Activation of HIF-1α/ACLY signaling axis promotes progression of clear cell renal cell carcinoma with VHL inactivation mutation / 中华病理学杂志

Objective: To explore the potential pathogenesis of clear cell renal cell carcinoma (ccRCC) based on the HIF-1α/ACLY signaling pathway, as well as to provide new ideas for the treatment of ccRCC. Methods: Seventy-eight ccRCC cases diagnosed at the First Affiliated Hospital of Soochow University, Suzhou, China were collected. The VHL mutation was examined using exon sequencing. The expression of HIF-1α/ACLY in VHL-mutated ccRCC was evaluated using immunohistochemical staining and further validated in VHL-mutated ccRCC cell lines (786-O, A498, UM-RC-2, SNU-333, and Caki-2) using Western blot. The mRNA and protein levels of ACLY were detected using real-time quantitative PCR and Western blot after overexpression or interference with HIF-1α in ccRCC cell lines. HeLa cells were treated with CoCl2 and hypoxia (1%O2) to activate HIF-1α and then subject to the detection of the ACLY mRNA and protein levels. The potential molecular mechanism of HIF-1α-induced ACLY activation was explored through JASPAR database combined with chromatin immunoprecipitation assay (ChIP) and luciferase reporter gene assay. The effect of HIF-1α/ACLY regulation axis on lipid accumulation was detected using BODIPY staining and other cell biological techniques. The expression of ACLY was compared between patients with ccRCC and those with benign lesions, and the feasibility of ACLY as a prognostic indicator for ccRCC was explored through survival analysis. Results: Exon sequencing revealed that 55 (70.5%) of the 78 ccRCC patients harbored a VHL inactivation mutation, and HIF-1α expression was associated with ACLY protein levels. The protein levels of ACLY and HIF-1α in ccRCC cell lines carrying VHL mutation were also correlated to various degrees. Overexpression of HIF-1α in A498 cells increased the mRNA and protein levels of ACLY, and knockdown of HIF-1α in Caki-2 cells inhibited the mRNA and protein levels of ACLY (P<0.001 for all). CoCl2 and hypoxia treatment significantly increased the mRNA and protein levels of ACLY by activating HIF-1α (P<0.001 for all). The quantification of transcriptional activity of luciferase reporter gene and ChIP-qPCR results suggested that HIF-1α could directly bind to ACLY promoter region to transcriptionally activate ACLY expression and increase ACLY protein level (P<0.001 for all). The results of BODIPY staining suggested that the content of free fatty acids in cell lines was associated with the levels of HIF-1α and ACLY. The depletion of HIF-1α could effectively reduce the accumulation of lipid in cells, while the overexpression of ACLY could reverse this process. At the same time, cell function experiments showed that the proliferation rate of ccRCC cells with HIF-1α knockdown was significantly decreased, and overexpression of ACLY could restore proliferation of these tumor cells (P<0.001). Survival analysis further showed that compared with the ccRCC patients with low ACLY expression, the ccRCC patients with high ACLY expression had a poorer prognosis and a shorter median survival (P<0.001). Conclusions: VHL mutation-mediated HIF-1α overexpression in ccRCC promotes lipid synthesis and tumor progression by activating ACLY. Targeting the HIF-1α/ACLY signaling axis may provide a theoretical basis for the clinical diagnosis and treatment of ccRCC.

Alteration and significance of serum lipid levels and nutritional status during BCMA-CAR-T-cell therapy in patients with refractory or relapsed multiple myeloma: a retrospective study based on LEGEND-2 / 中华血液学杂志

Objective: To explore the dynamic changes in serum lipid levels and nutritional status during BCMA-CAR-T-cell therapy in patients with refractory or relapsed multiple myeloma (R/R MM) based on LEGEND-2. Methods: The data of patients with R/R MM who underwent BCMA-CAR-T therapy at our hospital between March 30, 2016, and February 6, 2018, were retrospectively collected. Serum lipid levels, controlled nutritional status (CONUT) score, and other clinical indicators at different time points before and after CAR-T-cell infusion were compared and analyzed. The best cut-off value was determined by using the receiver operator characteristic (ROC) curve. The patients were divided into high-CONUT score (>6.5 points, malnutrition group) and low-CONUT score groups (≤6.5 points, good nutrition group), comparing the progression-free survival (PFS) and total survival (OS) of the two groups using Kaplan-Meier survival analysis. Results: Before the infusion of CAR-T-cells, excluding triglycerides (TG), patients' serum lipid levels were lower than normal on average. At 8-14 d after CAR-T-cell infusion, serum albumin (ALB), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and apolipoprotein A1 (Apo A1) levels dropped to the minimum, whereas CONUT scores reached the maximum. In addition to TG, apolipoprotein B (Apo B) levels increased compared with baseline. After CAR-T-cell therapy, the patients' serum lipid levels significantly increased with well-improved nutritional status. Spearman's related analysis showed that TC, HDL, and ApoA1 levels after CAR-T-cell injection were significantly negatively correlated with the grade of cytokine-release syndrome (CRS) (r=-0.548, P=0.003; r=-0.444, P=0.020; r=-0.589, P=0.001). Furthermore, survival analysis indicated that the CONUT score was unrelated to PFS, and the median OS of patients with R/R MM in the high-CONUT score group was shorter than that in the low-CONUT score group (P=0.046) . Conclusions: During CAR-T-cell therapy, hypolipidemia and poor nutritional status were aggravated, which is possibly related to CRS. The patients' serum lipid levels and nutritional status were significantly improved after CAR-T-cell treatment. The CONUT score affected the median OS in patients treated with CAR-T-cells. Therefore, specific screening and intervention for nutritional status in patients receiving CAR-T-cell therapy are required.

Lipid profile and response to statin therapy in patients with hypopituitarism

ABSTRACT Objective: Dyslipidemia is prevalent among patients with hypopituitarism, especially in those with growth hormone (GH) deficiency. This study aimed to evaluate the response to statin therapy among adult patients with dyslipidemia and hypopituitarism. Subjects and methods: A total of 113 patients with hypopituitarism following up at a neuroendocrinology unit were evaluated for serum lipid levels. Dyslipidemia was diagnosed in 72 (63.7%) of these patients. A control group included 57 patients with dyslipidemia and normal pituitary function. The distribution of gender, age, weight, and dyslipidemia type was well balanced across both groups, and all participants were treated with simvastatin at doses adjusted to obtain normal lipid levels. Results: Patients with hypopituitarism and dyslipidemia presented deficiency of TSH (69%), gonadotropins (69%), ACTH (64%), and GH (55%) and had a similar number of deficient pituitary axes compared with patients with hypopituitarism but without dyslipidemia. All patients with dyslipidemia (with and without hypopituitarism) had lipid levels well controlled with doses of simvastatin ranging from 20-40 mg/day. The mean daily dose of simvastatin was not significantly different between patients with and without hypopituitarism (26.7 versus 23.5 mg, p = 0.10). Similarly, no significant variation in simvastatin dose was observed between patients with different causes of hypopituitarism, presence or absence of GH deficiency, number of deficient pituitary axes, prior pituitary radiation therapy or not, and presence or absence of obesity. Conclusions: Patients with GH deficiency without GH replacement showed good response to simvastatin at a mean dose equivalent to that used in individuals with dyslipidemia and normal pituitary function.

Ação anti-inflamatória da fração lipídica do Ovis aries associado ao ultrassom terapêutico em modelo experimental de tendinite em ratos (Rattus norvegicus) / Anti-inflammatory action of the Ovis aries lipidic fraction associated to therapeutic ultrasound in an experimental model of tendinitis in rats (Rattus norvegicus)

CONTEXTUALIZAÇÃO: Estudos demonstram o efeito benéfico da aplicação tópica de ácidos graxos como agentes cicatrizantes. A fração lipídica do Ovis aries apresenta uma ação anti-inflamatória que acelera o processo de cicatrização. O ultrassom aumenta o fluxo sanguíneo bem como a extensibilidade das estruturas de colágeno e tendões. OBJETIVOS: Analisar a ação anti-inflamatória da fração lipídica do Ovis aries associado ao ultrassom terapêutico (UST) pulsado e à fricção em modelo de tendinite induzida. MÉTODOS: Cinquenta ratos Wistar foram distribuídos nos seguintes grupos: controle, gel Ovis aries - uso tópico - UST pulsátil + loção estéril (oil free), UST pulsátil + gel Ovis aries, loção estéril (oil free) - uso tópico. Para induzir a tendinite, utilizou-se uma injeção intratendínea de 10µL de colagenase no tendão do calcâneo direito. O tratamento consistiu em aplicações diárias de ultrassom, com os seguintes parâmetros: modo pulsado 10 por cento, frequência de 1 MHz, pulsátil a 10 por cento com intensidade de 0,5W/cm², durante sete ou 14 dias. RESULTADOS: A variação do número de células inflamatórias, para os animais tratados por 14 dias, com relação aos grupos controle, UST + oil free e UST + Ovis aries, apresentou resultados significativos p<0,001. O grupo Ovis aries + massagem e o grupo massagem + oil free apresentaram resultados significativos, p<0,01. Nos animais tratados por sete dias, observou-se que o grupo UST + Ovis aries, em relação ao controle, é estatisticamente significativo, p<0,05 CONCLUSÃO: Pode-se concluir que o tratamento com UST + Ovis aries é mais efetivo que os outros tratamentos, visto que consegue reduzir o número de células inflamatórias no tempo de sete e 14 dias.

BACKGROUND: Studies have demonstrated the beneficial effects of topical application of fatty acids as healing agents. The lipid fraction of Ovis aries have an anti-inflammatory action that accelerates the healing process. Ultrasound increases blood flow and the extensibility of collagen structures and tendons. OBJECTIVES: To assess the anti-inflammatory action of the Ovis aries lipid fraction associated to pulsed therapeutic ultrasound and friction in an induced tendinitis model. METHODS: Fifty Wistar rats were divided into four groups: control that consisted of Ovis aries gel for topical use; pulsed ultrasound plus oil free sterile lotion; pulsed ultrasound plus Ovis aries gel; and oil free sterile lotion for topical use alone. To induce tendinitis a 10µL intratendinous injection of collagenase was injected into the right Achilles tendon of rats. Treatment consisted of daily applications of ultrasound using the following parameters: 10 percent pulsed mode, 10 percent pulsed frequency of 1 MHz and intensity of 0.5 W/cm² for seven or fourteen days. RESULTS: After 7 days of treatment, only the Ovis aries plus ultrasound group showed statistically significant difference when compared to the control group.The variation in the number of inflammatory cells on animals treated for fourteen days for the control, ultrasound plus oil free, ultrasound plus Ovis aries, Ovis aries plus massage and massage plus oil free groups were statistically significant different, p<0.01. It was observed in animals treated for seven days that the ultrasound plus Ovis aries group was statistically significant better than the control group, p<0.05. CONCLUSION: It can be concluded that treatment using ultrasound plus Ovis aries is more effective than other treatments as it produces significantly better reduction on the number of inflammatory cells at 7 and 14 days.

Efecto de la terapia antirretroviral sobre el perfil lipídico de pacientes con sida en Maracaibo, estado Zulia, Venezuela / The effect of antiretroviral therapy on the lipid profile of aids patients in Maracaibo, state Zulia, Venezuela

Se realizó una investigación prospectiva con el objetivo de determinar el efecto de la terapia antirretroviral sobre el perfil lipídico en una población de 50 pacientes con sida, que recibían su primer esquema antirretroviral, que asisten a la consulta de VIH-SIDA del Hospital Universitario de Maracaibo durante los meses de Noviembre 2008 a Julio de 2009. Se determinaron los niveles séricos de colesterol, triglicéridos, HDL-colesterol, LDL-colesterol al inicio y al finalizar el estudio. Las combinaciones terapéuticas fueron; 47 (94,0%) con inhibidores de la proteasa/reforzado (IP/r) + inhibidores nucleosidos de la trancriptasa reversa (INTR) y 3 (6%) 2 INTR + 1 INNTR. En todos los pacientes los parámetros del perfil lipídico estaban dentro del rango de la normalidad. Al final del estudio, los niveles sanguíneos de triglicéridos, colesterol total y LDLc de los pacientes tratados aumentaron con respecto a los valores iniciales. Se concluye que la hipertrigliceridemia es una alteración lipídica frecuente en los pacientes que reciben el esquema de tratamiento IP/r combinado con INTR que constituyó la mayoría de la muestra estudiada

A prospective study was carried out to determine the effect of antiretroviral therapy on the lipid profile in a population of 50 patients with AIDS who received their first antiretroviral drug treatment in the HIV-AIDS clinic at the Maracaibo University Hospital from November 2008 to July 2009. Serum levels of cholesterol, triglycerides, HDL-cholesterol and LDL-cholesterol were determined at the beginning and the end of the study. The therapeutic combinations were: 47 patients (94.0%) with the protease/booster inhibitors (IP/b) + nucleoside inhibitors of reverse transcriptase (NRTI) and 3 (6%)with 2NRTI + 1 non-nucleoside inhibitors of reverse transcriptase inhibitors(NNRTIs). Initially, lipid profile parameters were inside the range of normality. By the end of the study, blood levels for triglycerides, total cholesterol and LDLc had increased with regard to the initial values. Conclusions are that hypertriglyceridemia is a frequent alteration in patients that receive antiretroviral therapy with PI/b combined with NRTI, since this constituted most of the sample studied

Relación entre los niveles de lipoproteinas y la circunferencia abdominal / Relationship between lipoprotein levels and abdominal circumference

Evaluar la relación entre las concentraciones de lípidos y la circunferencia abdominal en adultos. Estudio caso-control, realizado entre Agosto 2007 hasta Agosto 2008, en pacientes adultos que acudieron al Hospital Vargas de Caracas. Se empleó para el diagnóstico del perfil lipídico mediante métodos enzimáticos. Se dividió la muestra así: grupo de estudio: pacientes con circunferencia abdominal mayor de 90 y 80 cms para hombres y mujeres respectivamente; grupo control con circunferencia abdominal menor de 90 y 80 cms para hombres y mujeres. Se calculó la proporción de pacientes con dislipidemia en cada grupo y se compararon por la prueba del Chi cuadrado con corrección de Fisher. Se calcularon los promedios y valores de cada uno de los lípidos para cada grupo de pacientes y se compararon con la prueba T. Se estudiaron 98 pacientes de ambos sexos, La variable HDL estudiada resultó significativa al comparar los cuatro grupos (P= 0,0028), siendo el grupo de mujeres con circunferencia Abdominal menor o igual a 80 centímetros el Promedio más alto. La variable Triglicéridos, estudiada al comparar los cuatro grupos de estudio, en relación con los niveles de circunferencia Abdominal según los valores patrones establecidos, fue significativa (P=0,01). La tensión arterial diastólica obtuvo significancia estadística (P= 0,0000), igualmente la Sistólica (P= 0,0006) mm Hg, al ser comparada con los cuatro grupos estudiados, y el mayor promedio fue en los hombres con circunferencia abdominal mayor de 90 centímetros tanto para la diastólica como para la sistólica. No se encontró asociación entre los niveles de lipoproteínas y obesidad abdominal. La presión arterial diastólica está asociada a la obesidad abdominal.

To evaluate the relatioship between seric lipid levels and abdominal circunference Case- control, study done during the period August 2007-August 2008, in ambulatory patients of the Hospital Vargas, Caracas, Venezuela. Enzimatic assays were used for the seric measurements of cholesterol, glycemia and TSH. We divided the sample in two groups: one study group with abdominal circunference greater de 80 and 90 cm (men and women) and a control group with abdominal circunference smaller than de 80 and 90 cm respectively. The proportion of patients with dyslipidemia was calculated in each group. And compared through Chi Square test corrected by Fisher. Average for each group of lipids were calculated and compared by T test. We studied 98 pacients of both genders, HDL-cholesterol was significant when the four groups were compared (P= 0,0028), and the group of women with an abdominal circunference smaller of 80 o less cm a 80 centímetros had the highest average. Triglycerides in relation with abdominal circunference also showed a significant relationship (P=0,01). Diastolic blood pressure also had statistical significance (P= 0,0000), as did systolic BP Sistólica (P= 0,0006) mmHg, when compared in all groups, with the highest value in men with abdominal circunference greater than 90 cm. No association was found between levels of lipoproteins entre los niveles de lipoproteínas and abdominal obesidad. Diastolic BP was associated with abdominal obesity.

Lipídios em terapia nutricional pediátrica / Lipids in pediatric nutritional therapy

As funçöes dos lipídios na nutriçäo dos pacientes pediátricos säo discutidas neste artigo, com ênfase na absorçäo, no aproveitamento energético e, principalmente, no metabolismo dos acidos graxos essenciais e sua relaçäo com o desenvolvimento infantil. A mudança de composiçäo dos lipídios nas fórmulas enterais e parenterais pode alterar o aproveitamento energético e o metabolismo dos ácidos graxos essenciais. A adiçäo de ácido linoléico e alfa-linolênico nas fórmulas enterais infantis é suficiente para evitar sinais clínicos de carência destes nutrientes; entretanto, este fornecimento näo é garantia de resultar em status adequado de ácido araquidônico e docosahexaenóico, que säo componebtes estruturais das membranas celulares. Os prematuros alimentados com fórmulas suplementadas de ácidos graxos essenciais apresentam nLveis de ácidos graxos no plasma e nos eritrócitos mais elevados do que aqueles alimentados com fórmulas convencionais, mas abaixo dos prematuros alimentados com leite humano. A performance nos testes de desenvolvimento dos prematuros alimentados com fórmulas suplementadas de ácidos graxos é melhor do que a daqueles alimentados com fórmula sem suplementaçäo. Novas fórmulas enterais e parenterais com a adiçäo de ácidos graxos específicos abrem perspectivas atraentes para pesquisas das relaçöes entre a composiçäo da membrana celular e o desenvolvimento infantil.(au)

El uso clinico de emulsiones de lipidos / Clinical use of lipid emulsions

Se han realizado progresos sustanciales en la comprensión del metabolismo de las emulsiones endovenosas de lipidos y en la forma como sus componentes llegan a tejidos y células específicos. Las emulsiones de lipidos deben considerarse no solamente medios para proveer sustratos de energía, sino proveedores de compuestos específicos que participan en la regulación de funciones metabólicas claves. Estos mayores conocimientos deben encontrar su aplicación en el cuidado metabólico de diversos tipos de pacientes

Nutriçäo e imunidade / Nutrition and immunity

O sistema imune humano possui diferentes células que produzem substâncias destinadas a defender o organismo humano contra agentes infecciosos ou suas toxinas. Dividido em um sistema central e um periférico, permite a ação conjunta e sincronizada de diferentes células. Morbidades como infecção, trauma, câncer e doenças inflmatórias ativam este sistema, possibilitando a produção de substâncias pró-inflamatórias por diferentes elementos deste sistema, especialmente o tecido linfóide associado à mucosa intestinal, que tem papel central neste processo...

Há razäo para o uso de multivitamínicos em pacientes cirróticos / Is there a reason to use vitamin supplementation in cirhotic patients

O fígado é um órgäo essencialmente metabólico e, desta forma, orquestra uma série de eventos que culminam no controle protético-energético do organismo. Assim, a doença hepática, particularmente a cirrose,influencia sobrmaneira o metabolismo de hitdratos de carbono, proteínas e lipidios. o metabolismo de vitaminas e sais minerais näo foge à regra. No entanto, a suplementaçäo vitamínica näo ó uma prática generalizada dos portadores de cirrose. Os autores analisaram os motivos que levam a déficits vitaminicos nesses pacientes e sugerem que o uso de multivitaminicos deva ser considerado

Efecto de la fibra dietética no soluble sobre lípidos séricos en ratas / Effect of dietetic fiber on the seric lipids of male and female rats

Se utilizaron ratas Wistar machos y hembras para evaluar los efectos del afrecho de trigo sobre las concentraciones séricas de triglicéridos (TG), colesterol total (CT), colesterol de la LDL (CLDL) y de la HDL (CHDL). Se distribuyeron aleatoriamente en 4 grupos: dos grupos testigo (control 1: ratas machos y control 2: ratas hembras) y grupo 3(machos) y 4(hembras). El lapso de estudio se dividió en dos períodos: períodos de acondicionamiento (10 días) y período experimental (45 días). Durante el período experimental los grupos controles recibieron dieta normocalórica y los tratados una dieta hipercalórica, hipergrasa, hipoglucídica, suplementada con 25g de afrecho de trigo por 100g de muestra. Cada 15 días se les determinó los lípidos séricos. Los resultados muestran que el afrecho de trigo indujo reducción de los TG séricos en las ratas hembras (p<.005), mientras que el grupo de machos mantuvo las concentraciones estables. El CT y el CLDL descendió significativamente en las ratas machos y hembras (p<.005). Las concentraciones de CHDL solamente disminuyeron en las ratas de sexo masculino (p<005). Estos resultados sugieren que el afrecho de trigo modifica las concentraciones de lípidos séricos en las ratas adultas y que la respuesta está relacionada con el sexo.