Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trial.

Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5-6% of non-small cell lung cancer (NSCLC) cases and associated with increased risks of central nervous system (CNS) involvement. Envonalkib, a novel ALK inhibitor, demonstrated promising anti-tumor activity and safety in advanced ALK-positive NSCLC in the first-in-human phase I study. This phase III trial (ClinicalTrials.gov NCT04009317) investigated the efficacy and safety of first-line envonalkib in advanced ALK-positive NSCLC cases. Totally 264 participants were randomized 1:1 to receive envonalkib (n = 131) or crizotinib (n = 133). Median independent review committee (IRC)-assessed progression-free survival (PFS) times were 24.87 (95% confidence interval [CI]: 15.64-30.36) and 11.60 (95% CI: 8.28-13.73) months in the envonalkib and crizotinib groups, respectively (hazard ratio [HR] = 0.47, 95% CI: 0.34-0.64, p < 0.0001). IRC-assessed confirmed objective response rate (ORR) was higher (81.68% vs. 70.68%, p = 0.056) and duration of response was longer (median, 25.79 [95% CI, 16.53-29.47] vs. 11.14 [95% CI, 9.23-16.59] months, p = 0.0003) in the envonalkib group compared with the crizotinib group. In participants with baseline brain target lesions, IRC-assessed CNS-ORR was improved with envonalkib compared with crizotinib (78.95% vs. 23.81%). Overall survival (OS) data were immature, and median OS was not reached in either group (HR = 0.84, 95% CI: 0.48-1.47, p = 0.5741). The 12-month OS rates were 90.6% (95% CI, 84.0%-94.5%) and 89.4% (95% CI, 82.8%-93.6%) in the envonalkib and crizotinib groups, respectively. Grade ≥3 treatment-related adverse events were observed in 55.73% and 42.86% of participants in the envonalkib and crizotinib groups, respectively. Envonalkib significantly improved PFS and delayed brain metastasis progression in advanced ALK-positive NSCLC.

The Association between TREM2 Gene and Late-Onset Alzheimer's Disease in Chinese Han Population.

OBJECTIVE: The objective of this study was to evaluate the impact of single nucleotide polymorphisms (SNPs) in triggering receptor expressed on the myeloid cells 2 protein (TREM2) gene and their interaction with environmental factors and haplotypes on late-onset Alzheimer's disease (LOAD). METHODS: DNA was extracted from the whole blood of the participants and genotyped using PCR and followed by restriction fragment length polymorphism. The Hardy-Weinberg equilibrium test was used in the control group. Multivariate logistic regression analysis was used to determine the relationship between the 4 SNPs of the TREM2 gene and the risk of LOAD. Generalized multifactor dimensionality reduction was used to test the best interaction combination between SNPs and environmental factors. RESULTS: Logistic regression analysis showed that the T allele of rs75932628 and the T allele of rs2234253 were independently associated with increased risk of LOAD, and adjusted odds ratios (ORs) were 1.81 (1.271-2.35) and 1.59 (1.15-2.03), respectively. However, there was no significant association with LOAD for rs142232675 and rs143332484. We found a best model significantly associated with LOAD risk that consisted of rs75932628 and smoking, which scored 10/10 for both the sign test and cross-validation consistency (p = 0.012). Stratified analysis indicated that current smokers with rs75932628-CT/TT genotype have the highest LOAD risk compared to never smokers with rs75932628 - CC genotype, OR (95% confidence interval) = 2.73 (1.72-3.79). Haplotypes of rs75932628 and rs2234253 were analyzed using the SHEsis online software. However, no haplotype was found to be significantly associated with the risk of LOAD. CONCLUSIONS: The T allele of rs75932628 and the T allele of rs2234253 and interaction between rs75932628 and smoking were all correlated with increased risk of LOAD.

[Physiology and genetics research progress of teat traits in pigs].

The pig teat traits are important indices of genetic improvement in pig breeding, which belong to reproductive traits and can directly affect the sows lactation rate and piglet survival rate. Understanding the genetic mechanism underlying the variation of teat traits is of immense value for the improvement of pig reproductive performance. However, the genetic mechanism underlying teat traits (including teat number, type, location distribution, and fluctuating asymmetry) remains elusive. In this review, we summarize the studies on physiology and genetics of teat traits in pigs, including the development process of the mammary gland, the QTL mapping, and candidate gene researches. This review aims to provide a new perspective for the identification of causal mutations and major genes affecting the teat traits and revealing the complex genetic mechanism of the differences in teat number, type and location distribution during embryonic development in pigs.

Raman intensity enhancement of molecules adsorbed onto HfS2 flakes up to 200 layers.

Newly emerging two-dimensional transition metal dichalcogenide HfS2 has received considerable attention recently due to its ultrahigh photoresponsivity, well-balanced carrier mobility and an appropriate band gap which offer potential in electronic and optoelectronic devices. In this work, HfS2 flakes up to 200 layers with varying color contrasts are fabricated and transferred on a SiO2/Si substrate. The Raman intensities of HfS2 flakes and Raman intensities of molecules adsorbed on HfS2 flakes are quantitatively studied both theoretically and experimentally by considering an optical interference effect. The effects of the main experimental factors: thickness of SiO2 and excitation wavelength on Raman intensities are also theoretically investigated. Due to the low absorption of HfS2, many strong high-order interference-induced enhancement peaks are observed which are different from high absorption materials like graphene and MoS2, in which only 2-4 interference-induced enhancement peaks exist. Due to the environmental instability of single layer HfS2 under ambient conditions, multi-layer HfS2 is a better choice than single layer HfS2 as a Raman scattering substrate which has a stronger Raman enhancement and a better environmental stability. The discovery here will expand the application of HfS2 flakes in molecular detection.

Flavonoids from artificially induced dragon's blood of Dracaena cambodiana.

Dragon's blood is a rare traditional medicine used in many countries. Because of its various therapeutic uses, its requirement is increasing dramatically, while formation of dragon's blood need at least several years, so many researchers tried to induce the formation of dragon's blood artificially, but the chemical constituents of artificially induced dragon's blood were rarely studied. In our research, twenty constituents, including three new ones, were isolated from artificially induced dragon's blood of Dracaena cambodiana, five of which are the same with those from natural dragon's blood. In addition, six compounds exhibited cytotoxic activities, and eleven compounds demonstrated antibacterial activities. Artificially induced dragon's blood is expected to be the substituent of natural dragon's blood.

Von Willebrand factor and coagulation factor VIII in Moyamoya disease associated with Graves' disease: A case report.

The present study reported the case of a Chinese boy who was diagnosed with Moyamoya disease (MMD) associated with Graves' disease (GD). An overactivation of von Willebrand factor (vWF) and coagulation factor VIII (FVIII) was identified in the plasma of the patient. Thiamazole and metoprolol treatment was thus administrated. After 2 months of treatment, the patient's thyroid function returned to normal and the neurological symptoms improved gradually. At the same time, the activities of vWF and FVIII were depressed. During the 20-month follow-up, information regarding the neurological symptoms, cerebrovascular imaging, thyroid function, thyroid autoantibodies and coagulation parameters was collected. High levels of thyroid autoantibodies persisted throughout the follow-up period, while other coagulation parameters remained in the normal range. In conclusion, considering the vital role of vWF and FVIII in vascular diseases, it is hypothesized that these two factors may serve an important role in the occurrence of GD associated with MMD.

Label-free LC-MS/MS shotgun proteomics to investigate the anti-inflammatory effect of rCC16.

Clara cell protein (CC16) is an anti-inflammatory protein, which is expressed in the airway epithelium. It is involved in the development of airway inflammatory diseases, including chronic obstructive pulmonary disease and asthma. However, the exact molecular mechanism underlying its anti­inflammatory action remains to be fully elucidated. The aim of the present study was to define the protein profiles of the anti­inflammatory effect of CC16 in lipopolysaccharide (LPS)­treated rat tracheal epithelial (RTE) cells using shotgun proteomics. Protein extracts were obtained from control RTE cells, RTE cells treated with LPS and RTE cells treated with LPS and recombinant CC16 (rCC16). Subsequent label­free quantification and bioinformatics analyses identified 12 proteins that were differentially expressed in the three treatment groups as a cluster of five distinct groups according to their molecular functions. Five of the twelve proteins were revealed to be associated with the cytoskeleton: Matrix metalloproteinase­9, myosin heavy chain 10, actin­related protein­3 homolog, elongation factor 1­α­1 (EF­1­α­1), and acidic ribosomal phosphoprotein P0. Five of the twelve proteins were associated with cellular proliferation: DNA­dependent protein kinase catalytic subunit, EF­1­α­1, tyrosine 3­monooxygenase, caspase recruitment domain (CARD) protein 12 and adenosylhomocysteinase (SAHH) 3. Three proteins were associated with gene regulation: EF­1­α­1, SAHH 3 and acidic ribosomal phosphoprotein P0. Three proteins were associated with inflammation: Tyrosine 3­monooxygenase, CARD protein 12 and statin­related protein. ATPase (H+­transporting, V1 subunit A, isoform 1) was revealed to be associated with energy metabolism, and uridine diphosphate glycosyltransferase 1 family polypeptide A8 with drug metabolism and detoxification. The identified proteins were further validated using reverse transcription­quantitative polymerase chain reaction. These protein profiles, and their interacting protein network, may facilitate the elucidation of the molecular mechanisms underlying the anti­inflammatory effects of CC16.

Long-term expression of zinc transporters in hippocampus following penicillin-induced developmental seizures and its regulation by E-64d.

Autophagy has been shown to be involved in the pathophysiology of developmental seizure-induced brain damage. The present study aimed to examine whether E-64d, an autophagy inhibitor, was able to facilitate developmental seizure-induced hippocampal mossy fiber sprouting, in particular sprouting-associated zinc transporter signals. Recurrent seizures were induced by penicillin every other day in Sprague-Dawley rats from postnatal day 21 (P21). Rats were randomly assigned into the control group (CONT), recurrent seizure group (RS) and the seizure plus E-64d group (E64D). The expression levels of beclin-1 and B-cell lymphoma 2 were analyzed at 1.5, 3, 6 and 24 h after the last seizures using western blot analysis. At P51, mossy fiber sprouting and the mRNA expression levels of zinc transporter 2 (ZnT-2), ZnT-4, ZnT-5, ZnT-6, ZnT-7, divalent cation transporter 1, Zrt-Irt-like protein 6 (ZIP-6), ZIP-7, cathepsin D and cathepsin L in the rat hippocampus were assessed using Timm staining and reverse transcription-quantitative polymerase chain reaction analysis, respectively. Reduced hippocampal mossy fiber sprouting were detected in the E-64d-treated rats compared with the non-treated control. In parallel with these observations, there was a marked reduction in the mRNA expression levels of ZnT-4 at P51 in the E-64d-treated rat hippocampus compared with the non-treated seizure group. Linear correlation analysis showed significant inter-relationship among ZIP-7, ZnT-4, ZnT-5, ZnT-7, cathepsin D and cathepsin L. These results indicate that the ZnT-4/ZIP-7/cathepsin signaling pathway serves a crucial function in the neuroprotective effects of E-64d. Thus, E-64d may offer a novel strategy for the development of therapeutic interventions for developmental seizure-induced brain damage.

[Research advances in diagnosis and therapy of Niemann-Pick disease type C].

Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal lipid storage disease associated with impaired intracellular cholesterol trafficking. A wide spectrum of clinical phenotype has been described, with a possible onset at all ages of life from the neonatal period to adulthood, more often in childhood. Typically, hepatosplenomegaly, dystaxia, dysphagia, dysarthria and dementia are presented in NPC patients. Neurologic symptoms vary according to the onset age, but prolonged neonatal cholestasis, splenomegaly, cataplexy and vertical supranuclear gaze palsy are more specific signs to the diagnosis of the disease. Impaired cholesterol trafficking and unesterified cholesterol accumulation in the late endosomes and lysosomals, as a results of mutations in NPC1 or NPC2 genes, are initial for the disease, and defective cellular autophagy, defective lysosomal calcium homeostasis and oxidative stress may all play roles in the physiological processes. The definite diagnosis requires demonstration of unesterified cholesterol accumulated in fibroblasts cultured from skin biopsies or of pathogenic mutation of NPC1/NPC2 genes. Miglustat, the only available treatment approved to date, can alleviate neurological symptoms and slow disease progression when administered earlier.

Effect of p27 gene combined with Pientzehuang ([characters: see text]) on tumor growth in osteosarcoma-bearing nude mice.

OBJECTIVE: To observe the effect of p27 gene recombinant adenovirus combined with Chinese medicine Pientzehuang ([characters: see text]) on the growth of xenografted human osteosarcoma in nude mice. METHODS: Tissue transplantation was used to construct the orthotopic model of human osteosarcoma Saos-2 cell in nude mice. Thirty tumor-bearing nude mice were randomly divided into 5 groups with 6 mice in each group: blank control group (model of osteosarcoma), empty vector group (recombinant adeno-associated virus-multiple cloning site), Pientzehuang group, p27 gene group and combined treatment group (p27 gene combined with Pientzehuang). The effect of combined treatment on human osteosarcoma was analyzed through the tumor formation, tumor volume and inhibition rate of tumor growth. The expression of p27 was measured by immunohistochemical staining and Western blot. RESULTS: The orthotopic model of osteosarcoma in nude mice was successfully constructed. The general appearance of tumor-bearing nude mice in Pientzehuang and p27 gene groups was markedly improved compared with the blank control group; and in the combined treatment group it was significantly improved compared with the Pientzehuang and p27 gene groups. The tumor growth in the Pientzehuang and p27 gene groups was significantly inhibited compared with the blank control group P<0.05); while in the combined treatment group it was markedly inhibited compared with the Pientzehuang and p27 gene groups (P<0.05). The rates of tumor growth inhibition were 34.1%, 56.5% and 63.8% in the Pientzehuang, p27 gene and combined treatment groups, respectively. Meanwhile, the protein expression of p27 gene in the p27 gene group was significantly increased compared with the blank control group (P<0.05); and it was significantly increased in the combined treatment group compared with the p27 gene and Pientzehuang groups (P<0.05). CONCLUSION: p27 gene introduced by adenovirus combined with Pientzehuang can inhibit the growth of human osteosarcoma cell Saos-2 in nude mice.

A new flavonone from seeds of Alpinia katsumadai and its neuroprotective effect on PC12 cells.

A new flavonone, named as (2R, 3S)-pinobanksin-3-cinnamate(1), together with six known compounds, pinocem-brin (2), pinobanksin (3), 3-O-acetylpinobanksin (4), galangin (5), kumatakenin(6), and 3-methylkaempferol (7), were isolated from a 95% ethanol extract of seeds of Alpinia katsumadai through a combination of various chromatographic techniques, including silica gel and Sephadex LH-20. The structure of compound 1 was elucidated by spectroscopic data analysis. Compound 1 exhibits a potent neuroprotective effect against the corticosterone-damaged PC12 cells, which may be underlying the effect by scavenging intracellular ROS.

Expression profiles of hippocampal regenerative sprouting-related genes and their regulation by E-64d in a developmental rat model of penicillin-induced recurrent epilepticus.

E-64d (a calpain and autophagy inhibitor) has previously been shown safe for the treatment of Alzheimer's disease in humans. In the present study, the potential protective mechanism of E-64d on hippocampal aberrant mossy fiber sprouting was examined in a developmental rat model of penicillin-induced recurrent epilepticus. A seizure was induced by penicillin every other day in Sprague-Dawley rats from postnatal day 21 (P21). The rats were randomly assigned into the control group (CONT1), the control plus E-64d (CONT2), the seizure group (EXP1) and the seizure plus E-64d (EXP2). On P51, mossy fiber sprouting and related gene expression in hippocampus were assessed by Timm staining and real-time RT-PCR methods, respectively. To validate the RT-PCR results, western blot analysis was performed on selected genes. E-64d obviously suppressed the aberrant mossy fiber sprouting in the supragranular region of dentate gyrus and CA3 subfield of hippocampus. Among the total twelve genes, six genes were strongly up- (MT-3, ACAT1, clusterin and ApoE) or down- (ZnT-1 and PRG-3) regulated by developmental seizures (EXP1) compared with that in the CONT1. Up-regulation of ApoE and Clusterin was blocked by pretreatment with E-64d both in mRNA and protein levels. Further, E-64d-pretreated seizure rats (EXP2) showed a significant downregulation of mRNA expression of PRG-1, PRG-3 and PRG-5, cathepsin B and ApoE, as well as up-regulated nSMase and ANX7 in hippocampus when compared with EXP1 rats. The results of the present study suggest that E-64d, an elective inhibitor of calpain and autophagy, is potentially useful in the treatment of developmental seizure-induced brain damage both by regulating abnormal zinc signal transduction and through the modulation of altered lipid metabolism via ApoE/clusterin pathway in hippocampus.

[Textual research on the Han yao xin jue (New Recognition of Chinese Medicines), a representative book of amalgamation of Chinese and western medicines in the Republican period].

Guo Ruo-ding's Han yao xin jue (New Recognition of Chinese Medicines) was the representative work of amalgamating Chinese and western pharmacy of the Republican period. Its first volume was published in Medicine Tomorrow in Peiping in installments, also with offprints; while the second volume was collected by his relatives. The whole book was published by the Shanghai Press of Science and Technology, carrying 208 kinds of Chinese materia medica mainly with individual drug descriptions, some compound prescriptions, and some western medicines. The amalgamating idea was expressed in three points: collection of both Chinese and western drugs; inheritance and creation with new idea of amalgamating Chinese and western medical systems; mutual consultation of Chinese and western medicine aiming at their amalgamation.

[Ancient understanding and the method analysis of combined acupuncture and medication].

To study and analyze on the understanding of ancient physicians' experience about combined acupuncture and medication, the thought of combined acupuncture and medication in ancient Chinese medicine, and the concrete application are analyzed by reorganization of the treatises and literature of ancient physicians. It is found that physicians of past dynasties have the greatest esteem for such academic thought of combined acupuncture and medication as essential quality of physicians, and accumulate rich experience and understanding in the application rules of clinical treatment model of combined acupuncture and medication, and action characteristics of acupuncture and medical herbs, etc. which are worthy to be further studied, so as to better guide clinical practice and scientific researches.

[Studies on simultaneous quantitative determination of overlapping spectra using chemometric techniques].

Based on comparative study of eight chemometric denoising methods, a wavelet packet transform Elman recurrent neural network (WPERNN) method was developed to study simultaneous quantitative determination of overlapping spectra. The quality of noise removal and ability of regression were improved by combining wavelet packet transform with Elman recurrent neural network. Through optimization, the wavelet function, the wavelet packet decomposition levels as well as the structure and parameters of Elman recurrent neural network were selected. Two programs, PWPERNN and PERNN, were designed to perform WPERNN and ERNN calculation. Seven kinds of chemometric methods were applied in the present study for comparison. Experimental results showed that the WPERNN method was successful and better than the other 6 methods.

[Simultaneous resolution of overlapped spectra of three kinds of organic compounds using a wavelet packet transform-based generalized regression neural network].

A wavelet packet transform-based generalized regression neural network (WPTGRNN) was developed to perform simultaneous spectrophotometric determination of p-nitroaniline, alpha-naphthylamine and benzidine. This method combines wavelet packet transform (WPT) with generalized regression neural network (GRNN) for improving the quality of noise removal and enhancing the ability of prediction. Wavelet packet representations of signals provided a local time-frequency description and separation ability between information and noise. The quality of noise removal can be further improved by using best-basis algorithm and thresholding operation. Generalized regression neural network (GRNN) was applied for overcoming the convergence problem encountered in back propagation training and facilitating nonlinear calculation. The GRNN is also advantageous in that the training process is much faster and without making any assumption about the form of the prediction model. By optimization, the wavelet function, decomposition level and smoothing factor of GRNN were selected. The partial least squares (PLS) method was used for comparative study. PLS method uses both the response and concentration information to enhance its ability of prediction. Three programs, PWPTGRNN, PGRNN and PPLS, were designed to perform relative calculations. Experimental results showed WPTGRNN method to be successful and better than others. Compared with GRNN method, the relative standard errors of all components between the actual and estimated values of mass concentration for WPTGRNN method decreased from 4.0% to 2.3%. Aniline type compounds are widely applied in industries such as chemistry, printing and pharmacy, and are one of the most important raw materials for synthetic medicine, dye, insecticides, polymer and explosives. Aniline-type compounds are highly poisonous, and can also cause cancer. Simultaneous determinations of aniline-type compounds are very important in environmental and industrial analysis.

[Dysferlin expression in limb-girdle muscular dystrophy and Miyoshi myopathy: analysis of 45 cases].

OBJECTIVE: To clarify the expression patterns of dysferlin in limb-girdle muscular dystrophy (LGMD) and Miyoshi myopathy (MM), and to investigate the frequency and clinicopathologic features of dysferlinopathy. METHODS: The expressing patterns of dysferlin were analyzed by immunohistochemistry, with a set of antibodies against dystrophin, alpha-sarcoglycan and dysferlin, in the biopsied muscle specimens from 45 patients with LGMD or MM diagnosed on the basis of clinical manifestations and muscle pathological features. The specimens with abnormal dysferlin expression shown by IHC were further analyzed with Western blotting for a quantitative evaluation. RESULTS: Eight patients were proved to be primary dysferlinopathy according to total dysferlin deficiency or a significant decrease of dysferlin (less than 15% that of normal value). The clinical manifestations of 5 of the 8 dysferlinopathy patients were consistent with those of typical MM, and the other 3 were diagnosed as with LGMD. All patients had an average onset at the age of 18.8 years. Two of them had family history, and one patient had consanguineous mating parents, meaning an autosomal recessive inheritance pattern. The serum CK levels were 6240 IU/L on average. EMG showed myogenic patterns in all patients. Muscular pathology showed typical changes of muscular dystrophy in all patients. Focal or scattered inflammatory cellular infiltrations were found in 3 cases. CONCLUSION: The clinical and pathological features of dysferlinopathy are nonspecific. Inflammatory cellular infiltrations are relatively common in biopsied muscles of dysferlinopathy patients, which may cause misdiagnosis of inflammatory myopathy. Identification of dysferlin expression by IHC and Western blotting are essential for the diagnosis of dysferlinopathy and differential diagnosis of inflammatory myopathy.

[Simultaneous determination of Sm( III) and Y(III) by spectrophotometry with a wavelet packet transform latent variable regression].

A wavelet packet transform latent variable regression (WPLVR) method was developed to perform simultaneous quantitative analysis of Sm(III) and Y(III). The quality of the noise removal was improved by combining wavelet packet transform with latent variable regression (VLR). Wavelet packet representations of signals provided a local time-frequency description, thus in the wavelet domain, the quality of the noise removal can be improved. The latent variables were made by projecting the wavelet packet processed signals onto orthogonal basis eigenvectors. The latent variable is expressible in term of linear combination of the original signals. By this method one can obtain highly selective information from unselective full-spectrum data. Through optimization, the wavelet function and wavelet packet decomposition levels (L) were selected. Two programs, PWPLVR and PFTLVR, were designed to perform WPLVR and Fourier transform latent variable regression (FTLVR) calculations. Experimental results showed that both methods were successful, but the WPLVR methed was better than FTLVR.

[Simultaneous quantitative analysis of three kinds of phenols by Elman recurrent neural network].

Elman recurrent neural network ( ERNN) was applied to study the simultaneous quantitative analysis of seriously overlapped spectra of a p-nitrophenol, o-nitrophenol and 2,4-dinitrophenol system. The multivariate linear regression (MLR) method was also applied in this study for comparison. Two programs (PERNN and PMLR) were designed to perform the calculations. By optimization, the structure and parameters of Elman recurrent neural network were defined. The relative standard errors of prediction (RSEP) for all components with ERNN and MLR were 3.1% and 2 027.3%, respectively. Experimental results showed the method to be successful even where there was a severe overlap of spectra. The ERNN method is a valuable tool in solving the minimum problem and improving the convergence rate, and can be used to analyze the whole spectra rather than just picking out a few characteristic values. The method provides a new way of simultaneous determination of severely overlapped molecular spectra without prior separation.