, at a dose of 60 mg·kg-1·d-1 for 7 weeks); heart failure+sacubitril/valsartan+APJ antagonist F13A group (F13A group, n=12, adriamycin and sacubitril/valsartan, intraperitoneal injection of 100 μg·kg-1·d-1 APJ antagonist F13A for 7 weeks) and control group (n=10, intraperitoneal injection of equal volume of normal saline). One week after the last injection of adriamycin or saline, transthoracic echocardiography was performed to detect the cardiac structure and function, and then the rats were executed, blood and left ventricular specimens were obtained for further analysis. Hematoxylin-eosin staining and Masson trichrome staining were performed to analyze the left ventricular pathological change and myocardial fibrosis. TUNEL staining was performed to detect cardiomyocyte apoptosis. mRNA expression of left ventricular myocardial apelin and APJ was detected by RT-qRCR. ELISA was performed to detect plasma apelin-12 concentration. The protein expression of left ventricular myocardial apelin and APJ was detected by Western blot. Results: Seven rats survived in the heart failure group, 10 in the treatment group, and 8 in the F13A group. Echocardiography showed that the left ventricular end-diastolic diameter (LVEDD) and the left ventricular end-systolic diameter (LVESD) were higher (both P<0.05), while the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were lower in the heart failure group than in the control group (both P<0.05). Compared with the heart failure group, rats in the treatment group were featured with lower LVEDD and LVESD (both P<0.05), higher LVEF and LVFS (both P<0.05), these beneficial effects were reversed in rats assigned to F13A group (all P<0.05 vs. treatment group). The results of HE staining showed that the cardiomyocytes of rats in the control group were arranged neatly and densely structured, the cardiomyocytes in the heart failure group were arranged in disorder, distorted and the gap between cells was increased, the cardiomyocytes in the treatment group were slightly neat and dense, and cardiomyocytes in the F13A group were featured similarly as the heart failure group. Masson staining showed that there were small amount of collagen fibers in the left ventricular myocardial interstitium of the control group, while left ventricular myocardial fibrosis was significantly increased, and collagen volume fraction (CVF) was significantly higher in the heart failure group than that of the control group (P<0.05). Compared with the heart failure group, the left ventricular myocardial fibrosis and the CVF were reduced in the treatment group (both P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). TUNEL staining showed that the apoptosis index (AI) of cardiomyocytes in rats was higher in the heart failure group compared with the control group (P<0.05), which was reduced in the treatment group (P<0.05 vs. heart failure group), this effect again was reversed in the F13A group (P<0.05 vs. treatment group). The results of RT-qPCR and Western blot showed that the mRNA and protein levels of apelin and APJ in left ventricular myocardial tissue of rats were downregulated in heart failure group (all P<0.05) compared with the control group. Compared with the heart failure group, the mRNA and protein levels of apelin and APJ were upregulated in the treatment group (all P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). ELISA test showed that the plasma apelin concentration of rats was lower in the heart failure group compared with the control group (P<0.05); compared with the heart failure group, the plasma apelin concentration of rats was higher in the treatment group (P<0.05), this effect was reversed in the F13A group (P<0.05 vs. treatment group). Conclusion: Sacubitril/valsartan can partially reverse left ventricular remodeling and improve cardiac function in rats with heart failure through modulating Apelin/APJ pathways.