Crystallographic and modeling study of the human inorganic pyrophosphatase 1: A potential anti-cancer drug target.

Inorganic pyrophosphatases (PPases) catalyze the hydrolysis of pyrophosphate to phosphates. PPases play essential roles in growth and development, and are found in all kingdoms of life. Human possess two PPases, PPA1 and PPA2. PPA1 is present in all tissues, acting largely as a housekeeping enzyme. Besides pyrophosphate hydrolysis, PPA1 can also directly dephosphorylate phosphorylated c-Jun N-terminal kinases 1 (JNK1). Upregulated expression of PPA1 has been linked to many human malignant tumors. PPA1 knockdown induces apoptosis and decreases proliferation. PPA1 is emerging as a potential prognostic biomarker and target for anti-cancer drug development. In spite of the biological and physiopathological importance of PPA1, there is no detailed study on the structure and catalytic mechanisms of mammalian origin PPases. Here we report the crystal structure of human PPA1 at a resolution of 2.4 Å. We also carried out modeling studies of PPA1 in complex with JNK1 derived phosphor-peptides. The monomeric protein fold of PPA1 is similar to those found in other family I PPases. PPA1 forms a dimeric structure that should be conserved in animal and fungal PPases. Analysis of the PPA1 structure and comparison with available structures of PPases from lower organisms suggest that PPA1 has a largely pre-organized and relatively rigid active site for pyrophosphate hydrolysis. Results from the modeling study indicate the active site of PPA1 has the potential to accommodate double-phosphorylated peptides from JNK1. In short, results from the study provides new insights into the mechanisms of human PPA1 and basis for structure-based anti-cancer drug developments using PPA1 as the target.

Clinical assessment of uterine artery embolization combined with curettage when treating patients with cesarean scar pregnancy: A retrospective study of 169 cases.

AIM: Recent years have witnessed an elevated incidence of cesarean scar pregnancy (CSP). However, the clinical complications and consequences of uterine artery embolization (UAE) and curettage treatment for CSP patients are not clear. We aimed to assess menstrual recovery and other clinically pertinent factors after UAE and curettage treatment in CSP patients. METHODS: A total of 169 CSP patients who underwent UAE combined with curettage between August 2013 and August 2017 were enrolled in this study. The menstruation recovery was recorded, and the factors that potentially affected menstrual blood volume (MBV) were analyzed. RESULTS: Among the 169 CSP cases, 36 had asymptomatics (21.3%), 133 vaginal hemorrhage (78.7%) and 19 lower abdominal pain (11.2%). The success rate of treatment was 96.4% with six patients undergoing further treatment. The follow-up assessment was performed in 139 of 169 patients. About 83 of 139 (59.7%) patients had reduced MBV, and 2 patients (1.4%) had amenorrhea. There was a significant difference in numbers of abortions between the decreased and normal MBV group (P = 0.0276). Importantly, 16 of 42 cases who were planning on having babies became pregnant, with 8 from the decreased (8/27) and normal MBV (8/15) group each. CONCLUSION: UAE combined with curettage treatment in CSP patients demonstrates a favorable success rate, which can also reduce MBV and proceeding pregnancy rate.

Successful removal of an intrauterine device perforating the uterus and the bladder with the aid of a transurethral nephroscope.

AIM: An IUD perforating the uterus and bladder and creating a nidus for stone formation is a rare complication. We aim to demonstrate with a video a novel surgical technique that involves transcervically extracting a perforating IUD with a transurethral nephroscope after removal of the bladder stone on the IUD. METHODS: A 57-year-old woman was referred to our department 4 months ago following a 2-year history of suprapubic pain at the end of urination. Ultrasound and X-ray examination confirmed an IUD perforating the uterus and the bladder. The patient underwent transurethral holmium laser lithotripsy and transcervical removal of the IUD with the aid of a transurethral nephroscope. RESULTS: The stone on the perforating ectopic IUD was successfully removed and the IUD was extracted without complications. CONCLUSION: This video demonstrates a rare case of an IUD that perforated both the bladder and the uterine walls and created a nidus for stone formation in the bladder. The surgical technique involved in removing the stone and extracting the IUD is a new approach to treating this problem. It is suspected that this specific surgical intervention may also help to minimize the formation of a larger vesico-uterine fistula by decreasing the extent of trauma potentially created when extracting the IUD. However, this supposition merits further study.

Partial Perforation of the Bladder by an Intrauterine Device in a Pregnant Woman: A Case Report.

BACKGROUND: Perforation by intrauterine devices (IUDs) can involve. neighboring organs such as the bladder. CASE: A 29-year-old woman with 2 previous cesarean section deliveries was diagnosed in the early stage of pregnancy with an IUD that had partially perforated the bladder. The exact location of the migrated IUD was determined with pelvic ultrasonography and endoscopic techniques, and the IUD was successfully retrieved with a hysteroscope. CONCLUSION: The use of imaging studies and endoscopic techniques such as ultrasonic examination, hysteroscopy, and cystoscopy are essential for identifying the location of an IUD that has partially perforated the bladder. Depending on the application of the correct treatment method, good results can be achieved following partial perforation of the bladder by an IUD.

Asthmatic patients with vitamin D deficiency: Can vitamin D supplementation make a difference.

BACKGROUND: Asthma is a major public health concern due to its persistent inflammation of the airways. The intricate and widely variable epidemiology of asthma among nations and populations is a result of the interplay between genetic, environmental, and socioeconomic factors. OBJECTIVE: This study aims to investigate whether VitD supplementation can reduce the frequency of exacerbations (including the frequency of exacerbations requiring systemic corticosteroids and the frequency of exacerbations necessitating trips to the hospital or emergency room, or both) and improve pulmonary function (clinical indicators such as the FEV1% predicted value). METHODS: Computers were used to search Pubmed, Medline, ISI Web of Science, Embase, Cachrane Library, CNKI, CBM, VIP, and the Wanfang Database. Asthma/asthma, VitD/VitD, lung function/lung function, retrieval time is from database setup to October 8, 2021, to search all randomized controlled trials (RCTs) on the effect of VitD on human asthma and to retroactively incorporate references to literature were all included in the search criteria. After rigorous screening, quality evaluation, and data extraction of the included literature by two reviewers independently, heterogeneity tests and sensitivity analyses were performed. RESULTS: The findings show that a total of 12 relevant studies meeting the inclusion criteria were finally included, including 649 cases in the experimental group and 646 cases in the control group. VitD intervention reduced the number of asthma exacerbations, including the rate of exacerbations requiring systemic corticosteroid therapy and the rate of acute exacerbations requiring emergency department or hospital visits or both. CONCLUSIONS: In the outcome of lung function (FEV1% predicted value), it was shown that VitD supplementation improved lung function; in the outcome of serum 25-hydroxyVitD levels, it was shown that VitD supplementation increased serum 25-hydroxyVitD levels.

Evaluation of the impact of vindoline, an active components of Catharanthus roseus, on rat hepatic cytochrome P450 enzymes by using a cocktail of probe drugs.

The objection of this study was to investigate the effects of vindoline(VDL) on the cytochrome P450 (CYP 450) isoforms (CYP1A2, 2B, 2C11, 2D1 and 3A) in rats. Firstly, the rats were randomly divided into VDL pretreatment group and blank group, each group had six rats. VDL pretreatment group was administrated VDL (20 mg·kg-1) by oral gavage for fifteen days consecutively, and the equivalent CMC-Na solution without VDL was given to the blank group by gavage. Secondly, a cocktail of caffeine, bupropion, diclofenac, dextromethorphan and midazolam was then administered on the sixteenth day. Finally, blood samples were collected at the specified time point, and the plasma concentration of the probe drug was determined by UHPLC-QTOF-MS/MS. The effects of VDL on the activity of these CYP enzymes in rats were evaluated by pharmacokinetic parameters. VDL pretreatment group compared with the blank group, accelerated the metabolism of diclofenac, and weakened the metabolism of caffeine. These results suggested that VDL could induce the activity of CYP2C11, and inhibits the activity of CYP1A2, but had no significant effects on CYP2B, CYP2D1 and CYP3A. The results in this study can provide beneficial information for the later clinical application of VDL.

Repeated COVID-19 relapse during post-discharge surveillance with viral shedding lasting for 67 days in a recovered patient infected with SARS-CoV-2.

A case who revealed the longest duration of viral shedding (67 days) in current reports, presented complicated characteristic on the relapse of COVID-19 due to the inconsistent performance of chest radiography and SARS-CoV-2-RNA detection after discharge. Lopinavir-interferon α2b boosted ribavirin following with lopinavir boosted budesonide might be a potent treatment for viral clearance.

High Expression of Metallo-ß-Lactamase Contributed to the Resistance to Carbapenem in Clinical Isolates of Pseudomonas aeruginosa from Baotou, China.

BACKGROUND: Bacterial resistance to antibiotics has become a major public health concern. This study aimed to determine the resistance mechanisms to carbapenem in clinical isolates of Pseudomonas aeruginosa. METHODS: A total of 62 clinical isolates of carbapenem-resistant P. aeruginosa (CRPA) were collected from 2015 to 2017. Imipenem (IPM)-EDTA disk synergy test was used to screen strains that produced metallo-ß-lactamase. In addition, the genes for outer membrane protein OprD2, metallo-ß-lactamase and mexR gene were amplified and sequenced. Expression of mexA was detected by real-time PCR. RESULTS: Disk synergy test showed that 51.6% (32/62) of the strains were positive for metallo-ß-lactamase. PCR showed that 84.4% of the strains were SIM-positive (27/32), 15.6% of the strains were IMP-positive (5/32), and 12.5% of the strains were VIM-positive (4/32). SPM-positive and GIM-positive strains were not detected. In addition, 5 of the 62 strains had small deletions and/or point mutations in OprD2. Three strains had a high expression of mexA, while eight strains were positive for the regulatory gene mexR with no mutations detected by DNA sequencing. CONCLUSION: Expression of metallo-ß-lactamase is the main resistance mechanism of P. aeruginosa to carbapenem. Mutations in OprD2 and/or the overexpression of efflux pump MexAB-OprM may contribute to P. aeruginosa resistance to carbapenem.

From aerospace to screen: Multifunctional poly(benzoxazine)s based on different triarylamines for electrochromic, explosive detection and resistance memory devices.

Four kinds of main-chain benzoxazine polymers (PBZ) containing triarylamine (TAA) units were synthesized by Mannich reaction and characterized by 1H nuclear magnetic resonance (NMR), Fourier transform infrared (FT-IR) techniques, etc. Thermal, optical, photophysical and electrochemical properties were studied. The 50% of char residue is left in N2 at 800 °C. The polymers are soluble in common organic solvents and easily spin-coated onto indium­tin oxide (ITO) coated glass substrates. All the polymers have voltage window ranging from 0 to 1.8 V, and the colors change from yellowish to dark red when voltage is applied. Meanwhile, device assembled from polymer exhibit significant color changes. Furthermore, the polymers also have promising potential application in explosive detection and resistance memory devices.

Positive SARS-CoV-2 RNA recurs repeatedly in a case recovered from COVID-19: dynamic results from 108 days of follow-up.

The evidence of long-term clinical dynamic on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) RNA re-positive case are less. We performed a 108 days follow-up on dynamic clinical presentations in a case, who hospitalized three times due to the positive recurrence of SARS-CoV-2 RNA after discharge, to understand the prognosis of the 2019-Coronavirus disease (COVID-19). In this case, positive SARS-CoV-2 recurred even after apparent recovery (normal CT imaging, no clinical symptoms, negative SARS-CoV-2 on stool sample and negative serum IgM test) from COVID-19, viral shedding duration lasted for 65 days, the time from symptom onset to disappearance was up to 95 days. Erythrocyte-associated indicators, liver function and serum lipid metabolism presented abnormal throughout during the observation period. Awareness of atypical presentations such as this one is important to prompt the improvement of the management of COVID-19.

Interferon induced transmembrane protein 3 regulates the growth and invasion of human lung adenocarcinoma.

BACKGROUND: Interferon induced transmembrane protein 3 (IFITM3) plays an important role in the tumorigenesis and progression of multiple cancers. This study investigated the expression and function of IFITM3 in human lung adenocarcinoma. METHODS: Fifty human lung adenocarcinoma tissues were collected. IFITM3 expression was assessed by immunohistochemical staining. The clinicopathologic characteristics of all patients were analyzed. RESULTS: IFITM3 was mainly detected in the cytoplasm of advanced cancer tissues and its expression was correlated with tumor malignancy grade. Knockdown of IFITM3 in vitro markedly inhibited the proliferation and invasion of lung adenocarcinoma cells. CONCLUSION: IFITM3 represents a potential therapeutic target for the treatment of lung adenocarcinoma.

Silencing PPA1 inhibits human epithelial ovarian cancer metastasis by suppressing the Wnt/ß-catenin signaling pathway.

Inorganic pyrophosphatase (PPA1) activity is a key determinant of cellular inorganic pyrophosphate levels, and its expression is correlated with growth of several solid tumors. To investigate this relationship, we first examined PPA1 expression in human epithelial ovarian cancer (EOC) samples, and found that PPA1 was overexpressed in tumors from EOC patients. Higher PPA1 levels correlated with advanced grades, stages, and poor survival in EOC patients. Examination of PPA1 function in EOC revealed that silencing PPA1 inhibited EOC migration, epithelial-mesenchymal transition (EMT), and metastasis in vitro and in vivo. In addition, PPA1 may promote the dephosphorylation and translocation of ß-catenin. These results demonstrate that silencing PPA1 inhibits EOC metastasis by suppressing the Wnt/ß-catenin signaling pathway. Strategies for downregulating PPA1 may have therapeutic potential for the prevention and treatment of EOC.

The prevalence of aminoglycoside-modifying enzyme and virulence genes among enterococci with high-level aminoglycoside resistance in Inner Mongolia, China.

This study highlights the prevalence of aminoglycoside-modifying enzyme genes and virulence determinants among clinical enterococci with high-level aminoglycoside resistance in Inner Mongolia, China. Screening for high-level aminoglycoside resistance against 117 enterococcal clinical isolates was performed using the agar-screening method. Out of the 117 enterococcal isolates, 46 were selected for further detection and determination of the distribution of aminoglycoside-modifying enzyme-encoding genes and virulence determinants using polymerase chain reaction -based methods. Enterococcus faecium and Enterococcus faecalis were identified as the species of greatest clinical importance. The aac(6')-Ie-aph(2″)-Ia and ant(6')-Ia genes were found to be the most common aminoglycoside-modifying enzyme genes among high-level gentamicin resistance and high-level streptomycin resistance isolates, respectively. Moreover, gelE was the most common virulence gene among high-level aminoglycoside resistance isolates. Compared to Enterococcus faecium, Enterococcus faecalis harbored multiple virulence determinants. The results further indicated no correlation between aminoglycoside-modifying enzyme gene profiles and the distribution of virulence genes among the enterococcal isolates with high-level gentamicin resistance or high-level streptomycin resistance evaluated in our study.

Effects of two novel amino acid substitutions on the penicillin binding properties of the PBP5 C­terminal from Enterococcus faecium.

The low­affinity penicillin­binding protein (PBP)5 is responsible for resistance to ß­lactam antibiotics in Enterococcus faecium. (E. faecium). In order to evaluate more fully the potential of this species for the development of resistance to ß-lactam antibiotics, the present study aimed to examine the extent of penicillin-binding protein (PBP) variations in a collection of clinical E. faecium isolates. In the present study, the C­terminal domain of PBP5 (PBP5­CD) of 13 penicillin­resistant clinical isolates of E. faecium were sequenced and the correlation between penicillin resistance and particular amino acid changes were analyzed. The present study identified for the first time, to the best of our knowledge, two novel substitutions (Tyr460Phe and Ala462Thr or Val462Thr) of E. faecium PBP5­CD. The covalent interaction between penicillin and PBP5­CD was also investigated using homology modeling and molecular docking methods. The theoretical calculation revealed that Phe460 and Thr462 were involved in penicillin binding, suggesting that substitutions at these positions exert effects on the affinity for penicillin, and this increased affinity translates into lower resistance in vitro.

STIM1 accelerates cell senescence in a remodeled microenvironment but enhances the epithelial-to-mesenchymal transition in prostate cancer.

The importance of store-operated Ca(2+) entry (SOCE) and the role of its key molecular regulators, STIM1 and ORAI1, in the development of cancer are emerging. Here, we report an unexpected dual function of SOCE in prostate cancer progression by revealing a decrease in the expression of STIM1 in human hyperplasia and tumor tissues of high histological grade and by demonstrating that STIM1 and ORAI1 inhibit cell growth by arresting the G0/G1 phase and enhancing cell senescence in human prostate cancer cells. In addition, STIM1 and ORAI1 inhibited NF-κB signaling and remodeled the tumor microenvironment by reducing the formation of M2 phenotype macrophages, possibly creating an unfavorable tumor microenvironment and inhibiting cancer development. However, STIM1 also promoted cell migration and the epithelial-to-mesenchymal transition by activating TGF-ß, Snail and Wnt/ß-Catenin pathways. Thus, our study revealed novel regulatory effects and the mechanisms by which STIM1 affects cell senescence, tumor migration and the tumor microenvironment, revealing that STIM1 has multiple functions in prostate cancer cells.

The prevalence of aminoglycoside-modifying enzyme and virulence genes among enterococci with high-level aminoglycoside resistance in Inner Mongolia, China

ABSTRACT This study highlights the prevalence of aminoglycoside-modifying enzyme genes and virulence determinants among clinical enterococci with high-level aminoglycoside resistance in Inner Mongolia, China. Screening for high-level aminoglycoside resistance against 117 enterococcal clinical isolates was performed using the agar-screening method. Out of the 117 enterococcal isolates, 46 were selected for further detection and determination of the distribution of aminoglycoside-modifying enzyme-encoding genes and virulence determinants using polymerase chain reaction -based methods. Enterococcus faecium and Enterococcus faecalis were identified as the species of greatest clinical importance. The aac(6')-Ie-aph(2")-Ia and ant(6')-Ia genes were found to be the most common aminoglycoside-modifying enzyme genes among high-level gentamicin resistance and high-level streptomycin resistance isolates, respectively. Moreover, gelE was the most common virulence gene among high-level aminoglycoside resistance isolates. Compared to Enterococcus faecium, Enterococcus faecalis harbored multiple virulence determinants. The results further indicated no correlation between aminoglycoside-modifying enzyme gene profiles and the distribution of virulence genes among the enterococcal isolates with high-level gentamicin resistance or high-level streptomycin resistance evaluated in our study.