Lorlatinib: a third generation ALK inhibitor for treatment of non-small cell lung carcinoma / 药学学报

Lorlatinib (PF-06463922) is a highly selective and potent third generation anaplastic lymphoma kinase (ALK) inhibitor with dual activity against c-ros oncogene 1, a receptor tyrosine kinase (ROS1). In November 2018, the US Food and Drug Administration approved lorlatinib for treatment of disease progression in ALK-positive and late-stage NSCLC patients who receive the treatment with crizotinib and at least one of other ALK inhibitors; and those with disease progression after treatment of alectinib or ceritinib as the first ALK inhibitor. The results of phase I/II clinical trials showed that it has effective initial anti-tumor activity, strong intracranial therapeutic activity, with less tolerance and safety issues. This paper systematically reviewed the chemical structure, mechanism of action, pharmacodynamics, pharmacokinetics, usage and dosage, clinical research, safety and upcoming research fields of lolatinib, to provide an update on clinical or laboratory research and clinical practice.

Relationship between Gut Microbiota and Phosphorus Metabolism in Hemodialysis Patients: A Preliminary Exploration / 中华医学杂志(英文版)

Background@#Hyperphosphatemia is a risk factor associated with mortality in patients on maintenance hemodialysis. Gut absorption of phosphate is the major source. Recent studies indicated that the intestinal flora of uremic patients changed a lot compared with the healthy population, and phosphorus is an essential element of bacterial survival and reproduction. The purpose of this study was to explore the role of intestinal microbiota in phosphorus metabolism.@*Methods@#A prospective self-control study was performed from October 2015 to January 2016. Microbial DNA was isolated from the stools of 20 healthy controls and 21 maintenance hemodialysis patients. Fourteen out of the 21 patients were treated with lanthanum carbonate for 12 weeks. Thus, stools were also collected before and after the treatment. The bacterial composition was analyzed based on 16S ribosomal RNA pyrosequencing. Bioinformatics tools, including sequence alignment, abundance profiling, and taxonomic diversity, were used in microbiome data analyses. Correlations between genera and the serum phosphorus were detected with Pearson's correlation. For visualization of the internal interactions and further measurement of the microbial community, SparCC was used to calculate the Spearman correlation coefficient with the corresponding P value between each two genera.@*Results@#Thirteen genera closely correlated with serum phosphorus and the correlation coefficient was above 0.4 (P < 0.05). We also found that 58 bacterial operational taxonomic units (OTUs) were significantly different and more decreased OTUs were identified and seven genera (P < 0.05) were obviously reduced after using the phosphate binder. Meanwhile, the microbial richness and diversity presented downward trend in hemodialysis patients compared with healthy controls and more downward trend after phosphorus reduction. The co-occurrence network of genera revealed that the network complexity of hemodialysis patients was significantly higher than that of controls, whereas treatment with lanthanum carbonate reduced the network complexity.@*Conclusions@#Gut flora related to phosphorus metabolism in hemodialysis patients, and improving intestinal microbiota may regulate the absorption of phosphate in the intestine. The use of phosphate binder lanthanum carbonate leads to a tendency of decreasing microbial diversity and lower network complexity.

Correlation between the expression of aryl hydrocarbon receptor mRNA and tryptophan dioxygenase mRNA in patients with acute leukemia / 新乡医学院学报

Objective To investigate the correlation between the expression of aryl hydrocarbon receptor(AHR) mR-NA and tryptophan dioxygenase (TDO) mRNA in bone marrow mononuclear cells of patients with acute leukemia.Methods Sixty-five patients with newly diagnosed acute leukemia in Henan Provincial People's Hospital from August 2013 to August 2014 were selected as observation group,and there were 50 patients with acute myeloid leukaemia(AML) and 15 patients with acute lymphoblastic leukaemia(ALL).Fifteen patients with anemia were selected as control group in the same period(excluding the malignant disease of blood system).The expression of AHR mRNA and TDO mRNA in bone marrow mononuclear cells of patients in the groups was detected by real time fluorescence quantitative reverse transcription polymerase chain reaction.The correlation between AHR mRNA and TDO mRNA was analyzed.Results The expression of TDO mRNA and AHR mRNA in bone marrow mononuclear cells of AML and ALL patients in the observation group was significantly higher than that in the control group(P ＜0.05).There was no significant difference in the expression of TDO mRNA and AHR mRNA in bone marrow mononuclear cells between AML and ALL patients (P ＜ 0.05).There was significantly positive correlation between the expression of TDO mRNA and AHR mRNA in bone marrow mononuclear cells of AML and ALL patients(r =0.801,0.922;P ＜ 0.05).The levels of white blood cell,hemoglobin,platelet and lactate dehydrogenase were not related to the expression of TDO mRNA and AHR mRNA in AML and ALL patients(P ＜ 0.05).Conclusion The expression of TDO and AHR in bone marrow mononuclear cells of acute leukemia patients is high,and the TDO-KYN-AHR pathway promotes the development of acute leukemia.

Preliminary study of HCT-CI score system for prognosis prediction in elderly patients with acute myeloid leukemia after chemotherapy / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the value of the HCT-CI score in chemotherapy risk assessment and prognosis of elderly patients with acute myeloid leukemia (AML).</p><p><b>METHODS</b>The clinical data of 116 AML patients older than 60 years in the department of Hematology, Henan Provincial People's Hospital from January 2000 to December 2010 were analyzed retrospectively. All patients received cytarabine-based regimens, including protocol DA, MA, IA, AA or CAG, followed by cytarabine-based postremission treatment. (1) Comorbidities were evaluated by using HCT-CI score, the early death rates and median survival time were compared among these different groups. (2) These prognostic factors were analyzed by univariate and multivariate analyses.</p><p><b>RESULTS</b>(1) All 116 cases were followed-up. The patient cohort was divided into those with HCT-CI scores of 0, 1 or 2, or ≥ 3. Early death rates were 3.7%, 12.1% and 23.21% in above three groups, respectively (P < 0.01). Overall survival were 345, 225 and 113 days, respectively (P < 0.01). (2) HCT-CI score ≥ 3 (P < 0.01), antecedent MDS history (P = 0.035), high-risk karyotype (P = 0.018), white blood cells at diagnosis ≥ 100×10(9)/L (P = 0.041) were independent adverse prognostic factors with multivariate analysis.</p><p><b>CONCLUSION</b>(1) The HCT-CI score can objectively assess elderly AML patients with comorbidities and predict chemotherapy risk in older patients receiving AML induction therapy. (2) Antecedent MDS history, high-risk karyotype, high white blood cell, and HCT-CI score ≥ 3 are independent adverse prognostic factors of elderly AML patients.</p>

Preparation of bilayer spider silk protein vascular scaffold and its biomechanical properties and cell compatibility / 医用生物力学

Objective To prepare a bilayer spider silk protein vascular scaffold using electrospinning, observe microstructure of the vascular scaffold and study its biomechanical properties and cell compatibility. Methods Spinning solution was electrospun to prepare (pNSR16/PCL/CS)/(pNSR16/PCL/Gt) bilayer spider silk protein vascular scaffold using rotating receiving rod as the collection device. The effects of mass fraction and wall thickness on the porosity, bursting strength, tensile properties, suture retention strength and water permeability of the vascular scaffold were investigated, and cytotoxicity and cell adhesion property of the vascular scaffold were tested. Results The vascular scaffold presented three-dimensional porous microstructure with randomly distributed fibers. The bursting strength, tensile strength and suture retention strength were directly proportional to mass fraction and wall thickness, but the porosity, water permeability and elongation at break were inversely proportional to mass fraction and wall thickness. The bursting strength range of vascular scaffold was 43~183 kPa, which was higher than the physiological blood pressure; the suture strength was above 0.19 N, which was consistent with the transplantation requirement in vivo; the tensile strength was higher than that of human radial artery, which met the transplantation requirement in vivo; the range of water permeability was 0.3~0.6 mL•min-1•cm-2. The vascular scaffold had no cytotoxicity and facilitated the adhesion and proliferation of endothelial cells. Conclusions It is feasible to prepare the bilayer spider silk protein vascular scaffold through electrospinning. The superior biomechanical properties and biocompatibility properties show that the bilayer spider silk protein vascular can be used for construction of the tissue engineered blood vessels in vitro, with prospect for further vascular graft study, which lays a foundation for its clinical application.

Study on the diagnostic value of lung biopsy in hematologic patients with lung infection / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the diagnostic value and safety of percutaneous lung biopsy in hematologic patients with lung infection.</p><p><b>METHODS</b>28 cases hematologic patients received CT-guided percutaneous lung biopsy when they developed a fever associated with pulmonary nodules or lumps in CT scan whose clinical diagnosis were unclear during or after chemotherapy. Sample of each lesion were drawn twice. The lung tissue was re-scanned after lung biopsy to check up in order to discover bleeding and pneumothorax. Biopsy tissue was examined by bacteria culture, acid-fast staining and pathology. Pathological examination contained HE staining, acid-fast stain, PAS stain, TB-DNA, methenamine silver and others.</p><p><b>RESULTS</b>28 cases contain 24 males and 4 females. Median age was 40 15 - 77 years old. Blood tests were as follows: 3 cases with HGB > 110 g/L, 9 with HGB 90 - 110 g/L, 12 with HGB 60 - 89 g/L, 4 with HGB < 60 g/L. 8 with WBC > 10×10(9)/L, 6 with WBC (4 - 10)×10(9)/L, 13 with WBC < 4×10(9)/L, 1 with WBC < 2×10(9)/L; 14 with PLT > 100×10(9)/L, 5 with PLT (50 - 100)×10(9)/L, 5 with PLT < 50×10(9)/L, 4 with PLT < 30×10(9)/L. 4 cases had mild extended PT, 3 mild extended APTT, 3 FIB lower than normal. Lung CT scans were as follows: 4 cases with simply lesion in right lung, 4 with simply lesion in left lung, 20 with lesions in bilateral lung. 8 cases were diagnosed as fungal infection, 3 as tuberculosis infection, 1 as lung cancer, 1 as pulmonary infiltration of lymphoma, 1 as pulmonary infiltration of leukemia, and 14 as inflammatory changes with no specific diagnosis. 4 cases came with pneumothorax during lung biopsy, mild to moderate in 3 cases and severe in 1 case. Severe patient turned better after CT-guided suction. 3 cases with mild hemoptysis turned better after treatment.</p><p><b>CONCLUSION</b>When hematopathy patients are with pulmonary nodules or lumps in CT scan whose clinical diagnosis is unclear, CT-guided percutaneous lung biopsy is safe and conducive to early diagnosis and conducive to early rehabilitation of patients if the coagulation function is basically normal and platelet count is not too low.</p>

The effect of cyclosporine A on lipopolysaccharide-induced acute lung injury in mice / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the effect of mitochondrial permeability transition pore inhibitor cyclosporine A (CsA) on lipopolysaccharide (LPS)-induced acute lung injury in mice.</p><p><b>METHODS</b>All male ICR mice were randomly divided into five groups (n = 24): control group, LPS group, dexamethasone group, cyclosporine A(CsA) group and CsA + atractyloside(Atr) group. Six hours after treatment with LPS, the activity of lactate dehydrogenlase (LDH) in bronchoalveolar lavage fluid (BALF) and level of tumor necrosis factor-alpha (TNF-alpha) in lung tissue were detected. The lung wet weight/dry weight ratio and the pulmonary capillary permeability index were also detected.</p><p><b>RESULTS</b>In contrast to LPS group, the mitochondrial permeability transition pore inhibitor CsA induced a decrease in LDH activity in the BALF and TNF-alpha level in lung tissue, lung wet weight/dry weight ratio and the pulmonary capillary permeability index were declined. Atractyloside, the activator of mitochondrial permeability transition pore, almost abolished the role of CsA on LPS-induced lung injury.</p><p><b>CONCLUSION</b>These results suggested that CsA plays the protective effect on LPS-induced lung injury in mice, it is likely through inhibiting the opening of mitochondrial permeability transition pore.</p>

Molecular mechanism of anti-apoptotic action of survivin in NCI-H446 lung cancer cells / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate cell apoptosis induced by survivin ASODN and clarify the precise mechanism of anti-apoptotic action of survivin.</p><p><b>METHODS</b>Cells of lung cancer cell line NCI-H446 were treated with survivin ASODN at different concentrations. The changes of survivin mRNA and protein expression were assessed by RT-PCR and Western blot assay. The apoptosis index (AI) and proliferation index (PI) were determined by flow cytometry (FCM). After 500 mmol/L survivin ASODN treatment, cells were stained with Rh123 to detect changes of mitochondrial membrane potential (deltapsim) by FCM. The concentration of cytoplasmic cytochrome c (cyt-c) was continuously determined by ELISA. Relative activities of caspase-9 and caspase-3 were assessed by colorimetric assay. The expression of caspase-8 protein was measured by Western blot assay. The apoptotic rates of lung cancer cells induced by survivin ASODN with or without mitochondrial permeability transition pole (MPTP) inhibitor CsA treatment were assessed by FCM.</p><p><b>RESULTS</b>Down-regulated survivin mRNA was shown to be in dose-dependent and time-dependent manners. Its maximal effect was achieved at a concentration of 500 nmol/L for 72 h, at which mRNA was down-regulated by 62.7%, the expression of survivin protein in NCI-H446 cells was also obviously decreased. After treatment with survivin ASODN at concentration of 500 mmol/L for 72 h, AI was 48.35%, higher than that of control, lipofectin, NSODN, survivin ASODN 100 mmol/L and 300 mmol/L groups (3.75%, 3.41%, 4.69%, 19.85% and 34.39%, respectively). PI was 24.38%, lower than that of control, lipofectin, NSODN, survivin ASODN100 and 300 mmol/L groups (75.74%, 73.12%, 71.76%, 51.03% and 38.94%, respectively). Deltapsim was decreased in 9.54% of NCI-H446 cells treated with survivin ASODN for 3 h and 97.06% for 24 h. Following it, release of cyt-c from mitochondria to cytosol and activation of caspase-9 and caspase-3 increased significantly. The above mentioned indicators changed with a time-dependent and time diversity relationship. In the presence of CsA, the apoptotic rate of lung cancer cells induced by survivin ASODN was decreased significantly. No up-regrulation and activation in caspase-8 protein was observed.</p><p><b>CONCLUSION</b>Survivin inhibits apoptosis via regulation of mitochondrial-dependent pathway. survivin ASODN can not only induce apoptosis but also inhibit cell proliferation through blocking the expression of survivin mRNA and protein.</p>

Significance and mechanisms of overexpression of PAK1 gene in epithelial ovarian neoplasms / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the significance and mechanisms of overexpression of p21-activated kinase 1 gene (PAK1) in epithelial ovarian neoplasms.</p><p><b>METHODS</b>Immunohistochemistry, fluorescence in situ hybridization and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling methods were used to examine the protein expression and amplification of PAK1 and cell apoptosis in 30 benign ovarian adenomas, 20 borderline tumors and 80 ovarian carcinomas by tissue microarray.</p><p><b>RESULTS</b>In immunohistochemistry study, overexpression of PAK1 protein was observed in 7 (25.9%) informative benign ovarian adenomas, 7 (36.8%) borderline tumors and 53 (68.8%) ovarian carcinomas. A significant inverse correlation of PAK1 overexpression and cell apoptosis was observed in these epithelial ovarian neoplasm cohorts (P = 0.002). In addition, 27/31 (87.1%) poorly differentiated (G3) carcinomas showed overexpression of PAK1, the frequency was significantly higher than that in tumors of G1 - G2 (26/46, 56.5% , P =0.01). In fluorescence in situ hybridization study, only 2 (4.7%) informative ovarian carcinomas showed amplification of PAK1 gene. None of the borderline and benign ovarian tumors showed PAK1 amplification.</p><p><b>CONCLUSION</b>Overexpression of PAK1 protein may be involved in the tumorigenesis of epithelial ovarian neoplasms and it is associated closely with the malignant histological phenotype of ovarian carcinomas. Mechanism other than gene amplification of PAK1 may play a more important role in the regulation of protein expression of PAK1 in ovarian tumors.</p>

Identification of Puumala like viruses in China / 中华实验和临床病毒学杂志

<p><b>BACKGROUND</b>To confirm if Puumala like viruses exist in China.</p><p><b>METHODS</b>RNA was extracted from lungs of bank voles captured in the Northeast China, partial S segments genome of Puumala viruses were amplified and sequenced.</p><p><b>RESULTS</b>926 bp cDNA of S segments of Puumala like virus was amplified and sequenced. The phylogenetic analysis revealed that the Puumala like viruses found in China were most close to that found in Far East region of Russia.</p><p><b>CONCLUSIONS</b>Puumala like virus does exist in Northeast China, and the nucleotides sequence of the viruses have high homolog to Puumala viruses found in Russia.</p>

Diagnostic value of LUNX gene to marrow micrometastases of lung cancer / 中华检验医学杂志

Objective To explore the diagnostic value of LUNX gene to marrow micrometastases of lung cancer.Methods To detect LUNX mRNA of marrow samples of 51 patients of lung cancer,4 patients of breast cancer,6 patients of lymphadenoma,3 patients of liver cancer and 22 patients of benign disease by real-time RT-PCR.Results The positive detection rate and meso-copies of lung cancer were 58.8% (30/51) and 35copies/ml respectively.The positive detection rate and meso-copies of other diseases were all 0,The positive detection rate and meso-copies of lung cancer was significantly higher than that of patients with other diseases (x~2=11.12,U_c=3.7329,P