Brain Tumor Heterogeneity

Tumor heterogeneity is the concept that different tumor cells provide distinct biomorphological lesions, gene expressions, proliferation, microenvironment and graduated capacity of metastatic lesions. Brain tumor heterogeneity has been recently discussed about the interesting interaction of chronic inflammation, microenvironment, epigenetics and glioma steam cells. Brain tumors remain a challenge with regards to medication and disease, due to the lack of treatment options and unsatisfactory results. These results might be the result of the brain tumor heterogeneity and its multiple resistance mechanisms to chemo and radiotherapy.

Research Progress of Discoidin Domain Receptor 1 in Breast Cancer and Other Malignant Tumors / 中国医学科学院学报

Discoidin domain receptor 1(DDR1)is a critical member of the receptor tyrosine kinase family.It may be related to tumor invasion and metastasis,and the abnormal activation of DDR1 can lead to the occurrence and development of malignant tumors,inflammation,and fibrosis.DDR1 are involved in cell adhesion,migration,proliferation,secretion of cytokines,and remodeling of extracellular matrix,thus playing a critical role in various pathophysiological processes of the human body.In this review,we demonstrate the research progress of DDR1 in breast cancer and other malignant tumors,in order to provide a new theoretical basis for the prevention and treatment of breast cancer and other tumors.

Recommendations from Experts in the Management of Adverse Reactions to ALK Inhibitors (2021 Version) / 中国肺癌杂志

Anaplastic lymphoma kinase (ALK) fusion gene, as a tumor driver gene, was crucial for the occurrence and development of non-small cell lung cancer (NSCLC). Recently, targeted ALK fusion gene has become the main treatment method for ALK-positive NSCLC. The first and second generation ALK inhibitors (ALKi), such as crizotinib, ceritinib, alectinib and ensartinib have been approved in China. However, there was no guidance for the management of ALKi adverse reactions. Therefore, this "Recommendations from experts in the management of adverse reactions to ALK inhibitors (2021 version)" has been summarized, led by Lung Cancer Professional Committee of Sichuan Cancer Society and Sichuan Medical Quality Control Center for Tumor Diseases, to provide practical and feasible strategies for clinical ALKi management specification of adverse reactions.
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Miastenia gravis: Registro de 190 casos en un centro único / Myasthenia gravis. Register of 190 cases in a single center

La miastenia gravis (MG) es una enfermedad autoinmune mediada por anticuerpos dirigidos contra proteínas post sinápticas de la unión neuromuscular. El objetivo de este estudio fue describir los aspectos clínicos, epidemiológicos y serológicos de pacientes con MG en un Hospital Público de la Ciudad de Buenos Aires. Se realizó un análisis retrospectivo sobre 190 enfermos con diagnóstico de MG. La edad media de inicio de la enfermedad fue de 38 años; 57 (30%) fueron MG de inicio tardío (inicio de síntomas > 50 años). La relación mujer/hombre fue 1.7/1. La enfermedad se inició más tempranamente en las mujeres que en los hombres, media 32 vs. 48 años (p < 0.0001). La MG familiar autoinmune representó el 3.2 % (6 casos). La forma más común de presentación fue con manifestaciones oculares puras (52%). El 12.1% (23/190) fue considerada MG ocular en el seguimiento. La MG asociada a timoma se presentó en 22 casos (11.6%). El 27.1% presentó otra enfermedad autoinmune asociada, siendo las tiroideas las más frecuentes. El 81.4% tuvo anticuerpos anti-receptores de acetilcolina (ACRA) positivos y 22.7% de los ACRA negativos fueron positivos para anticuerpos anti-tirosina quinasa musculo especifica (anti-MusK). La evolución clínica fue favorable, hallándose más de la mitad de los casos en remisión o manifestaciones mínimas en la última visita. La mayoría requirió inmunosupresión para control de la sintomatología, el 78% recibió corticoides y el 48% un inmunosupresor no esteroideo.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. The aim of this study was to evaluate clinical, epidemiological and serological features of patients with MG in a Public Hospital of Buenos Aires City. A retrospective analysis of 190 patients diagnosed with MG was performed. The mean age of MG onset was 38 years, 30% had late-onset MG (onset age > 50 years). The female/male ratio was 1.7 / 1. Disease started earlier in women than in men, mean 32 vs. 48 years (p < 0.0001). Familial autoimmune MG represented 3.2% of the cases. Most of the patients initiated their disease with a pure ocular form (52%). 12.1% (23/190) were considered ocular MG at follow-up. Thymoma-associated MG represented 11.6% of cases. 27.1% had other associated autoimmune disease, thyroid disorders were the most frequent. 81.4% were anti-acetylcholine receptor antibody (AChR-ab) positive MG; 22.7% of AChR-ab negatives were positive for anti-muscle specific kinase (MusK) antibodies. Clinical outcome was relatively good; more than half of cases were in remission or minimal manifestations at the last visit. The majority of patients required immunosuppression to control the symptoms, 78% received corticosteroids and 48%, a non-steroidal immunosuppressant.

miR-324-5p inhibits lipopolysaccharide-induced proliferation of rat glomerular mesangial cells by regulating the Syk/Ras/c-fos pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effect of miR-324-5p on the proliferation of rat glomerular mesangial (HBZY-1) cells and the role of Syk/Ras/c-fos signaling pathway in mediating this effect.@*METHODS@#HBZY-1 cells cultured in vitro were transiently transfected with miR-324-5p mimics or miR-324-5p-mimics-NC followed by treatment with lipopolysaccharide (LPS). MTT assay was used to detect the proliferation activity of HBZY-1 cells, and RT-qPCR was used to detect the expressions of miR-324-5p and the mRNA expressions of Syk, Ras, MEK1/2, ERK1/2 and c-fos mRNA. The protein expressions of p-Syk, Ras, p-MEK1/2, p-ERK1/2 and c-Fos were detected by Western blotting and immunofluorescence assay.@*RESULTS@#MTT assay showed that exposure to LPS significantly enhanced the proliferative activity of HBZY-1 cells. Compared with the cells treated with LPS and LPS + mimics NC, the cells transfected with miR-324-5p mimics prior to LPS exposure exhibited significantly lowered proliferative activity. Transfection with miR-324-5p mimics significantly lowered the mRNA expressions of Syk, Ras, MEK1/2, ERK1/2 and c-fos and the protein expressions of p-Syk, Ras, MEK1/2, ERK1/2 and c-Fos (@*CONCLUSIONS@#miR-324-5p can inhibit the proliferation of rat chronic glomerulonephritis cells induced by LPS by inhibiting Syk/Ras/c-fos signaling pathway and may potentially serve as a diagnostic indicator and a therapeutic target for chronic glomerulonephritis.

Efficacy of Pemetrexed-based Chemotherapy in Comparison to Non-Pemetrexed-based Chemotherapy in Advanced, ALK+ Non-Small Cell Lung Cancer

PURPOSE: Previous retrospective studies suggest that anaplastic lymphoma kinase (ALK) mutation-positive (ALK+) non-small cell lung cancer (NSCLC) patients are sensitive to pemetrexed. To determine its efficacy, we retrospectively evaluated clinical outcomes of pemetrexed-based chemotherapy in patients with ALK+ NSCLC. MATERIALS AND METHODS: We identified 126 patients with advanced, ALK+ NSCLC who received first-line cytotoxic chemotherapy. We compared response, progression-free survival (PFS), and overall survival (OS) rates according to chemotherapy regimens. Furthermore, we evaluated intracranial time to tumor progression (TTP) and proportion of ALK+ cells as prognostic factors. RESULTS: Forty-eight patients received pemetrexed-based chemotherapy, while 78 received other regimens as first-line treatment. The pemetrexed-based chemotherapy group showed superior overall response (44.7% vs. 14.3%, p < 0.001) and disease control (85.1% vs. 62.3%, p=0.008) rates. The pemetrexed-based chemotherapy group also exhibited longer PFS (6.6 months vs. 3.8 months, p < 0.001); OS rates were not significantly different. The lack of exposure to second-generation ALK inhibitors and intracranial metastasis on initial diagnosis were independent negative prognostic factors of OS. Intracranial TTP was similar between the treatment groups (32.7 months vs. 35.7 months, p=0.733). Patients who harbored a greater number of ALK+ tumor cells (≥70%) showed prolonged OS on univariate analysis (not reached vs. 44.8 months, p=0.041), but not on multivariate analysis (hazard ratio: 0.19, 95% confidence interval: 0.03–1.42; p=0.106). CONCLUSION: Pemetrexed-based regimens may prolong PFS in patients with ALK+ NSCLC as a first-line treatment, but are not associated with prolonged OS. Exposure to second-generation ALK inhibitors may improve OS rates in patients with ALK+ NSCLC.

Peptide Nucleic Acid Clamping and Direct Sequencing in the Detection of Oncogenic Alterations in Lung Cancer: Systematic Review and Meta-Analysis

PURPOSE: Molecular testing in non-small cell lung cancer (NSCLC) aids in identifying oncogenic alterations. The aim of this study was to compare the rates of detection of oncogenic alterations and responsiveness to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) according to EGFR mutation status as determined by peptide nucleic acid (PNA) clamping or direct sequencing (DS). MATERIALS AND METHODS: We performed a systematic literature search using MEDLINE, EMBASE, and the Cochrane Central Register. Data from included studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and receiver operating characteristic curves. A meta-regression analysis was conducted to identify potential sources of heterogeneity between selected studies. RESULTS: We identified 10 studies comprising 924 patients. Oncogenic alterations were detected in 340 of 924 cases (36.8%) with PNA clamping and in 250 of 924 (27.1%) with DS. The pooled sensitivities of PNA clamping and DS were 0.93 [95% confidence interval (CI): 0.90−0.95] and 0.69 (95% CI: 0.64−0.73), respectively. According to meta-regression analysis, none of the covariates were found to be significant sources of heterogeneity. With respect to treatment responses to EGFR-TKIs, there was no significant difference therein between EGFR mutations detected by PNA clamping and DS (53.4% vs. 50.8%; risk ratio, 0.99; 95% CI 0.83−1.19; p=0.874). CONCLUSION: We demonstrated that PNA clamping has a higher sensitivity than DS for detecting oncogenic alterations in NSCLC. Our findings suggest that PNA clamping is a more useful method for clinical practice.

Analysis of the First Diagnosis Symptom and Its Influencing Factors in 500 Patients with Lung Cancer / 中国肺癌杂志

BACKGROUND@#As the morbidity and mortality in lung cancer keep raising, we are here to discuss the effect of clinical features especially the initial symptomon on diagnosis and follow-up treatment of newly diagnosed lung cancer patients.@*METHODS@#The clinical features of the 500 patients with lung cancer in our hospital from March, 2017 to May, 2017 were analyzed retrospectively, including the initial symptom, stage, biomarkers, pathology, etc. RESULTS: There were 266 famle (53.3%), 372 adenocarcinoma (74.4%), 285 smokers (58%), status score of most patients (98.2%) was 0-1. 58.2% (n=291) of all the patients got biomarkers test, of which epidermal growth factor receptor (EGFR) mutations was 61.2%(178/291), anaplasticlymphoma kinase (ALK) fusion gene positive was 4.1% (12/291). Smoking status, initial symptom, pathological typing, TNM staging and EGFR mutation were the main factors affecting follow-up treatment.@*CONCLUSIONS@#Patients with typical symptoms have shorter diagnosis time. Smoking status, lung cancer-related symptoms, pathology, TNM staging and EGFR mutation status are the main factors that affect the follow-up treatment.

Association between EGFR, ALK and KRAS Gene Status and Synchronous Distant Organ Metastasis in Non-small Cell Lung Cancer / 中国肺癌杂志

Lung cancer is the leading cause of morbidity and mortality of malignant diseases in China. Approximately 57% lung cancer patients harbored distant metastases at initial diagnosis which is relevant to poor outcomes. The research strategy of anti-lung cancer metastasis now has became the new treatment directions and thoughts for lung cancer treatment. Previous studies have shown that changes in the corresponding driving genes on different signaling pathways may be related to the transfer of different organs, and the biological alteration of tumor to some extent can affect the metastatic behavior and metastatic pattern of tumor. However, current clinical and basic studies have not elucidated the molecular mechanism of the specific distant organ metastasis in the pathway of lung cancer related signal transduction, clinical research on the correlation between gene mutation and organ transfer specificity is also relatively rare. This review aims to summarize the characteristics of the expression of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) in non-small cell lung cancer, and the correlation between the distribution of metastatic organs.
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Advances in Double Mutations of EGFR and ALK Gene in Non-small Cell Lung Cancer / 中国肺癌杂志

Molecular target therapy is one of the most popular field of non-small cell lung cancer (NSCLC) treatmnet. Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearragement are the most important two oncogenic drivers in NSCLC, early studies suggested that EGFR mutations and ALK rearrangements are mutually exclusive, but isolated cases or small sample research with concomitant EGFR and ALK alterations have been constantly reported. The co-occurrence of EGFR mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular, the frequency of EGFR/ALK co-alterations was about 1%, however, little has been known about clinicopathologic feature and treatment. This review summarized published case report, EGFR and ALK alterations are common in female, Asian origin, never smoker, IV stage, and denocarcinomas. First-line treatment can choose EGFR or ALK tyrosine kinase inhibitors (TKIs). However, studies about the origin and resistance mechanism in EGFR/ALK co-alterations are little, require more experimental and clinical research.
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Current Status for Anaplastic Lymphoma Kinase in Non-small Cell Lung Cancer / 中国肺癌杂志

The incidence of ALK gene rearrangement in non-small cell lung cancer (NSCLC) was about 3% to 5%. ALK gene inhibitors have made great breakthrough in recent years, significantly extending the survival period of patients with ALK(+) advanced NSCLC. But the majority of patients will be acquired drug resistance after treatment. This article has been explained separately from the ALK genetic background, the detection method, the treatment of the three generations of ALK inhibitors and the strategy after drug resistance. It is desire to have reference value and reference meaning for clinical work.
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Gastrointestinal stromal tumors treated at a Brazilian Cancer Center: evaluation of clinical, epidemiological, and therapeutic profiles

Background: Gastrointestinal stromal tumors (GISTs) originate as precursor cells of the interstitial cells of Cajal in the myenteric plexus and generally have a mutation in the tyrosine kinase receptor, C-KIT (CD117). The objective is to evaluate the clinical, epidemiological, and therapeutic profiles of GIST cases available from a hospital specializing in cancer treatment. Methods: A retrospective, longitudinal study of 85 GIST cases in a Cancer Center (São Paulo, Brazil) was conducted. Results: The cases identified involved 40 men and 45 women and the average age at diagnosis was 55.7 ± 14. 8 years (median, 57). The symptoms present at diagnosis depended on the location and dimensions of each lesion. In 49 cases (57.6%), the tumors had a gastric location and the mean dimensions were 7.2 ± 2.3 cm (median, 3.4 cm). Recurrent metastatic disease presented in 27 cases (with the liver mainly affected). Locoregional recurrence was detected in 16 cases. C-KIT was positive in 79/81 (97.5%) of the cases examined. Most of the tumors were initially treated with surgery, while clinical treatment was applied to the recurrent cases. The overall survival rate was 76.4% 162 months after diagnosis. Conclusions: The GISTs examined most commonly originated in the stomach, while the liver was the main site affected by metastatic lesions. Most of the lesions appeared to be slow-growing neoplasms that were positive for C-KIT (CD117). Complications, as well as death, mostly affected the elderly patients that had comorbidities or more aggressive forms of the disease (AU)

Informe de evaluación científica basada en la evidencia disponible: cáncer renal metastásico / Scientific evaluation report based on available evidence: metastatic renal cancer

INTRODUCCIÓN: El Cáncer Renal (CR) representa el 2-3% de los cánceres del adulto a nivel mundial, presentando la mayor incidencia en los países occidentales. En 2014, se estimó que habría 63.920 casos nuevos de cáncer de riñón en EEUU, con 13.860 muertes estimadas por esta enfermedad y una tasa de sobrevida global a 5 años de aproximadamente el 70%. En Chile, según el Primer Informe de Registros Poblacionales la tasa de incidencia al 2012 fue de 6,9 x 100.000 hab., y la tasa general de mortalidad el año 2011 de 3,8 x 100.000 hab. Según el Departamento de Estadísticas e Información en Salud (DEIS) del MINSAL, el año 2011 se produjeron 657 fallecidos por esta causa, 401 hombres y 256 mujeres, con una relación Hombre: Mujer de 1,57:1. La tasa de mortalidad general va en ascenso: 2,7 x 100.000 el año 1997 v/s 3,8 en el año 2011. En cuanto a su histología, más de 90% de los cánceres de riñón surgen en el parénquima renal (siendo la mayoría carcinomas de células renales), y el resto en la pelvis renal. Antes de 2005, el tratamiento se limitaba a citoquinas terapia con IL-2 o IFN-a, cuya eficacia era limitada y de alta toxicidad. Este informe evalúa sunitinib, pazopanib y axintinib para pacientes con CR avanzado o metastásico de células claras en pacientes aptos para recibir inmunoterapia. TECNOLOGÍAS SANITARIAS ANALIZADAS: Sunitinib (SUTENT®); Pazopanib (VOTRIENT®, VORIFAS®, KIPANIB®, INOXTAR®); Axitinib (INYTA®). EFICACIA DE LOS TRATAMIENTOS: Se encontraron seis revisiones sistemáticas relevantes que compararon el uso de pazopanib contra placebo, y que muestran el resultado de 2 Ensayos Clínicos Aleatorizados (ECAs). Además, se encontraron 2 revisiones sistemáticas con meta-análisis de redes que inclueron 20 ECAs que comparaban directa o indirectamente axitinib y sunitinib contra placebo. Pazopanib, en comparación a placebo, probablemente no tiene un efecto importante en la mortalidad de pacientes con cáncer renal metastásico, pero reduce la progresión de la enfermedad. Sunitinib, en comparación a placebo podría hacer poca o ninguna diferencia respecto de la mortalidad de pacientes con cáncer renal metastásico, mientras que podría reducir la mortalidad de pacientes con cáncer renal metastásico. Axitinib, en comparación a placebo podría reducir la mortalidad de pacientes con cáncer renal metastásico. ANÁLISIS ECONÓMICO: Las agencias de distintos países (Canadá, Inglaterra y Australia) recomiendan el uso de Sunitinib, Pazopanib y Axitinib para el tratamiento del cáncer renal metastásico. Algunas agencias (Canadá e Inglaterra) han realizado esta recomendación siempre y cuando se considere un costo razonable para estos medicamentos. En consideración se tiene también en las distintas líneas que se consideran los tratamientos. El impacto presupuestario calculado para el primer año es de MM$ 2.049 (Sunitinib), MM$2.674 (Pazopanib) y MM$1.303 (Axitinib). CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera favorable para los 3 tratamientos considerados, de acuerdo a lo establecido en el Título III. de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.

Molecular biology of human epidermal receptors, signaling pathways and targeted therapy against cancers: new evidences and old challenges

ABSTRACT Human epidermal receptors (HER1/2/3/4) belong to the class of receptor-type tyrosine kinases. After binding a ligand, dimerization, it will ocurr activation of intracellular kinases after two-dimensional and cytoplasmic tail reciprocal transphosphorylation. This transphosphorylation recruits signaling pathways such as Ras/Raf/MEK/Erk1-2, PI3-K/AKT and JAK/STAT, which can affect the cell cycle, cytoskeleton reorganization, apoptosis, metastasis, differentiation, angiogenesis and transcription. HER deregulation is found in epithelial, mesenchymal and nervous neoplasms and is associated with poor prognosis and tumor severity. Since HER are promiscuous proteins when subjected to mutations, resultant modifications confer cellular metabolic superiority and activate complex, interconnected and overlapping networks of cytoplasmic signaling. Moreover, overexpression of HER1/2 is involved in tumor resistance to radiation and anti-hormone therapies. Indeed, HER2 expression is up to 100-fold higher in 25-30% of invasive breast cancers. These characteristics support the development of resistance to anti-HER1/2 chemotherapy such as monoclonal antibodies and tyrosine kinase inhibitors. Then, the challenges in research with HER-positive cancers include planning therapeutic strategies against known resistance mechanisms and identifying novel mechanisms as a way to overcome and control cell growth and malignant progression.

Combination of musk and olibanum promotes proliferation of prostate stem cells in mice: An experimental study / 中华男科学杂志

Objective@#To study the effects of muskolibanum combination on the proliferation and differentiation of prostate stem cells.@*METHODS@#We cultured prostate epithelial cells and urogenital sinus mesenchymal (UGSM) cells from 7－10 d old C57BL/6 mice and 16－18 d old pregnant C57BL/6 mice, transplanted the mixed suspension of the two types of cells under the kidney envelope of SCIDCB.17 male mice, and harvested the transplants 30 days later. We randomly divided the SCIDCB.17 mice into four groups to be treated intragastrically with musk (n = 8), olibanum (n = 8), musk+olibanum (n = 7), and normal saline (blank control, n = 8)) respectively, all for 14 days. Then we collected the kidney tissue for observation of the morphology of the glandular tubes and differentiation of different subsets of stem cells by HE staining and determination of the expressions and distribution of P63, CD133, CD117 and Sca1 by immunohistochemistry and Western blot.@*RESULTS@#A system was successfully established for the isolation and mixed culture of Sca1 Lin+ CD49f+ (LSC) cells of prostate stem cells and UGSM cells of the mouse embryonic prostate. Immunohistochemistry showed positive expressions of P63, CD133, Sca1, and CD117 in the prostatic acinar epithelia and proved the presence of prostatic acinar epithelial structure in the transplants. Compared with the blank control group, the expressions of CD133, Sca1 and CD117 were significantly increased in the musk, olibanum, and musk+olibanum groups (P< 0.05), higher in the musk+olibanum than in the musk or olibanum group (P< 0.05), and their protein expressions were even more elevated in the musk+olibanum group (P< 0.01), with statistically significant difference from the olibanum group (P< 0.05).@*CONCLUSIONS@#The combination of musk and olibanum can improve the proliferation and differentiation of prostate stem cells.

Expression of AXL enhances docetaxel-resistance of prostate cancer cells / 中华男科学杂志

Objective@#To explore the effect of the AXL expression on the chemosensitivity of prostate cancer PC-3 and DU145 cells to docetaxel and possible mechanisms.@*METHODS@#Using Western blot, we examined the expressions of the AXL protein, p-AXL and Gas6 in the docetaxel-resistant PC-3 (PC-3-DR) and DU145 (DU145-DR) cells stimulated with gradually increased concentrations of docetaxel. We transfected the PC-3 and DU145 cells with negative NC ShRNA and AXL-ShRNA, respectively, which were confirmed to be effective, detected the proliferation, apoptosis and cycle distribution of the cells by CCK8, MTT and flow cytometry after treated with the AXL-inhibitor MP470 and/or docetaxel, and determined the expression of the ABCB1 protein in the PC-3-DR and DU145-DR cells after intervention with the AXL-inhibitor R428 and/or docetaxel.@*RESULTS@#The expression of the AXL protein in the PC-3 and DU145 cells was significantly increased after docetaxel treatment (P <0.05). The expressions AXL and p-AXL were remarkably higher (P <0.05) while that of Gas6 markedly lower (P <0.05) in the PC-3 and DU145 than in the PC-3-DR and DU145-DR cells. The inhibitory effect of docetaxel on the proliferation and its enhancing effect on the apoptosis of the PC-3 and DU145 cells were significantly decreased at 48 hours after AXL transfection (P <0.05). MP470 obviously suppressed the growth and promoted the apoptosis of the PC-3-DR and DU145-DR cells, with a higher percentage of the cells in the G2/M phase when combined with docetaxel than used alone (P <0.05). R428 markedly reduced the expression of ABCB1 in the PC-3-DR and DU145-DR cells, even more significantly in combination with docetaxel than used alone (P <0.05).@*CONCLUSIONS@#The elevated expression of AXL enhances the docetaxel-resistance of PC-3 and DU145 prostate cancer cells and AXL intervention improves their chemosensitivity to docetaxel, which may be associated with the increased cell apoptosis in the G2/M phase and decreased expression of ABCB1.

Insulin binding characteristics in canine muscle tissue: effects of the estrous cycle phases / Características de ligação da insulina no tecido muscular canino: efeitos da fase do ciclo estral

Hormonal fluctuations during the different estrous cycle are a well-recognized cause of insulin resistance in bitches, and little is known about insulin receptor binding or post-binding defects associated with insulin resistance in dogs. To evaluate insulin binding characteristics in muscle tissue of bitches during the estrous cycle, 17 owned bitches were used in the study (six in anestrus, five in estrus, and six in diestrus). An intravenous glucose tolerance test (IVGTT) was performed in all patients by means of injection of 1mL/kg of a glucose 50% solution (500mg/kg), with blood sample collection for glucose determination at 0, 3, 5, 7, 15, 30, 45 and 60 minutes after glucose infusion. Muscle samples, taken after spaying surgery, were immediately frozen in liquid nitrogen and then stored at -80 ºC until the membranes were prepared by sequential centrifugation after being homogenized. For binding studies, membranes were incubated in the presence of 20,000cpm of human 125I-insulin and in increasing concentrations of unlabeled human regular insulin for cold saturation. The IVGTT showed no differences among bitches during the estrous cycle regarding baseline glycemia or glycemic response after glucose infusion. Two insulin binding sites - high-affinity and low-affinity ones - were detected by Scatchard analysis, and significant statistical differences were observed in the dissociation constant (Kd1) and maximum binding capacity (Bmax1) of the high-affinity binding sites. The Kd1 for the anestrus group (6.54±2.77nM/mg of protein) was smaller (P<0.001) than for the estrus (28.54±6.94nM/mg of protein) and diestrus (15.56±3.88nM/mg of protein) groups. Bmax1 in the estrus (0.83±0.42nM/mg of protein) and diestrus (1.24±0.24nM/mg of protein) groups were also higher (P<0.001) than the values observed in anestrus (0.35±0.06nM/mg of protein). These results indicate modulation of insulin binding characteristics during different phases of the estrous cycle in dogs, showing that muscle insulin binding affinity for its receptor is reduced during estrus and diestrus. However, this poor hormone-receptor affinity is compensated for by a greater total binding capacity, once there is no difference in patients' glycemic response after an intravenous glucose load.(AU)

As flutuações hormonais durante as diferentes fases do ciclo estral são uma causa importante de resistência insulínica em fêmeas caninas, e poucas informações são conhecidas sobre defeitos na ligação da insulina ao seu receptor, ou defeitos pós-receptor associados com resistência à insulina em cães. Para avaliar as características da ligação insulina-receptor no tecido muscular de cadelas durante o ciclo estral, dezessete pacientes foram utilizadas no estudo (seis em anestro, cinco em estro e seis em diestro). Um teste de tolerância à glicose intravenosa (IVGTT) foi realizado em todas as pacientes por meio da infusão de 1mL/kg de uma solução de glicose 50% (500mg/kg), com coletas de sangue para determinação de glicemia nos tempos 0, 3, 5, 7, 15, 30, 45 e 60 minutos da injeção de glicose. Amostras de tecido muscular foram coletadas durante ovariohisterectomia, imediatamente congeladas em nitrogênio líquido, e posteriormente armazenadas a -80°C até a preparação das membranas por meio de homogeneização e centrifugação sequencial. Para os experimentos de ligação hormônio-receptor, as membranas foram incubadas na presença de 20.000cpm de 125I-insulina humana, e concentrações crescentes de insulina regular humana não marcada para saturação fria. O IVGTT não mostrou diferenças entre as pacientes em diferentes fases do ciclo estral com relação a glicemia basal, ou na resposta glicêmica após infusão de glicose nos tempos estudados. Dois sítios de ligação da insulina, um de alta-afinidade, e outro de baixa afinidade, foram detectados pela análise de Scatchard, e diferenças significativas foram detectadas na constante de dissociação (Kd1) e capacidade de ligação máxima (Bmax1) dos sítios de ligação de alta-afinidade. O Kd1 para o grupo anestro (6,54±2,77nM/mg de proteína) foi menor (P<0,001) que os Kd1 dos grupos estro (28,54±6,94 nM/mg de proteína) e diestro (15,56±3,88nM/mg de proteína). Os Bmax1 dos grupos estro (0,83±0,42nM/mg de proteína) e diestro (1,24±0,24nM/mg de proteína) também foram maiores que os valores encontrados no grupo anestro (0,35±0,06nM/mg de proteína). Estes resultados demonstram uma modulação das características de ligação da insulina nas diferentes fases do ciclo estral em cães, evidenciando uma menor afinidade de ligação da insulina ao seu receptor no tecido muscular durante o estro e diestro. Contudo, esta menor afinidade de ligação hormônio-receptor é compensada por uma maior capacidade de ligação, o que fica também evidenciado pela ausência de diferenças na resposta glicêmica das pacientes após um desafio com glicose por via endovenosa.(AU)

A meta-analysis reveals prognostic role of programmed death ligand-1 in Asian patients with non-small cell lung cancer / 华中科技大学学报（医学）（英德文版）

Accumulating studies explored the clinicopathologic and prognostic value of programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC), but the results were controversial. We therefore conducted a meta-analysis to evaluate the predictive role of PD-L1 in NSCLC patients. We systematically collected relevant studies from PubMed, Embase, Web of Science and China National Knowledge Infrastructure. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS), and odd ratios (ORs) with 95% CIs for clinicopathologic factors were calculated. A total of 15 studies involving 3605 patients were included in this meta-analysis. The results showed no prognostic role of PD-L1 in the whole patients (HR=1.60, 95% CI: 0.88-2.89, P=0.123). Subgroup analysis showed that PD-L1 was associated with decreased OS in Asian patients (HR=2.00, 95% CI: 1.55-2.57, P<0.001). Among all the clinicopathologic factors, PD-L1 overexpression was significantly in relevance with poor tumor cell differentiation (HR=1.84, 95% CI: 1.49-2.28, P<0.001), late stage (HR=1.21, 95% CI: 1.02-1.43, P=0.026) and anaplastic lymphoma kinase (ALK) translocation (HR=2.63, 95% CI: 1.08-6.40, P=0.034), but not with other factors. In conclusion, our meta-analysis demonstrated that PD-L1 has a prognostic role in Asian patients with NSCLC.

Role of axl in preeclamptic EPCs functions / 华中科技大学学报（医学）（英德文版）

Axl encodes the tyrosine-protein kinase receptor, participating in the proliferation and migration of many cells. This study examined the role of Axl in functions of endothelial progenitor cells (EPCs). Axl was detected by RT-PCR and Western blotting in both placentas and EPCs from normal pregnancy and preeclampsia patients. The Axl inhibitor, BMS777-607, was used to inhibit the Axl signalling pathway in EPCs. Cell proliferation, differentiation, migration and adhesion were measured by CCK-8 assay, cell differentiation assay, Transwell assay, and cell adhesion assay, respectively. Results showed the expression levels of Axl mRNA and protein were significantly higher in both placentas and EPCs from preeclampsia patients than from normal pregnancy (P<0.05). After treatment with BMS777-607, proliferation, differentiation, migration and adhesion capability of EPCs were all significantly decreased. Our study suggests Axl may play a role in the function of EPCs, thereby involving in the pathogenesis of preeclampsia.

IRF6, RYK, and PAX9 expression in facial tissue of children with cleft palate / Expresión de IRF6, RYK y PAX9 en el tejido facial de niños con paladar fisurado

Cleft lip and palate (CLP) is a congenital anomaly characterized by the inappropriate fusion of the upper lip, alveolus, and secondary palate. This study investigated whether expression of interferon regulatory fac tor 6 (IRF6), receptor-like tyrosine kinase (RYK), and paired-box 9 (PAX9), which are essential for the normal development and morphogenesis of craniofacial structures, is dysregulated in children with CLP. Oral mucosa tissue samples were obtained from patients with complete bilateral (CB) CLP (n= 19) during corrective plastic surgery and unaffected control subjects (n= 7). IRF6, RYK, and PAX9 expression was assessed by immunohistochemistry, and data were analyzed with the Mann-Whitney test. In patients, IRF6 immunoreactivity in the connective tissue was moderate to high, but the overall number of IRF6-positive oral epithelial cells was lower than that in controls (z= -3.41; P= 0.01). RYK expression was observed only sporadically in the oral epithelium of 4 patients, in contrast to the control group (z= -3.75; P< 0.001). PAX9-positive epithelial cells were present in low to moderate numbers in patients with CBCLP, while an abundance of these cells was observed in the basal layer of the oral epithelium in controls (z= -3.60; P<0.001). IRF6 is the main connective tissue regulatory factor in CBCLP, and its low level of expression in the oral epithelium suggests a reduced potential for epitheliocyte differentiation, while low PAX9 and RYK expression may explain the decreased cell migration and cleft remodeling in CBCLP.

La fisura labial y palatina (FLP) son anomalías congénitas caracterizadas por la fusión inadecuada del labio superior, alvéolo y paladar secundario. En este estudio se investigó si en niños con FLP hay una desregulación de la expresión del factor regulador de interferón 6 (IRF6), del receptor de la tirosina quinasa (RYK), y del factor de transcripción PAX9, que son esenciales para el desarrollo normal y la morfogénesis de las estructuras craneofaciales. Se obtuvieron muestras de la mucosa oral de pacientes con FLP completa bilateral (CB) (n= 19), tomadas durante la realización de cirugía plástica correctiva, y de sujetos de control no afectados (n= 7). Se evaluó la expresión de IRF6, RYK y PAX9 por inmunohistoquímica, y los datos se analizaron con la prueba de Mann-Whitney. En los pacientes, la inmunoreactividad de IRF6 en el tejido conectivo fue de moderada a alta, pero el número total de células epiteliales orales positivas para IRF6 fue menor que en los controles (z= -3,41; P= 0,01). La expresión de RYK se observó sólo esporádicamente en el epitelio oral de 4 pacientes, en contraste con el grupo control (z= -3,75; P<0.001). Células epiteliales positivas para PAX9 estaban presentes en números bajos a moderados en pacientes con FLP completa bilateral, mientras que se observó una abundante cantidad de estas células en la capa basal del epitelio oral en los controles (z= -3,60; P<0,001). IRF6 es el principal factor regulador del tejido conectivo con FLP completa bilateral, y su bajo nivel de expresión en el epitelio oral sugiere un potencial reducido para la diferenciación del epitelio, mientras que la expresión baja de PAX9 y RYK pueden explicar la disminución de la migración celular y la remodelación de la fisura con FLP completa bilateral.