Tislelizumab Combined with Carboplatin-Paclitaxel for Treatment of Metastatic or Recurrent Endometrial Cancer: a Retrospective Clinical Study.

BACKGROUND: Metastatic or recurrent endometrial cancers with low survival rate had no standard or limited therapy choice. The aim of our study was to determine the efficiency and safety of tislelizumab combined with carboplatin-paclitaxel as a front-line therapy for patients with metastatic or recurrent endometrial cancer. METHODS: This clinical retrospective cohort study examined 24 Chinese patients with metastasis or recurrence but had not yet received treatment. The therapeutic regimen consisted of 6 cycles of intravenous paclitaxel (175 mg/m2) and carboplatin (target AUC: 5 mg/mL/min) with tislelizumab (200 mg) once every 3 weeks, and then intravenous tislelizumab (200 mg) once every 3 weeks until disease progression or unacceptable toxicity. RESULTS: At the 18-month follow-up, 8 patients were still receiving treatment, 13 were dead, and 3 withdrew. The objective response rate (ORR) was 62.5%, the disease control rate was 75.00%. The ORR was 77.78% for patients positive for PD-L1 and 69.23% for patients positive for MSI-H. The median overall survival time was 11.50 months, and the median progression-free survival time was 6.00 months. Half of the patients experienced 3 - 4 grade adverse events. There were no allergic reactions or treatment-related deaths. CONCLUSIONS: Tislelizumab combined with carboplatin-paclitaxel was used as a front-line therapy, had a beneficial effect and was safe for patients with metastatic or recurrent endometrial cancer.

Reduced System Complexity of Heart Rate Dynamics in Patients with Hyperthyroidism: A Multiscale Entropy Analysis.

Studying heart rate dynamics would help understand the effects caused by a hyperkinetic heart in patients with hyperthyroidism. By using a multiscale entropy (MSE) analysis of heart rate dynamics derived from one-channel electrocardiogram recording, we aimed to compare the system complexity of heart rate dynamics between hyperthyroid patients and control subjects. A decreased MSE complexity index (CI) computed from MSE analysis reflects reduced system complexity. Compared with the control subjects (n = 37), the hyperthyroid patients (n = 37) revealed a significant decrease (p < 0.001) in MSE CI (hyperthyroid patients 10.21 ± 0.37 versus control subjects 14.08 ± 0.21), sample entropy for each scale factor (from 1 to 9), and high frequency power (HF) as well as a significant increase (p < 0.001) in low frequency power (LF) in normalized units (LF%) and ratio of LF to HF (LF/HF). In conclusion, besides cardiac autonomic dysfunction, the system complexity of heart rate dynamics is reduced in hyperthyroidism. This finding implies that the adaptability of the heart rate regulating system is impaired in hyperthyroid patients. Additionally, it might explain the exercise intolerance experienced by hyperthyroid patients. In addition, hyperthyroid patients and control subjects could be distinguished by the MSE CI computed from MSE analysis of heart rate dynamics.

Rabbit umbilical cord mesenchymal stem cells: A new option for tissue engineering.

BACKGROUND: The source and availability of cells for tissue engineering in large scale research or clinical trials requires special attention. We propose the idea of applying rabbit umbilical cord mesenchymal stem cells for this purpose. METHODS: Here, the structure of the rabbit umbilical cord was analyzed and compared to that of human umbilical cord, both macroscopically and histologically. Next, we isolated, cultured and identified the proliferative activity and immunological characteristics of rabbit umbilical cord mesenchymal stem cells in vitro using mixed lymphocyte reaction, flow cytometry and an enzyme-linked immunosorbent assay. Furthermore, we evaluated the effects of biphasic calcium phosphate ceramic scaffolds seeded with rabbit umbilical cord mesenchymal stem cells in rat cranial defect models using multiple techniques, including radiological, histological and immunohistochemistry. RESULTS: In vitro studies demonstated a high level of proliferation and multi-lineage differentiation potential in rabbit umbilical cord mesenchymal stem cells. Rabbit umbilical cord mesenchymal stem cells exibited low immunogenicity properties and immune suppression capability with respect to both the allogeneic and xenogeneic immune response. The results of the in vivo study showed that rabbit umbilical cord mesenchymal stem cells could promote osteogenesis in heterogeneous hosts. CONCLUSIONS: The rabbit umbilical cord mesenchymal stem cells may be a new source for tissue engineering.

Triplexed Tracking Labile Sulfur-Containing Species on a Single-Molecule "Nezha" Sensor.

Sulfur-containing species (SCS), especially sulfur dioxide-relevant species, play an essential role in ecological balance. Owing to the intrinsically labile and mobile characteristics of SCS, it is still considered to be an insurmountable challenge for multiplexed tracking dynamics of SCS with distinct molecular structure, valence state, and condensed state. To address this key problem, we proposed herein alternative versatile single-molecule sensors (VSMs) that intramolecularly integrate high affinity target-guided multiple recognition units into a single sensory molecule, clarified as molecular Nezha available in triplexed responses to gaseous sulfur dioxide, liquid sulfur trioxide, and aqueous bisulfite through ubiquitous charge transfer and nucleophilic addition. High-performance molecular Nezha remarkably facilitated promising applications in a quantitative visualization of SCS on lab-on-paper and tracking the dynamics transformation of SCS as well comprehensive evaluation of multiphase adsorption science of SCS on an advanced Zeolitic imidazolate framework-8 (ZIF-8).

Cancer-associated fibroblasts induce epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer via CXCL12/CXCR4 axis.

Aim: Cancer-associated fibroblasts (CAFs) are closely related to epithelial-mesenchymal transition (EMT) and chemoresistance in various cancers. Patients & methods: Experiments in vivo and retrospective studies were applied to explore the role of CAFs in epithelial ovarian cancer (EOC). Results: We found that CXCL12 expression was significantly increased in interstitial CAFs by immunofluorescence. CAF-derived CXCL12 induced EMT though CXCR4/Wnt/ß-catenin pathway in EOC cells. Inhibited EMT led to increased apoptosis and cisplatin sensitivity. Multivariate regression analysis shows that CXCL12 expression in the stromal cells and cytoreduction satisfaction are independent prognostic markers of platinum-containing chemotherapy sensitivity in 296 EOC patients. Conclusion: CAFs may activate the Wnt/ß-catenin pathway in EOC cells via CXCL12/CXCR4 axis, and then induce EMT and cisplatin resistance.

[Microecology and geoherbalism of traditional Chinese medicine].

Microecology was directly or indirectly involved in the growth and development, metabolism process, and component accumulation of traditional Chinese medicine(TCM) in various ways, which affected the formation and changes of the geoherbalism of TCM. It was one of the main tasks of traditional Chinese medical microecology(TCMM) to reveal the relationship among microecological structure and its change rule and the quality effect of TCM. The heterogeneity of soil environment caused by geographical and climatic factors, as well as the discreteness limitation caused by isolation factors such as distance and host selection, were the main causes of the differentiation of microecological geography of TCM. The microecology of TCM had important influences and contributions on the distinctive origin and quality of Dao-di herbs, which was mainly reflected in the formation of excellent germplasm(including disease and insect resistance, drought resistance, salt resistance, cold resistance, etc.), the increase of yield, the formation of medicinal parts, the metabolism and accumulation of effective components, the time limit of harvesting, and the toxicity, increasing efficiency or reducing toxicity of TCM in the processing, the changes of product efficiency after introduction, and the authenticity of fungus medicine. With the vigorous development of metabonomics and modern information technology, the following aspects would become the future research trends, including the microecologically mediated biogenic pathway of chemical components, the metabolic synthesis reactor of TCM based on the microecological quantitative effect relationship, the cultivation of genuine Chinese medicine based on reconstruction of microecological structure, the origin identification barcode traceability technology, and the toxicity reduction and efficiency enhancement technology of TCM based on the microecological.

Eudesmane-type sesquiterpene diols directly synthesized by a sesquiterpene cyclase in Tripterygium wilfordii.

Cryptomeridiol, a typical eudesmane diol, is the active principle component of the antispasmodic Proximol. Although it has been used for many years, the biosynthesis pathway of cryptomeridiol has remained blur. Among terpenoid natural products, terpenoid cyclases are responsible for cyclization and generation of hydrocarbon backbones. The cyclization is mediated by carbocationic cascades and ultimately terminated via deprotonation or nucleophilic capture. Isoprene precursors are, respectively, converted into hydrocarbons or hydroxylated backbones. A sesquiterpene cyclase in Tripterygium wilfordii (TwCS) was determined to directly catalyze (E,E)-farnesyl pyrophosphate (FPP) to unexpected eudesmane diols, primarily cryptomeridiol. The function of TwCS was characterized by a modular pathway engineering system in Saccharomyces cerevisiae The major product determined by NMR spectroscopy turned out to be cryptomeridiol. This unprecedented production was further investigated in vitro, which verified that TwCS can directly produce eudesmane diols from FPP. Some key residues for TwCS catalysis were screened depending on the molecular model of TwCS and mutagenesis studies. As cryptomeridiol showed a small amount of volatile and medicinal properties, the biosynthesis of cryptomeridiol was reconstructed in S. cerevisiae Optimized assays including modular pathway engineering and the CRISPR-cas9 system were successfully used to improve the yield of cryptomeridiol in the S. cerevisiae The best engineered strain TE9 (BY4741 erg9::Δ-200-176 rox1::mut/pYX212-IDI + TwCS/p424-tHMG1) ultimately produced 19.73 mg/l cryptomeridiol in a shake flask culture.

[Research advancement in mechanisms of processing and compatibility for detoxication of Aconitums].

Aconitums,represented by Aconite Radix,Aconiti Lateralis Radix Praeparata and Aconiti Kusnezoffh Folium,is a kind of traditional Chinese medicine with a long medicinal history in China. They possess the significant toxicity and therapeutic effects simultaneously. Their potent effects of rescuing from dying,curing rheumatism,anti-inflammation,and analgesia make Aconitums highly regarded by physicians and pharmacists of various dynasties. However,countless poisoning cases caused by an irrational use of Aconitums were reported. In case of improper application and exceeding the therapeutic window,the acute cardiotoxicity and neurotoxicity would be caused,seriously threatening health and even life of the users. Therefore,the clinical application of Aconitums is limited to some extent. To avoid its toxicity and ensure the safety of medicinal use,Aconitums is usually used in a form of its processed products instead of the crude herbs,or combined with some other traditional Chinese medicines in a normal prescription. A proper processing and compatibility method can detoxicate its severe toxicity,reduce the adverse reactions,and also significantly broaden the indications and application range of Aconitums. This provides a guarantee for the secondary exploitation and utilization of Aconitums. In this paper,the traditional processing methods of Aconitums,along with the modern advancement were reviewed,and the mechanisms of detoxification by processing and compatibility were also illuminated. The physical detoxification mode and chemical detoxification mode were found as two main detoxification ways for Aconitums. In particular,the detoxification by hydrolysis,ion-pair,and saponification were three main means. The mechanisms illustrated in this paper can be a reference to the development of modern processing method and a guidance for appropriate use of Aconitums in clinical application.

Application of computer-assisted surgery techniques in the management of zygomatic complex fractures.

Patients suffering from zygomatic complex fractures always present facial deformity and dysfunctions, and thereafter develop psychological and physiological problems. It is really hard to get an ideal prognosis for the zygomatic complex fractures because of the complicated anatomical structures. Computer-assisted surgery techniques, as the new emerging auxiliary methods, can optimize the surgical protocol, predict operation outcomes, and improve the accuracy and quality of the operation. Meanwhile the postoperative complications can be reduced effectively. This review aims to provide a comprehensive overview of the application of computer-assisted surgery techniques in the management of zygomatic complex fractures.

Indirect enzyme-linked immunosorbent assay method based on Streptococcus agalactiae rSip-Pgk-FbsA fusion protein for detection of bovine mastitis.

OBJECTIVE: The aim of this study was to establish a rapid and accurate method for the detection of the Streptococcus agalactiae antibody (SA-Ab) to determine the presence of the bovine mastitis (BM)-causative pathogen. METHODS: The multi-subunit fusion protein rSip-Pgk-FbsA was prokaryotically expressed and purified. The triple activities of the membrane surface-associated proteins Sip, phosphoglycerate kinase (Pgk), and fibronectin (FbsA) were used as the diagnostic antigens to establish an indirect enzyme-linked immunosorbent assay (ELISA) method for the detection of SA-Ab in BM. RESULTS: The optimal antigen coating concentration was 2 µg/mL, the optimal serum dilution was 1:160, and the optimal dilution of the enzyme-labeled secondary antibody was 1:6000. The sensitivity, specificity, and repeatability tests showed that the method established in this study had no cross-reaction with antibodies to Streptococcus pyogenes, Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis in the sera. The results of the sensitivity test showed that a positive result could be obtained even if the serum dilution reached 1:12,800, indicating the high sensitivity and good repeatability of the method. The positive coincidence rate of this method was 98.6%, which is higher than that of previous tests established with the Sip or Pgk mono-antigen fusion protein, respectively, demonstrating the relatively higher sensitivity of this newly established method. The detection rate for 389 clinical samples was 46.53%. CONCLUSIONS: The indirect ELISA method established in this study could provide a more accurate and reliable serological method for the rapid detection of S. agalactiae in cases of BM.

Neuroprotective effect of lignans extracted from Eucommia ulmoides Oliv. on glaucoma-related neurodegeneration.

Glaucoma is a progressive neurodegenerative disease, characterized by retinal ganglion cells (RGCs) and axon degeneration. The development of neuroprotective drug is required for improving the efficiency of glaucoma treatment. Eucommia ulmoides Oliv. has been used as a source of traditional medicine and as a beneficial health food. Lignans is one of the main bioactive components of Eucommia ulmoides. Here, we show that lignans protects RGCs against oxidative stress-induced injury in vitro. Moreover, lignans exerts neuroprotective effect on glaucoma-associated optic neuropathy in glaucomatous rats. Lignans treatment could improve oxidative stress response in RGCs and retinas of glaucomatous rats. Lignans plays an anti-oxidative stress role via the activation of AMPK signaling. This study provides evidence that lignans possesses protective effect on glaucoma-associated optic neuropathy. Lignans might be an alternative for the prevention and treatment of glaucomatous neurodegeneration.

Decreased complexity of glucose dynamics in diabetes: evidence from multiscale entropy analysis of continuous glucose monitoring system data.

Parameters of glucose dynamics recorded by the continuous glucose monitoring system (CGMS) could help in the control of glycemic fluctuations, which is important in diabetes management. Multiscale entropy (MSE) analysis has recently been developed to measure the complexity of physical and physiological time sequences. A reduced MSE complexity index indicates the increased repetition patterns of the time sequence, and, thus, a decreased complexity in this system. No study has investigated the MSE analysis of glucose dynamics in diabetes. This study was designed to compare the complexity of glucose dynamics between the diabetic patients (n = 17) and the control subjects (n = 13), who were matched for sex, age, and body mass index via MSE analysis using the CGMS data. Compared with the control subjects, the diabetic patients revealed a significant increase (P < 0.001) in the mean (diabetic patients 166.0 ± 10.4 vs. control subjects 93.3 ± 1.5 mg/dl), the standard deviation (51.7 ± 4.3 vs. 11.1 ± 0.5 mg/dl), and the mean amplitude of glycemic excursions (127.0 ± 9.2 vs. 27.7 ± 1.3 mg/dl) of the glucose levels; and a significant decrease (P < 0.001) in the MSE complexity index (5.09 ± 0.23 vs. 7.38 ± 0.28). In conclusion, the complexity of glucose dynamics is decreased in diabetes. This finding implies the reactivity of glucoregulation is impaired in the diabetic patients. Such impairment presenting as an increased regularity of glycemic fluctuating pattern could be detected by MSE analysis. Thus, the MSE complexity index could potentially be used as a biomarker in the monitoring of diabetes.

Norditerpenoids from Flickingeria fimbriata and their inhibitory activities on nitric oxide and tumor necrosis factor-α production in mouse macrophages.

Bioassay-guided fractionation of the ethanolic extract of the leaves of Flickingeria flimbriata led to the isolation of two new degraded diterpenoids 1 and 2, a new ent-pimarane type diterpenoid 3, and four known steroids 4-7. The structures of 1-3 were elucidated by spectroscopic analysis, and their absolute configurations were determined by chemical methods, TDDFT quantum chemical calculations of ECD spectra, and CD exiton chirality method. Compounds 1 and 2, named flickinflimilins A and B, possess a rare 15,16-dinor-ent-pimarane skeleton. Compounds 1-7 were screened for the inhibitory activity against lipopolysaccharide (LPS)-induced NO and TNF-α production in RAW264.7 cells. Compounds 1-3 exhibited potent inhibitory activities, with IC50 values of less than 10 µM.

Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.

Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo in mice. We first constructed Mef2cL35P heterozygous mice. Male heterozygous mice exhibited hyperactivity, repetitive behavior and social abnormalities. We then programmed AeCBE to edit the mutated C·G base pairs of Mef2c in the mouse brain through the intravenous injection of blood-brain barrier-crossing adeno-associated virus. This treatment successfully restored Mef2c protein levels in several brain regions and reversed the behavioral abnormalities in Mef2c-mutant mice. Our work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.

Discovery of INT131: a selective PPARγ modulator that enhances insulin sensitivity.

PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.

Transgenic nude mouse with green fluorescent protein expression-based human glioblastoma multiforme animal model with EGFR expression and invasiveness.

Previously, we developed an orthotopic xenograft model of human glioblastoma multiforme (GBM) with high EGFR expression and invasiveness in Balb/c nu/nu nude mice. Now we also developed the same orthotopic xenograft model in transgenic nude mice with green fluorescent protein (GFP) expression. The present orthotopic xenografts labeled by phycoerythrin fluorescing red showed high EGFR expression profile, and invasive behavior under a bright green-red dual-color fluorescence background. A striking advantage in the present human GBM model is that the change of tumor growth can be observed visually instead of sacrificing animals in our further antitumor therapy studies.

Discovery and characterization of a potent and selective antagonist of melanin-concentrating hormone receptor 2.

A series of spiropiperidine carbazoles were synthesized and evaluated as MCHR2 antagonists using a FLIPR assay. The pharmacokinetic properties of selected compounds have also been studied. This effort led to the discovery of potent and specific MCHR2 antagonists. Compound 38 demonstrated good pharmacokinetic properties across rat, beagle dog and rhesus monkey and had a favorable selectivity profile against a number of other receptors. These MCHR2 antagonists are considered appropriate tool compounds for study of the function of MCHR2 in vivo.

Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition.

An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076.

Uterus didelphys complicated with endometrial carcinoma: A case report of uterus didelphys with endometrial carcinoma.

RATIONALE: The incidence of uterine malformations is low (4%-7%). Currently, the National Comprehensive Cancer Network clinical practice guidelines in oncology recommend minimally invasive surgery for early endometrial cancer. Minimally invasive surgery for the treatment of uterine didelphys with endometrial cancer is rare due to the large size of the uterus. To date, only 2 such patients have been reported to have undergone laparoscopy. Whether such patients can be treated with minimally invasive surgery needs to be further explored. PATIENT CONCERNS: A 40-year-old woman with uterine didelphys was hospitalized for menorrhagia in the past 2 months. DIAGNOSIS: Endometrial adenocarcinoma was found in both the uterus and cervix using fractional dilation and curettage. INTERVENTIONS: The patient underwent laparoscopic surgery. Postoperative adjuvant radiotherapy and chemotherapy were administered. OUTCOMES: There was no sign of recurrence during routine follow-up. LESSONS: The use of a uterine manipulator to lift either side of the uterus could help to expose the narrow ipsilateral para-uterine field. It is difficult to remove the uterus entirely through the vagina, making it necessary to select appropriate cases wherein screening is performed to check if the vagina is loose, and the uterus is of appropriate size. Minimally invasive surgery may be feasible for suitable patients.

Identification of ZDHHC1 as a Pyroptosis Inducer and Potential Target in the Establishment of Pyroptosis-Related Signature in Localized Prostate Cancer.

Pyroptosis or cellular inflammatory necrosis is a programmed cell death kind. Accumulating evidence shows that pyroptosis plays a crucial role in the invasion, metastasis, and proliferation of tumor cells, thus affecting the prognosis of tumors and therapeutic effects. Prostate cancer (PCa), a common malignancy among men, is associated with inflammation. Pathophysiological effects of pyroptosis on tumor development and progression, as well as the mediation of PCa, are known, but its effects on the potential prognosis for PCa warrant in-depth investigation. Herein, we built a risk model of six pyroptosis-related genes and verified their predictive abilities for prognostic and therapeutic effects. Higher risk scores indicated a higher probability of biochemical recurrence (BCR), higher immune infiltration, and worsened clinicopathological features. To derive scientific and reliable predictions for BCR in patients having PCa, the findings of the current study were verified in the Gene Expression Omnibus (GEO) cohort following evaluation in The Cancer Genome Atlas (TCGA) dataset. Additionally, after evaluating the six genes in the model, ZDHHC1 was found to be an important component. Its antitumor role was further assessed through in vivo and in vitro experiments, and its promoting effect on pyroptosis was further evaluated and verified. The above results provided a new perspective for further studies on pyroptosis and its clinical utility for PCa.