[Biography of Moody Meng].

Moody Meng(1897-1983) was a pioneer of pharmacy in China. He was the main editor of the first Chinese Pharmacopoeia, the first president of the National College of Pharmacy (now China Pharmaceutical University), the first director of Chongqing Union Pharmaceutical Factory during the Anti-Japanese War and the first director of the China National Institute for the Control of Pharmaceutical and Biological Products. He made important contributions in many fields of pharmacy in China.

[Association of vitamin D receptor gene polymorphisms with idiopathic hypoparathyroidism phenotypes].

Objective: To explore the association of vitamin D receptor (VDR) gene polymorphisms with idiopathic hypoparathyroidism (IHP). Methods: Two hundred and three patients with IHP and 209 healthy age- and sex-matched subjects were recruited at Peking Union Medical College Hospital between December 1987 and December 2015 as case group and control group, respectively. The VDR gene polymorphisms including rs739837, rs3847987 and rs2228570 were analyzed by Sequenom Mass Array. The frequency of different genotypes and alleles was detected, then their association with pathogenesis of IHP was analyzed. The clinical characteristics, biochemical indicators were collected to explore the genotype-phenotype relationship. The role of reactions to vitamin D treatment were compared between patients with different genotypes. Results: There was no significant difference in the genotypes and allele frequency distribution of SNPs between the two groups (all P>0.05). However, in the initially-treated patients, the genotypes of rs739837 were related to serum calcium level (r=0.186, P=0.026). And patients with GG genotype of rs2228750 had higher level of urine calcium than GA and AA (277.7 mg vs 141.1 mg, P=0.024) after treating with oral vitamin D(3) and calcium. Conclusions: Functional SNPs of VDR gene including rs739837, rs3847987 and rs2228570 might be irrelevant to the pathogenesis of IHP. But the genotypes of rs739837 were related to serum calcium level, and rs2228570 may have an effect on the different responses to vitamin D and its analogues in IHP patients.

[Clinical characteristics of adult-onset primary hypoparathyroidism: a retrospective analysis of 200 cases].

Objective: To study the clinical characteristics of primary hypoparathyroidism in adults. Methods: The clinical data of 200 cases with adult-onset primary hypoparathyroidism in Peking Union Medical College Hospital during December 1987 to December 2015 were collected and analyzed retrospectively. Among them, 128 cases were followed up for a median period of 3 years. Results: The major manifestations at their first visits were tetany and numbness in the distal extremities(81.5%, 163/200 and 62.0%, 124/200). Thirty-two percent of the cases (62 cases) had history of seizures, and 60.9%(98/161) and 74.4%(96/129) of them were with intracerebral calcifications and cataracts, respectively.Most of subjects(155/200)had more than one year delay in diagnosis. Hypercalciuria occurred in 67.2%(86/128) of the cases during the follow-up. No significant differences in the clinical characteristics and biochemical markers between the hypercalciuria subjects and the non-hypercalciuria subjects. Renal nephrocalcinosis or stones were found in 6.5%(5/77) of the cases, and kidney function decreased in 6.6%(6/91) of the patients. Kidney function was negatively associated with age and duration of disease. Conclusions: The predominant manifestations of primary hypoparathyroidism in adults included tetany and numbness in the distal extremities and seizures. It is often misdiagnosed. Calcium supplement combined with vitamin D or its metabolites effectively relieve clinical symptoms and signs. The serum and urinary calcium levels should be monitored frequently to reduce renal complications.

[The expression of p27Kip1 and ß-catenin in multiple endocrine neoplasia type 1-related parathyroid tumors].

Objective: To explore tissue expression of cyclin-dependent kinase inhibitor p27Kip1 and ß-catenin in multiple endocrine neoplasia type1 (MEN1)-related parathyroid tumors (MHPT). Methods: Immunohistochemistry was performed to analyze the expression of p27Kip1 and ß-catenin in parathyroid glands from 31 subjects with MHPT collected at Peking Union Medical College Hospital from 2002 to 2013. Five normal parathyroid glands were used as control. Results: In MHPT subjects, nuclear expression of p27Kip1 was absent in 4 (12.9%), weak in 10 (32.3%) and moderated staining in 17 parathyroid specimens (54.8%), respectively. While, in normal subjects, the nuclear expression of p27Kip1 was observed in all subjects and was stronger than that from MHPT subjects (P=0.001). As to the expression of ß-catenin, normal parathyroid showed a distinct to moderate membrane staining, a moderate to weak cytoplasmic staining and negative nuclear staining. Similarly, MHPT exhibited a marked to moderate membrane (P=0.087), a moderated to weak cytoplasmic (P=0.357), and negative nuclear ß-catenin staining. Conclusions: The expression of p27Kip1 is reduced or absent in MHPT tissue, and no nuclear expression of ß-catenin is observed in the tumors, which suggesting p27Kip1, but not ß-catenin nuclear accumulation, play a role in the development of the tumors.

[The clinical characteristics of 128 childhood- and adolescent-onset hypoparathyroidism in Peking Union Medical College Hospital: a retrospective analysis].

Objective: To study the clinical characteristics of childhood- and adolescent- onset hypoparathyroidism. Methods: The clinical data of 128 hypoparathyroidism patients with onset before the age of 18 years were collected and analyzed retrospectively. Results: The predominant features of the hypoparathyroidism were carpopedal spasm (89.3%, 108/121) and seizures (66.1%, 84/127). Intracranial calcification was identified in 89.4%(101/113) of the patients. Duration is an independent predictive factor (OR=1.483, P=0.011) for intracranial calcification. All the patients were treated with calcium and vitamin D or its metabolites. Hypercalciuria was associated with serum calcium (P=0.016). Conclusions: Carpopedal spasm and seizures were the main manifestations of childhood- and adolescent- onset hypoparathyroidism. Calcium and vitamin D or its metabolites are effective. Monitoring the concentration of serum and urinary calcium is of highly importance for the prevention of hypercalciuria.

[A genomic study of adult-onset idiopathic hypoparathyroidism in Chinese by targeted next-generation sequencing].

OBJECTIVE: Several genes have been recognized to be associated with non-surgical hypoparathyroidism. Data about gene mutations in adult-onset hypoparathyroidism patients is lacking. This study was designed to screen gene mutation in adult-onset hypoparathyroidism in Chinese through the targeted next-generation sequencing (NGS). METHODS: We recruited 17 patients with adult-onset hypoparathyroidism who were regularly followed or newly diagnosed at our centre during the past one year. Nine of them developed hypercalciuria during the treatment with calcium and vitamin D. Eight of them were newly diagnosed with no treatment. Targeted NGS was performed to screen 11 related genes, including AIRE, AP2S1, CASR, CLDN16, FAM111A, GATA3, GCM2, PTH, TBCE, TBX1 and TRPM6. RESULTS: A novel homozygosis mutation of GCMB gene[c.130G>A (p.G44S)]was identified which was predicted to be deleterious by PolyPhen2. The patient was a 36-year-old woman who suffered from paroxysmal carpopedal spasms for ten years. Before treatment, the serum calcium and phosphorus was 1.48 mmol/L and 2.29 mmol/L, respectively.Parathyroid hormonel (PTH) concentration was lower than 3.0 ng/L. Intracranial calcification and cataract were also identified. She developed hypercalciuria during treatment with calcium and vitamin D. She had no physical deformity or family history of hypoparathyroidism. CONCLUSIONS: In this study, the genetic defect was only identified in 1 patient (5.9%). In adult-onset hypoparathyroidism without other diagnostic clues, the gene mutation screening as the first choice to clarify the etiology was not recommended.

Over-expression of lncRNA SBF2-AS1 is associated with advanced tumor progression and poor prognosis in patients with non-small cell lung cancer.

OBJECTIVE: Emerging evidence suggest that long non-coding RNAs (lncRNAs) may play important roles in human cancers. The aim of this study was to investigate the expression of SBF2-AS1 in non small cell lung cancer (NSCLC) and its correlation with clinicopathological features and prognosis in NSCLC. PATIENTS AND METHODS: The expression of lncRNA SBF2-AS1 was measured in 174 NSCLC samples and their matched non-tumor tissues by using RT-PCR. Association of SBF2-AS1 expression with clinicopathological features was analyzed in NSCLC. Kaplan-Meier analysis was performed to evaluate the overall survival of NSCLC patients. RESULTS: The expression of SBF2-AS1 was higher in NSCLC tissues compared with adjacent non-tumor tissues (p < 0.01). Additionally, high expression level of SBF2-AS1 was significantly associated with NSCLC histological grade, and lymph node metastasis. Furthermore, a higher SBF2-AS1 expression was demonstrated to be associated with poor overall survival times in NSCLC patients (p < 0.001). Multivariate analysis suggested that SBF2-AS1 expression was an independent prognostic factor for overall survival of patients with NSCLC (p = 0.013). CONCLUSIONS: Our data suggest that SBF2-AS1 could represent a novel prognostic marker and potential therapeutic target in patients with NSCLC.

MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors.

MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML.

Nonstraight nanochannels transfer water faster than straight nanochannels.

Understanding the flow of liquids and particularly water in nanochannels is important for scientific and technological applications, such as for filtration and drug delivery. Here we perform molecular dynamics simulations to investigate the transfer of single-file water molecules across straight or nonstraight single-walled carbon nanotubes (SWCNTs). In contrast with the macroscopic scenario, the nonstraight nanostructure can increase the water permeation. Remarkably, compared with the straight SWCNT, the nonstraight SWCNT with the minimal bending angle of 35° in the simulations can enhance the water transport up to 3.5 times. This enhancement mainly originates from the Lennard-Jones interaction between water molecules and nonstraight nanostructures. Our work offers an additional freedom to design high-flux nanochannels by choosing nonstraight nanostructures and provides an insight into water flow across biological water nanochannels, which are often nonstraight since they are composed of integral membrane proteins.

Enhanced permeation of single-file water molecules across a noncylindrical nanochannel.

We utilize molecular dynamics simulations to study the effect of noncylindrical shapes of a nanochannel (which are inspired from the shape of real biological water nanochannels) on the permeation of single-file water molecules across the nanochannel. Compared with the cylindrical shape that has been tremendously adopted in the literature, the noncylindrical shapes play a crucial role in enhancing water permeation. Remarkably, the maximal enhancement ratio reaches a value of 6.28 (enhancement behavior). Meanwhile, the enhancement becomes saturated when the volume of the noncylindrical shape continues to increase (saturation behavior). The analysis of average diffusivity of water molecules helps to reveal the mechanism underlying the two behaviors whereas Poiseuille's law fails to explain them. These results pave a way for designing high-flow nanochannels and provide insight into water permeation across biological water nanochannels.

Phosphatidylserine exposure during apoptosis reflects bidirectional trafficking between plasma membrane and cytoplasm.

Phosphatidylserine (PS) exposure on the external leaflet of the plasma membrane is widely observed during apoptosis and forms the basis for the annexin V binding assay to detect apoptotic cell death. Current efforts to explain PS exposure focus on two potential mechanisms, activation of a phospholipid scramblase or calcium-mediated trafficking of lysosomes to the cell surface. Here, we provide evidence that apoptotic PS exposure instead reflects bidirectional trafficking of membrane between the cell surface and cytoplasm. Using a series of cell lines, some of which expose large amounts of PS during apoptosis and some of which do not, we demonstrate that accumulation of plasma membrane-derived cytoplasmic vesicles in a dynamin-, clathrin- and Cdc42-independent manner is a previously undescribed but widely occurring feature of apoptosis. The apoptotic exposure of PS occurs when these vesicles traffic back to cell surface in a calcium-dependent process that is deficient in a substantial fraction of human cancer cell lines. These observations provide a new model for PS externalization during apoptosis and simultaneously identify an altered step that accounts for the paucity of apoptotic PS exposure in many cell lines.

Gating of a water nanochannel driven by dipolar molecules.

On the basis of molecular dynamics simulations, we investigate water permeation across a single-walled carbon nanotube (SWCNT) under the influence of four symmetrical half-rings, each having six LiF dipolar molecules. The flux remains almost fixed as the separation, R, between the rings and SWCNT is larger than 1.562 nm, but decreases significantly as 0.944 nm < R < 1.562 nm, and reaches zero as R < 0.944 nm. This nanochannel shows an excellent on-off gate that is both effectively resistant to dipole noises and sensitive to available signals. The finite element method reveals that the electrostatic field generated by LiF molecules plays a unique role in achieving the gating of the water SWCNT. Each water molecule tends to stay at the most stable state by moving to the location with the highest field strength in order to maintain its lowest electric energy. These findings may have biological implications because membrane water nanochannels made up of proteins accompanied with co-ions and counterions (due to ionization) share a similar single-file water chain inside the SWCNT with dipoles. The Appendix shows a possible link between the model system and a membrane water nanochannel with co-ions and counterions. Furthermore, our observations may have significance for the design of SWCNT-based nanoscale devices with dipolar molecules.

Wnt/ß-catenin signaling regulates MAPK and Akt1 expression and growth of hepatocellular carcinoma cells.

In hepatocellular carcinoma (HCC), Wnt/ß-catenin, Ras/MAPK and PI3K/AKT signaling pathways form a complex network and play important roles during HCC genesis and development. To study their relationship and the influence on cell growth, the siRNA directed against ß-catenin was transfected into HCC HepG2 cells. ß-catenin mRNA and protein levels were measured respectively at various times by RT-PCR and Western blot. Furthermore, HCC cell growth was measured by MTT assay. Finally, MAPK family and Akt1 protein levels were also measured by Western blot. After the transfection, ß-catenin mRNA levels were markedly inhibited at 24 h and increased gradually at 48, 72 and 96 h; ß-catenin protein levels decreased gradually at 24, 48 and 72 h and slightly increased at 96 h. HCC cell growth was inhibited from 24-72 h, but this inhibition decreased at 96 h. ERK1/2 (p42/p44 MAPK), JNK/SAPK, p38 MAPK, and Akt1 protein levels showed no change following transfection, while their phosphorylated protein levels showed changes. Thus, siRNA directed against ß-catenin markedly decreased ß-catenin gene expression and inhibited cell growth. Wnt/ß-catenin signaling pathway might regulate Ras/MAPK and PI3K/Akt signaling pathways through regulation of the phosphorylation state of ERK1/2, JNK/SAPK and Akt1 protein in HCC HepG2 cells. These pathways might compensate for the inhibitory effect of ß-catenin, thereby affecting tumor cell growth and others downstream factors.

Clinical significance of TT virus in chronic hepatitis C.

BACKGROUND AND AIMS: Much is still unknown about the clinical significance of TT virus (TTV), which has been reported as a candidate for non A-G hepatitis virus. The aim of this study was to clarify the clinical significance of TTV in patients coinfected with TTV and hepatitis C virus (HCV). METHODS: The 95 subjects studied had chronic hepatitis C (CHC), and underwent interferon (IFN) therapy. TT Virus DNA was detected by using polymerase chain reaction. The nucleotide sequences were determined by using a dideoxy chain termination method. A phylogenetic tree was drawn up by using the neighbor-joining method. RESULTS: TT Virus DNA was detected in 37.9% of patients with the use of an open reading frame 1 (ORF1) primer, and in 88.4% of patients by using a 5' untranslated region (5' UTR) primer. Using both sets of primers, no differences were found between TTV-DNA-positive and -negative subjects with CHC in the clinical findings. Serum TTV DNA was eradicated in 30.6% of patients with the ORF1 primer, and in 19.1% of patients with the 5' UTR primer at 6 months after the cessation of IFN therapy. The levels of TTV DNA before IFN therapy were significantly lower in the viral eradication group than in non-eradication group. The changes in alanine aminotransferase (ALT) concentrations were significantly correlated with changes in HCV-RNA in CHC patients with TTV. Moreover, there was no correlation between the changes in TTV DNA and the course of ALT. CONCLUSION: Hepatocellular injury in patients with chronic hepatitis who are coinfected with HCV and TTV appears to primarily be caused by HCV and is less attributable to TTV.

[Polymorphism of parathyroid hormone gene and its association with bone mineral density of Han nationality women in Beijing area].

OBJECTIVE: To investigate the distribution of frequency of parathyroid hormone(PTH) gene polymorphisms in healthy adults of Han nationality in Beijing area and relationship between PTH genotypes and bone mineral density(BMD) in young and postmenopausal women. METHODS: Polymorphism of PTH gene were detected by polymerase chain reaction restriction fragment length polymorphism(PCR-RFLP) of restriction enzyme Bst B1 in 270 subjects. If the site of enzyme Bst B1 existed, the PTH genotype was "B". On the contrary, if base mutation occurred, the genotype was "b". Some of the PTH genotypes were confirmed by DNA sequences analysis. Bone mineral density(BMD) was measured by dual-energy X-ray absorptiometry. RESULTS: Genotype frequencies of BB, Bb, bb were 73.7%, 25.9%, and 0.4% respectively in adults of Beijing areas. The frequencies of RFLP alleles B, b were 86.7% and 13.3%. Beijing postmenopausal women frequencies of BB, Bb, bb were 67.1%, 32.2% and 0.7%. B, b alleles frequencies were 83.2% and 16.8%. We statistically compared bone mineral density at the lumbar 2-4, neck, wards triangle and trochanter major, there was no significant difference between BB and Bb genotype of young women and postmenopausal women groups. Otherwise, no obvious relationship was found between the BMD and PTH genotype in Beijing women. CONCLUSIONS: PTH gene polymorphisms were not associated with BMD in Beijing women.

[Study of normal range of speed of sound in tibia in Beijing area].

OBJECTIVE: To study the normal reference value of adult tibial speed of sound (tibia SOS) in Beijing region. METHODS: 951 normal volunteers (male/female = 461/490) were included in this study. Speed of sound were measured in the middle of tibia by ultrasound scan (Sound Scan 2000, Myrid, Isereal). According to their gender and age, all subjects were divided into different subgroup by 10 year-age period. RESULTS: The peak value of SOS presented in 30-39 years period in both male and female. The peak value was higher in males than in females. After reach the peak value, the tibial SOS begin to decline. The decreasing rate was fast in SOS were found at 50-59 period in female and over 50-59 years old in male. The tibia values of SOS of postmenopausal was obviously lower than that of premenopausal women. The relationship of menopausal duration and the values if tibial SOS was found to be a non-linear curve, which included 3 stages: the quick decrease, stabilization and further decrease. CONCLUSION: The tibia values of SOS provides a kind of meaningful diagnostic criteria of osteoporosis.

Causes of anorexia in untreated hyperthyroidism: a prospective study.

Seventeen consecutive patients (mean (SD) 46 (11) years) with untreated hyperthyroidism and anorexia and 29 patients (35 (9) years) with untreated hyperthyroidism without anorexia were studied. The study was conducted at the thyroid clinic of the PUMC Hospital, Beijing, China from March to August 1997. The patients' ages, serum free calcium, liver function and emotional state, specifically the level of anxiety (using the self anxiety scale, Chinese version), were compared before and/or after antithyroid drug treatment in the two groups. This prospective study suggested that the causes of anorexia in untreated hyperthyroidism are complicated. Older age, abnormal liver function, and the level of anxiety are significantly related to anorexia in untreated hyperthyroidism, but hypercalcaemia was not confirmed to be related to anorexia in the study.

Iatrogenic GB virus C/hepatitis G virus infection in an area endemic for hepatitis C virus.

GB virus C/hepatitis G virus (GBV-C/HGV) is reported to be transmitted by blood products. This study reports infection with GBV-C/HGV from Area-O of town T, an area of high prevalence of antibody to hepatitis C virus (anti-HCV). Four hundred and thirty-five inhabitants of Area-O in town T were examined. Three hundred and forty-three inhabitants of Area-H in town T (where differences of age or sex are not markedly different to Area-O) were studied as controls. We investigated the virus markers and conducted a survey of life history in both areas. The seroprevalence of anti-HCV and GBV-C/HGV markers in Area-O was 17.7% and 11.7%, significantly higher than in Area-H (1.5% and 4.4%). The prevalence of GBV-C/HGV markers was significantly higher in the anti-HCV-positive group than in the sero-negative group. Anti-HCV- or GBV-C/HGV positive subjects tended to have a history of intravenous medications at hospital C in town T, suggesting iatrogenic infection through insufficient sterilization of needles and/or syringes.

Caspase-3-dependent and caspase-3-independent pathways leading to chromatin DNA fragmentation in HL-60 cells.

Apoptosis induced by etoposide (VP-16) in HL-60 cells was confirmed to be caspase-dependent. It was fully inhibited by the broad-spectrum caspase inhibitor Z-VAD-fmk. However, the caspase-3-specific inhibitor Z-DEVDfmk only partially inhibited apoptosis. This indicated that a second caspase is required in vivo for full activation of the apoptotic nucease CAD. Aurin tricarboxylic acid (ATA) did not inhibit VP-16-induced apoptosis. In contrast, apoptosis induced by hydroxychloroquine (HCQ) in HL-60 cells was caspase-3 independent and was fully inhibited by ATA. Thus, CAD does not appear to be involved in chromatin DNA degradation in this case. A second apoptotic nuclease is postulated to degrade the DNA, likely endo- exonuclease, an abundant nuclear enzyme that acts on both DNA and RNA and is present in latent form. HCQ, but not VP-16, stimulated DNA degradation ("laddering") in isolated nuclei. This indicates that the drug can act directly in the nuclei to trigger activation of the second latent apoptotic nuclease.