KRAS mutation is one of the most frequent driver gene mutations found in patients with non-small cell lung cancer (NSCLC). KRAS-mutant NSCLC is highly heterogeneous. Various mutation types and different co-mutational signatures affect tumor biological behavior and therapeutic responses. NSCLC patients with KRAS mutations could relatively benefit from immunotherapy, while the effects of KRAS mutations on chemotherapy are still controversial. The treatment methods of KRAS-mutant lung cancer have followed the therapy of NSCLC without driver gene mutation for a long time. With the introduction of novel KRAS G12C inhibitors in the clinic, the therapeutic landscape has begun to change and has made the preliminary advance, and the combined therapies resulted in encouraging signals of efficacy both in preclinical and early phase trials. This paper reviews the biological and clinical characteristics as well as the latest treatment progress of KRAS-mutant NSCLC.

Objective To evaluate the precision of BREEZE~(TM) glucose monitor and correlation of glucose measurements between fingertip capillary whole blood glucose(CBG)using BREEZE~(TM) glucose monitor and venous plasma glucose(VPG)using autoanalyzer.Methods All samples of venous plasma and fingertip blood from 188 diabetes or non-diabetes patients were detected for glucose level at fasting,30,60 and 120 min postprandial.BREEZE~(TM) glucose monitor and autoanalyzer measured CBG and VPG respectively.Intra-and inter- coefficients of variations were determined using 10 BREEZE~(TM) glucose monitors with normal,slight high and high glucose levels for the three lots of strips.Results The correlation coefficients between CBG and VPG were all higher than 0.950 at fasting and different postprandial time.98.94% of all measurements were in the A zone when using error-grid analysis.The relevant differences between CBG and VPG were less than 5% at different blood glucose concentrations.The intra-and inter-coefficients of variations of blood glucose values at different blood glucose concentrations using different lots of strips were within 5%.Conclusion BREEZE~(TM) glucose monitor provides high accurate and precise glucose readings on fasting and different postprandial time points over a variety of blood glucose concentrations.

BACKGROUNDRecently, some studies had shown that elevated serum uric acid (SUA) itself may increase the risk for development of renal disease in patients with diabetes. This study aimed to explore whether SUA was a predictor of microalbuminuria and impaired renal function in type 2 diabetes in Chinese patients.

METHODSThis cross-sectional study included 2108 type 2 diabetic patients. Kidney function was estimated using the simplified modification of diet in renal disease (MDRD) equation to obtain estimated glomerular filtration rate. The urine samples were obtained for measuring the albumin-to-creatinine ratio (ACR).

RESULTSAccording to the ACR level, these patients were divided into two groups, normal ACR (NA) and non-normal ACR (non-NA). Both SUA and creatinine were significantly higher in the non-NA group than those in the NA group ((318.89 ± 107.52) vs. (283.44 ± 88.64) µmol/L, and (95.08 ± 53.24) vs. (79.63 ± 18.20) µmol/L, respectively). Logistic regression analysis showed that diabetic duration, systolic blood pressure, creatinine and SUA were the independent predictors of albuminuria. Furthermore, to identify the factors associated with renal function, these patients were divided into two groups according to the MDRD level (MDRD < 90 or MDRD ≥ 90). Both SUA and creatinine were significantly higher in the lower MDRD group than those in the higher MDRD group ((301.90 ± 96.46) vs. (264.07 ± 84.74) µmol/L, and (89.10 ± 31.00) vs. (66.37 ± 11.15) µmol/L, respectively). Logistic regression analysis showed that only age and SUA were the independent predictors of MDRD.

CONCLUSIONHigh-normal SUA was associated with albuminuria and impaired glomerular filtration rate in Chinese type 2 diabetic patients.

Adult ; Aged ; Albuminuria ; blood ; physiopathology ; Diabetes Mellitus, Type 2 ; blood ; complications ; physiopathology ; Female ; Glomerular Filtration Rate ; physiology ; Humans ; Male ; Middle Aged ; Uric Acid ; blood

BACKGROUNDRecently, it has been suggested that the serum uric acid (SUA) level decreased in diabetic patients. The aim of this study was to explore the association between SUA level and different state of glucose metabolism and glomerular filtration rate (GFR) reflected by the simplified Modification of Diet in Renal Disease (MDRD) equation and to test the hypothesis that high MDRD is one of the determinants of SUA level.

METHODSThis cross-sectional study included 2373 subjects in Beijing who underwent a 75 g oral glucose tolerance test (OGTT) for screening of diabetes. According to the states of glucose metabolism, they were divided into normal glucose tolerance, impaired glucose regulation and diabetes.

RESULTSMultiple stepwise linear regression analysis showed that adjusted by gender, SUA was positively correlated with body mass index (BMI), waist/hippo ratio, systolic blood pressure (SBP) and triglyceride, meanwhile negatively correlated with age, hemoglobin A1c, fasting insulin and MDRD. There was an increasing trend in SUA concentration and a decreasing trend in MDRD when the levels of fasting plasma glucose (FPG) increased from low to high up to the FPG level of 8.0 mmol/L; thereafter, the SUA concentration started to decrease with further increases in FPG levels, and the MDRD started to increase with further increases in FPG levels.

CONCLUSIONThis study confirmed the previous finding that SUA decreased in diabetes and provided the supporting evidence that the increased MDRD might contribute to the fall of SUA.

Adult ; Aged ; Blood Glucose ; metabolism ; Cross-Sectional Studies ; Female ; Glomerular Filtration Rate ; physiology ; Humans ; Linear Models ; Male ; Middle Aged ; Uric Acid ; blood

OBJECTIVETo evaluate the association of Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma (PPARgamma) gene with type 2 diabetes (T2DM) in Chinese Han population.

METHODSThe present investigation was carried out using the keywords "PPARgamma", "pparg", "Pro12Ala", "type 2 diabetes", and "Chinese. The odds ratios (OR) for Ala12 used as the metric of choice were calculated in the dominant and additive model separately. The Meta-analysis was conducted by software STATA 11.0.

RESULTS(1) We identified 22 studies, of which 17 studies involving 3927 type 2 diabetes cases and 3364 controls fell into the inclusion criteria. The analysis indicated no significant inter-study heterogeneity and publication bias. (2) The frequencies of the minor allele Ala12 in type 2 diabetes and control groups were 4.8% and 4.6% respectively. (3) The combined overall OR of dominant and additive model calculated by fix-effects meta-analysis for type 2 diabetes and the Pro12Ala polymorphism, were 0.95 (95% CI: 0.80, 1.12) and 0.93 (95% CI: 0.79, 1.09) respectively.

CONCLUSIONIn this meta-analysis, the Pro12Ala gene variant (rs1801282) is not found to be associated with the susceptibility for type 2 diabetes in Chinese Han population.

Asian Continental Ancestry Group ; genetics ; Diabetes Mellitus, Type 2 ; genetics ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; PPAR gamma ; genetics ; Polymorphism, Genetic

The essence of endogenous turbidity in Chinese medicine (CM) is different from cream, fat, phlegm, retention, damp, toxicity, and stasis. Along with the development of modern scientific technologies and biology, researches on the essence of endogenous turbidity should keep pace with the time. Its material bases should be defined and new connotation endowed at the microscopic level. The essence of turbidity lies in abnormal functions of zang-fu organs. Sugar, fat, protein, and other nutrient substances cannot be properly decomposed, but into semi-finished products or intermediate metabolites. They are inactive and cannot participate in normal material syntheses and decomposition. They cannot be transformed to energy metabolism, but also cannot be synthesized as executive functioning of active proteins. If they cannot be degraded by autophagy-lysosome or ubiquitin-prosome into glucose, fatty acids, amino acids, and other basic nutrients to be used again, they will accumulate inside the human body and become endogenous turbidity. Therefore, endogenous turbidity is different from final metabolites such as urea, carbon dioxide, etc., which can transform vital qi. How to improve the function of zang-fu organs, enhance its degradation by autophagy-lysosome or ubiquitin-prosome is of great significance in normal operating of zang-fu organs and preventing the emergence and progress of related diseases.
Autophagy ; Humans ; Medicine, Chinese Traditional ; Proteasome Endopeptidase Complex

OBJECTIVETo investigate the influence of tissue inhibitor of metalloproteinase 2 (TIMP-2) on the infiltrative patterns of human monocytic leukemic cell line SHI-1 in nude mice.

METHODS1) 1 x 10(7) TIMP-2 gene transduced SHI-1 (SHI-1-TIMP-2) and SHI-1 transduced MSCV gene (SHI-1-MSCV) cells were inoculated via tail vein into 6-week nude mice, which pretreated by splenectomy, cytoxan intraperitoneal injection, and sublethal irradiation(referred as SCI nude mice). 30 days after inoculation, half of the mice were sacrificed, and the infiltration patterns were investigated by histological exam and human CD45 immunohistochemistry, other mice were observed for survival time. 2) Leukemic cells inoculated subcutaneously into the axillary area of mice without any pre-treatment. On day 23 and 30, mice were sacrificed to measure the volume of neoplasm. TIMP-2 protein expression and the micro vein density were detected by immunohistochemistry.

RESULTSIn SCI nude mice inoculated via caudal vein with SHI-1-TIMP-2 cells, the survival time was shorter and infiltration (including in central nervous system) was higher than that in those inoculated with SHI-1-MSCV cells. However, in inoculated subcutaneously group, the neoplasm though grew rapidly at first, over expression of TIMP-2 limited the tumor growth and angiogenesis.

CONCLUSIONThe functions of TIMP-2 are diversity; the role of TIMP-2 in tumor infiltration and metastasis was worthy of further investigation.

Animals ; Cell Line, Tumor ; DNA, Complementary ; genetics ; Genetic Vectors ; Humans ; Leukemia, Experimental ; genetics ; pathology ; Leukemic Infiltration ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Tissue Inhibitor of Metalloproteinase-2 ; genetics ; Transfection

OBJECTIVETo study the expression of CXCR4 in acute leukemic cells and its clinical significance.

METHODBone marrow samples from 73 acute leukemia patients and leukemic cell lines were investigated by flow cytometry (FCM), the expression of SDF-1 in human marrow stromal cells and meninges were studied by using reverse transcription polymerase chain reaction (RT-PCR). Adhesion, migration and invasion of U937, NB4 and K562 cells were studied in vitro.

RESULTSThe expression rates of CXCR4 in ALL and AML patients was 65.6% and 17.1%, respectively. And it was 0.2%, 41.0% and 52.0% in K562, U937 and NB4 cells, respectively. The extramedullary infiltration rates were 61.9% and 18.2% for CXCR4 positive and negative groups of ALL, respectively (P < 0.05); while in AML, the number of peripheral white blood cells in CXCR4 positive group was lower than that in CXCR4 negative group (P < 0.05). SDF-1alpha could enhance the adhesion, migration and invasion capacity of leukemic cells in vitro.

CONCLUSIONOverexpression of CXCR4 in AL cells might be the molecular mechanism of extramedullary infiltration in leukemia.

Acute Disease ; Adolescent ; Adult ; Aged ; Bone Marrow Cells ; metabolism ; pathology ; Cell Adhesion ; Cell Line, Tumor ; Cell Movement ; Chemokine CXCL12 ; genetics ; Female ; Fibroblasts ; metabolism ; pathology ; Flow Cytometry ; Gene Expression Regulation, Neoplastic ; Humans ; K562 Cells ; Leukemia ; genetics ; metabolism ; pathology ; Leukemic Infiltration ; metabolism ; pathology ; Male ; Meninges ; metabolism ; pathology ; Middle Aged ; Receptors, CXCR4 ; biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction ; U937 Cells

OBJECTIVETo study the expression ratio of AML1-ETO9a (AE9a) isoform in t(8;21) acute myeloid leukemia (AML) and its clinical significance.

METHODSBone marrow samples from 44 newly diagnosed t(8;21) AML patients co-expressed AE9a and AE were screened by RT-PCR. The alteration of the AE9a expression ratio was monitored during follow-up by using quantitative real-time RT-PCR (qPCR).

RESULTSThe expression level of AE9a was markedly lower than that of AE in these patients. There was a positive correlation between the expression level of AE9a and AE in most of bone marrow samples. The transcript level of both AE9a and AE was decreased in the 44 patients after one course of standard chemotherapy, but the percentage of AE9a expression level was increased in comparison with that before treatment (P < 0.05). After one course of standard chemotherapy treatment, the percentage of AE9a in incomplete remission (ICR) patients was significantly higher than that in CR patients (P < 0.05). Relapsed patients had a higher AE9a ratio than the unrelapsed patients (P < 0.05). During the remission, the percentage of AE9a in 11/17 relapsed patients obviously elevated even while the expression of AE fusion gene at low level.

CONCLUSIONSAE9a and AE co-expressed in most of AML patients with t(8;21) translocation. The expression level of AE9a was lower than that of AE, and there is a positive correlation between the expression level of these two isoforms. The sensitivity of AE9a gene to the standard chemotherapy is less than that of the AE fusion gene. Monitoring the AE9a to AE ratio during the CR can predict the early relapse of the disease compared to monitoring the AE alone.

Adolescent ; Adult ; Child ; Chromosomes, Human, Pair 21 ; Chromosomes, Human, Pair 8 ; Core Binding Factor Alpha 2 Subunit ; genetics ; Female ; Gene Expression ; Humans ; Leukemia, Myeloid, Acute ; genetics ; pathology ; Male ; Middle Aged ; Oncogene Proteins, Fusion ; genetics ; Protein Isoforms ; genetics ; RUNX1 Translocation Partner 1 Protein ; Translocation, Genetic ; Young Adult

OBJECTIVETo observe the effect of leukemic cells on blood-brain barrier (BBB) in mice with central nervous system leukemia (CNSL) by establishing mice CNSL model and an in vitro BBB model and explore the mechanism of leukemic cell infiltrating central nervous system (CNS).

METHODSAfter splenectomy, cytoxan intraperitoneal injection, and sublethal irradiation, 10 BALB/c nu/nu mice were transplanted intravenously with 1.2 × 10(7) of SHI-1 human monocytic leukemic cells. Mice were monitored for survival and clinical manifestation of nerve palsy. The leukemic cells engrafted were examined by RT-PCR, histopathology and bone marrow (BM) smears. Immunofluorescence analysis with laser scanning fluorescence confocal microscopy was used to determine the expression of fibrinogen and tight-junction protein ZO-1. An in vitro BBB model composed of human brain microvascular endothelial cells (BMVECs) was developed on a Matrigel-based insert. Different leukemic cell lines were seeded onto the upper compartment of transwell insert. After incubated for 24 h with BMVECs, cells that had migrated into the lower compartment were counted and analyzed.

RESULTS(1) Paralysis with or without sight loss was developed in half the mice 30-35 d after innoculated with SHI-1 cells. Leukemic cells infiltrates were observed in BM and in different part of brain tissues including brain parenchyma. The transcriptions of human MLL/AF6 fusion gene were also detected in BM and brain tissues in paralysis mice. The fibrinogen expression and ZO-1 disruption were detected in the infiltrated tissue. (2) After 24 h incubation with leukemic cells, the BMVECs sheets were disrupted and grew singly and ZO-1 expression was down-regulated markedly. SHI-1 cells showed more injurious to BMVECs and higher invasive rate \[(40.33 ± 1.53)% vs (11.83 ± 1.44)%, P < 0.05\] than HL-60 cells did.

CONCLUSIONOne of the mechanisms of leukemic cells infiltrates CNS in CNSL is injure to the BBB.

Animals ; Blood-Brain Barrier ; physiology ; Central Nervous System ; pathology ; Central Nervous System Neoplasms ; pathology ; HL-60 Cells ; Humans ; Leukemia ; pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude