[A real-world study of the effects of endocrine therapy on liver function in breast cancer].

Objective: To compare the effect of different endocrine therapy drugs on liver function in patients with early breast cancer. Methods: A retrospective cohort study was conducted to include 4 318 patients with early breast cancer who received adjuvant endocrine therapy in Department of Breast Surgery, Peking Union Medical College Hospital from January 1, 2013 to December 31, 2021. All the patients were female, aged (51.2±11.3) years (range: 20 to 87 years), including 1 182 patients in the anastrozole group, 592 patients in the letrozole group, 332 patients in the exemestane group, and 2 212 patients in the toremifene group. The mixed effect model was used to analyze and compare the liver function levels of patients at baseline, 6, 12, 18, 24, 36, 48, 60 months of medication, and 1 year after drug withdrawal among the three aromatase inhibitors (anastrozole, letrozole, exemestane) and toremifene. Results: ALT and AST of the 4 groups were significantly higher than the baseline level at 6 months (all P<0.01), and there were no significant differences in total bilirubin, direct bilirubin and AST levels among all groups one year after drug withdrawal (P: 0.538, 0.718, 0.061, respectively). There was no significant difference in the effect of all groups on AST levels (F=2.474, P=0.061), and in the effect of three aromatase inhibitors (anastrozole, letrozole, and exemestane) on ALT levels (anastrozole vs. letrozole, P=0.182; anastrozole vs. exemestane, P=0.535; letrozole vs. exemestane, P=0.862). Anastrozole and letrozole had significantly higher effects on ALT levels than toremifene (P<0.01, P=0.009). The proportion of abnormal liver function in each group increased significantly at 6 months compared with baseline, and then the proportion showed a decreasing trend over time. Conclusions: Three aromatase inhibitors (anastrozole, letrozole, and exemestane) and toremifene can significantly increase the level of ALT and AST in patients with breast cancer, and the levels can gradually recover to the baseline after 1 year of drug withdrawal. The effect of non-steroidal aromatase inhibitors (anastrozole, letrozole) on ALT levels is greater than toremifene.

Effects of surface roughness on the time-dependent wear performance of lithium disilicate glass ceramic for dental applications.

OBJECTIVES: Purpose of the present study was to evaluate the effect of surface roughness on the time-dependent wear performance of lithium disilicate (LD) glass-ceramic. METHODS: Friction pairs (pin and disk specimens) were prepared by IPS e.max® Press lithium disilicate glass-ceramic. The lateral faces of friction pairs (N = 12) were grinded with silicon carbide papers, and 6 friction pairs were polished with a 0.25 µm diamond suspension after grinding. The friction pairs were tested for wear performance using a pin-on-disk tribometer with 10 N for 1.02 × 106 wear cycles in artificial saliva. Wear analysis of the pin and disk was performed with a 3D profilometer. The microstructure and worn surface morphology were examined with scanning electron microscopy. One-way analysis of variance and Tukey's post-hoc pairwise comparison were used to analyze the wear data. RESULTS: The two group LD friction pairs presented strong time-dependent wear performance. The polished group (GP) exhibited a high wear rate and extensive surface wear during 0-1 × 105 cycles (running-in wear stage). The wear rate, height loss and surface roughness were obviously lower than those of grinded group (GG) in running-in wear stage. However, these wear parameters were similar during the steady wear stage. The worn surface topographies of the pin and disk in GP were smoother at the same cycle before the GG entering the steady wear stage. CONCLUSION: Running-in, which means the initial stage of wear process, is a critical period to determine the final wear loss and surface degradation, when compare the wear behavior of lithium disilicate ceramic with different initial surface states. Ceramic layer with smooth contact area leads to low wear rate and short running-in wear stage.

[HPV E6 and E7 mRNA combined with HPV 16 and 18 or 45 genotyping testing as a means of cervical cancer opportunistic screening].

Objective: To evaluate Aptima HPV E6 and E7 mRNA assay (Aptima HPV) combined with Aptima HPV 16 and 18 or 45 (18/45) genotype assay (Aptima HPV-GT) as a means of cervical cancer opportunistic screening. Methods: From October 2016 to October 2017, a total of 23 258 women aged 25-65 years were enrolled in the physical examination center and gynecological clinic of Huzhou Maternity and Child Health Care Hospital. All the women had Aptima HPV tested, further Aptima HPV-GT testing for positive women and liquid-based thin layer cytology Thinprep cytologic test (TCT). Women with Aptima HPV (+) or ≥low-grade squamous intraepithelial lesion (LSIL) or obvious clinical symptoms (including vaginal bleeding after intercourse and watery, bloody vaginal discharge) were referred for colposcopy and further biopsy with or without endocervical curettage (ECC) if indicated. Expression of Aptima HPV, HPV 16 and HPV 18/45 with different cytological diagnostic groups and histological diagnosis groups were compared respectively. Sensitivity, specificity, positive predictive value and negative predictive value of Aptima HPV detection and TCT in identifying histological diagnosis of high-grade squamous intraepithelial lesion (HSIL) or worse (HSIL(+)) were compared. Results: (1) The positive rates of Aptima HPV, HPV 16 and HPV 18/45 were 14.00% (3 257/23 258), 1.85% (430/23 258) and 0.86% (199/23 258) respectively.The positive rates of Aptima HPV, HPV 16 and HPV 18/45 increased with cytology grading in squamous epithelium [negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASCUS), LSIL, atypical squamous cell cannot exclude HSIL (ASC-H), HSIL and squamous cell carcinoma (SCC), all P=0.000)]. According to histology results, the positive rates of Aptima HPV, HPV 16 and HPV 18/45 increased with histology grading in squamous epithelium (normal cervical tissue, LSIL, HSIL and SCC, all P=0.000). The positive rate of Aptima HPV was significantly higher in HSIL(+) group than that in the LSIL or better (LSIL(-)) group [98.11% (311/317) vs 12.84% (2 946/22 941), P=0.000]. The positive rate of Aptima HPV-GT was significantly higher in HSIL(+) group than that in LSIL(-) group [58.36% (185/317) vs 1.91% (439/22 941), P=0.000]. (2) Compared with cytology, Aptima HPV resulted in significant higher sensitivity (98.11% vs 59.62%, P=0.000) and negative predictive value (99.97% vs 99.42%, P=0.000), significant lower specificity (87.16% vs 95.37%, P=0.000) and positive predictive value (9.55% vs 15.10%, P=0.000) when identified HSIL(+). Conclusions: Women with Aptima HPV positive, especially those with Aptima HPV-GT positive, are more likely to have histological diagnosis of HSIL(+). Aptima HPV combined with Aptima HPV-GT is feasible as a means of cervical cancer opportunistic screening in tertiary hospitals.

[Observation on clinical efficacy and prognosis analysis of endoscopic surgery treatment for rT1-rT2 recurrent nasopharyngeal carcinoma].

Objective:To investigate the feasibility of endoscopic surgery for treatment of rT1-rT2 recurrent nasopharyngeal carcinoma.Method: The clinical data and of 57 patients who had recurrence of the primary lesion after treatment of nasopharyngeal carcinoma from February 2011 to December 2015 were retrospectively analyzed. The patients were re-staged according to Union for International Cancer Control(UICC, 2010) staging system for nasopharyngeal carcinoma before surgery. Patients suitable for surgery underwent endoscopic surgery to remove nasopharyngeal lesions; those combined with cervical lymph node metastases underwent cervical lymph node dissection at the same time; patients with positive surgical margins of pharyngeal lesions and cervical lymph node extramembranous filtration were treated with radiotherapy combined with chemotherapy; patients unsuitable for surgery were treated with radiotherapy combined with chemotherapy directly. All patients were followed up regularly to observe clinical efficacy and survival. Result:Fifty-seven patients were re-staged according to UICC(2010) staging system for nasopharyngeal carcinoma: 19 cases in stage Ⅰ,30 cases in stage Ⅱ, 6 cases in stage Ⅲ and 2 cases in stage Ⅳ,including 27 cases in stage rT1, 30 cases in stage rT2, and 43 cases in stage rN0,6 cases in stage rN1,6 cases in stage rN2,2 cases in stage rN3. Forty-four cases of primary lesions were sected for endoscopic surgery. Patients combined with cervical lymph node metastases underwent cervical lymph node dissection at the same time, with 6 cases of positive surgical margins of pharyngeal lesions and 4 cases of cervical lymph node extramembranous infiltration, who were treated with radiotherapy combined with chemotherapy after surgery. Thirteen patients received radiotherapy combined with chemotherapy directly. At a median follow-up of 36 months, the 3-year overall survival rate of 57 patients was 61.4%. The 3-year overall survival rates of patients in stage Ⅰ, Ⅱ, Ⅲ and Ⅳ were 73.7%, 63.3%, 33.3%, 0.0% respectively. Kaplan-Meier survival curve analysis showed a significant difference in the overall survival rate of patients in different stages(P=0.002). The 3-year overall survival rates of rT1 and rT2 patients were 63.0%, 60.0% respectively, and KaplanMeier survival curve analysis showed no significant difference in the overall survival rate between rT1 and rT2 patients(P=0.707). The 3-year overall survival rates of patients in stages rN0, rN1, rN2, rN3 were 69.8%, 50.0%, 33.3%, 0.0% respectively, and Kaplan-Meier Survival curve analysis showed a significant difference in overall survival between patients in different rN stages(P=0.002). The 3-year overall survival rate was 68.2% in 44 surgical patients, and 38.5% in 13 non-surgical patients. Kaplan-Meier survival curve analysis showed significant difference in overall survival rate between surgical and non-surgical patients(P=0.014).Conclusion: Endoscopic surgery for recurrent nasopharyngeal carcinoma is a safe and effective treatment to improve survival.

A metallic metal oxide (Ti5O9)-metal oxide (TiO2) nanocomposite as the heterojunction to enhance visible-light photocatalytic activity.

Coupling titanium dioxide (TiO2) with other semiconductors is a popular method to extend the optical response range of TiO2 and improve its photon quantum efficiency, as coupled semiconductors can increase the separation rate of photoinduced charge carriers in photocatalysts. Differing from normal semiconductors, metallic oxides have no energy gap separating occupied and unoccupied levels, but they can excite electrons between bands to create a high carrier mobility to facilitate kinetic charge separation. Here, we propose the first metallic metal oxide-metal oxide (Ti5O9-TiO2) nanocomposite as a heterojunction for enhancing the visible-light photocatalytic activity of TiO2 nanoparticles and we demonstrate that this hybridized TiO2-Ti5O9 nanostructure possesses an excellent visible-light photocatalytic performance in the process of photodegrading dyes. The TiO2-Ti5O9 nanocomposites are synthesized in one step using laser ablation in liquid under ambient conditions. The as-synthesized nanocomposites show strong visible-light absorption in the range of 300-800 nm and high visible-light photocatalytic activity in the oxidation of rhodamine B. They also exhibit excellent cycling stability in the photodegrading process. A working mechanism for the metallic metal oxide-metal oxide nanocomposite in the visible-light photocatalytic process is proposed based on first-principle calculations of Ti5O9. This study suggests that metallic metal oxides can be regarded as partners for metal oxide photocatalysts in the construction of heterojunctions to improve photocatalytic activity.

VNP: Interactive Visual Network Pharmacology of Diseases, Targets, and Drugs.

In drug discovery, promiscuous targets, multifactorial diseases, and "dirty" drugs construct complex network relationships. Network pharmacology description and analysis not only give a systems-level understanding of drug action and disease complexity but can also help to improve the efficiency of target selection and drug design. Visual network pharmacology (VNP) is developed to visualize network pharmacology of targets, diseases, and drugs with a graph network by using disease, target or drug names, chemical structures, or protein sequence. To our knowledge, VNP is the first free interactive VNP server that should be very helpful for systems pharmacology research. VNP is freely available at http://cadd.whu.edu.cn/ditad/vnpsearch.

γ-Aminobutyric acid-mediated neurotransmission in cerebellar-hypothalamic circuit attenuates gastric mucosal injury induced by ischemia-reperfusion.

BACKGROUND: Excessive greater splanchnic nerve (GSN) activation contributes to the progression of gastric ischemia-reperfusion (GI-R) injury. This study was designed to investigate the protective mechanism of cerebellar fastigial nucleus (FN) stimulation against GI-R injury. METHODS: The GI-R injury model was induced in rats by clamping the celiac artery for 30 min, and then reperfusion for 30 min, 1, 3, 6, or 24 h, respectively. KEY RESULTS: Microinjection of L-Glu (3, 6, 12 µg) into the FN dose-dependently attenuated GI-R injury and GSN activity. In addition, there was an enhancement of gastric mucosal blood flow in GI-R rats. Pretreatment with the glutamic acid decarboxylase antagonist into the FN, the GABAA receptor antagonist into the lateral hypothalamic area or lesion of superior cerebellar peduncle all reversed the protective effects of the FN stimulation. Furthermore, the FN stimulation reduced the TUNEL-positive gastric mucosal cell and Bax-positive gastric mucosal cell in GI-R rats. CONCLUSIONS & INFERENCES: These results indicate that the protective effects of the FN stimulation against GI-R injury may be mediated by attenuation of the excessive GSN activation, gastric mucosal cell apoptosis, and Bax expression in GI-R rats.

A rare leucine codon in adpA is implicated in the morphological defect of bldA mutants of Streptomyces coelicolor.

Streptomycetes are mycelial bacteria that produce sporulating aerial hyphae on solid media. Bald (bld) mutants fail to form aerial mycelium under at least some conditions. bldA encodes the only tRNA species able to read the leucine codon UUA efficiently, implying the involvement of a TTA-containing gene in initiating aerial growth. One candidate for such a gene was bldH, because the bldH109 mutant of Streptomyces coelicolor resembles bldA mutants in some aspects. In the work reported here, adpAc, an S. coelicolor gene similar to the Streptomyces griseus A factor-regulated adpAg, was found to complement the bldH109 mutant partially at both single and multiple copies. The sequence of adpAc from the bldH109 mutant revealed a frameshift. A constructed in frame deletion of adpAc conferred a bald colony phenotype, and the mutant behaved like bldA mutants and bldH109 in its pattern of extracellular signal exchange. Both adpAc and adpAg contain a TTA codon. A TTA-free version of adpAc was engineered by replacing the TTA leucine codon with a cognate TTG leucine codon. The adpA(TTATTG) gene could partially restore aerial mycelium formation to a bldA mutant when it was followed in cis by the gene ornA, as in the natural chromosomal arrangement. This indicated that the UUA codon in adpAc mRNA is the principal target through which bldA influences morphological differentiation. It also implied that translational arrest at the UUA codon in adpAc mRNA caused a polar effect on the downstream ornA, and that the poor translation of both genes contributes extensively to the deficiency of aerial mycelium formation in bldA mutants. Unlike the situation in S. griseus, adpAc transcription does not depend on the host's -butyrolactone signalling system, at least in liquid cultures. In addition, sigma factor BldN, which is the homologue of an S. griseus sigma factor AdsA that is absent from adpAg mutants of S. griseus, was present in the constructed adpAc null mutant of S. coelicolor.

The synthesis of nanocrystalline anatase and rutile titania in mixed organic media.

The synthesis of anatase and rutile titania could be achieved in mixed organic media with the variation of alcohols in the media under mild conditions. Although a nonhydrolytic process cannot be excluded, it is suggested that the formation of titania in these systems is based mainly on the hydrolytic process initiated by the water generated as a result of an esterification reaction between the alcohols and acetic acid. It has been found that the phase of the TiO2 produced depends on the choice of alcohols and temperature. Partial morphology and size are also affected by these factors. It is proposed that the viscosity and pressure of the reaction media influence the particle size. X-ray diffraction, transmission electron microscopy, Raman spectroscopy, and UV-visible adsorption spectroscopy were employed to characterize the final products.

[Over-expression of a polyketide synthase (PKS) module of a giant polyene antibiotic gene cluster in E. coli by double induction].

A 2,671 bp DNA carrying a type I PKS module with KS and AT domains from Streptomyces sp. FR-008 was cloned in-frame into the BamHI site immediately downstream of the PT7 promoter of the E. coli expression vector pET-15b, no considerable expression under IPTG induction was detected. The same PKS gene cloned downstream of the tandem PRPL promoters of pBV220 also yielded no over-expression under 42 degrees C induction. This gene was, however, over-expressed when it was cloned downstream of the tandem PRPT7 or PRPLPT7 promoters. In the case of the tandem PRPLPT7 promoters, the over-expression was dependent on the 42 degrees C plus IPTG double induction. While in the case of the tandem PRPT7 promoters, over-expression could be achieved when the gene was induced by IPTG or 42 degrees C individually or by IPTG and 42 degrees C double induction. Based on these experiences an expression vector pHZ330 containing the tandem PRPT7 promoters was constructed. In addition, the PKS protein expressed in E. coli was injected into rabbits to generate PKS-specific antibodies. Western blotting experiment indicated that these antibodies were PKS-specific which could be used either for the study of the PKS gene cluster or for the detection of the heterologous expression of Streptomyces sp. FR-008 PKS genes.

Molecular cloning of a DNA segment essential for replication from Streptomyces hygroscopicus strain 10-22 and localization of its minimal functional region.

The 13 kb DNA segment responsible for replication has been isolated from Streptomyces hygroscopicus subsp. yingchengensis strain 10-22 using a pBR322-derived Streptomyces replication-probe vector pIJ2703. The restriction map of the hybrid plasmid, pHZ54, has been constructed. Following a series of deletion and subcloning experiments, the minimal functional region for replication was located within a 2.86 kb DNA fragment. Subsequently, this region was further shortened into a 2 kb region by exonuclease III deletion. A few small bifunctional plasmids able to replicate in E. coli as well as in Streptomyces, were obtained during the above process. Some plasmids could be used as shuttle vectors.

"Strong incompatibility" between derivatives of the Streptomyces multi-copy plasmid pIJ101.

Some derivatives of pIJ101, a 8.9 kb Streptomyces multi-copy plasmid, can co-exist with each other at similar copy numbers but others are strongly incompatible. The DNA sequence, sti, which causes this "strong incompatibility" was localised on a DNA segment of about 200 bp which is not part of the essential replication region of pIJ101. The sti function is active only when the DNA fragment carrying it is present in the natural orientation with respect to the basic replicon region of pIJ101. Pairs of plasmids which either both possess sti in the correct orientation (Sti+) or both lack sti or carry it in reverse orientation (Sti-) can co-exist, but Sti+ and Sti- plasmids cannot; in this case the Sti+ plasmid is retained and the Sti- plasmid is lost. This phenomenon is called strong incompatibility to distinguish it from classical incompatibility where identical or related plasmids are incompatible and dissimilar plasmids are compatible. pIJ101 probably replicates via a single-stranded intermediate; sti would be a site where the synthesis of the second (lagging) DNA strand is initiated because Sti- plasmids accumulate more single-stranded plasmid DNA than Sti+ plasmids. The copy number of pIJ101 and its derivatives is influenced by sti and by an additional trans-acting function (cop).

Activity of a Streptomyces transcriptional terminator in Escherichia coli.

A 205bp DNA fragment from the Streptomyces multi-copy plasmid pIJ101 has in vivo terminator activity both in Streptomyces lividans and in Escherichia coli. Termination of RNA synthesis, detected by high-resolution S1 nuclease mapping, occurs at precisely the same nucleotides in both organisms. This suggests that the E. coli RNA polymerase recognizes the same sequence elements and chooses the point(s) of termination in the same way as the corresponding S. lividans enzyme.