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Copper complexes are considered as potential candidates for anticancer therapy and medical applications. In this paper, three new Cu(II) complexes, [Cu(IPY)

Two new copper(II) complexes of sparfloxacin (sf), [Cu(Hsf)(HPB)(H

In this paper, a set of 3-methylquniazolinone derivatives were designed, synthesised, and studied the preliminary structure-activity relationship for antiproliferative activities. All target compounds performed significantly inhibitory effects against wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and tumour cells (A431, A549, MCF-7, and NCI-H1975). In particular, compound 4d 3-fluoro-N-(4-((3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)phenyl)benzamide showed higher antiproliferative activities against all tumour cells than Gefitinib (IC50 of 3.48, 2.55, 0.87 and 6.42 μM, respectively). Furthermore, compound 4d could induce apoptosis of MCF-7 cells and arrest in G2/M phase at the tested concentration. Molecular docking and ADMET studies showed that compound 4d could closely form many hydrogen bonds with EGFRwt-TK. Therefore, compound 4d is potential to develop as novel anti-cancer drug.

Background Hepatitis D virus (HDV) infection is a major global health issue around the world. There are approximately 15–20 million individuals infected with HDV worldwide. HDV infection usually causes increased mortality compared with infection with hepatitis B virus (HBV) alone. However, testing for the detection of HDV is not widely available in Taiwan. Therefore, the General Biologicals Corporation (GB) HDV Ab kit was developed for detecting anti-HDV antibodies. Methods A total of 913 serum and 462 EDTA-treated plasma samples were obtained from HBsAg-positive individuals in three hospitals in Taiwan from June 2014 to November 2017. We used three commercially available ELISA kits, DiaPro HDV Ab, DiaSorin ETI-AB-DELTAK-2 and GB HDV Ab, which were utilized strictly according to the instructions of the manufacturers. Results A comparative study of the results from the GB HDV Ab kit and the other commercial ELISA kits (DiaPro and DiaSorin) was performed to determine their efficacy for anti-HDV detection. The results indicated that the sensitivity of the GB HDV Ab kit for serum and EDTA samples was 100% compared to that of the DiaPro and DiaSorin kits, whereas the specificity for serum and EDTA samples was 99.3 and 98.1%, respectively. In addition, the overall agreement of the results of the GB HDV Ab kit for the serum and EDTA samples was 99.3 and 98.3%, respectively. It is worth noting that the performance of the GB HDV Ab kit was not affected by interference from triglyceride, bilirubin, hemoglobin, or human anti-mouse antibody. The limit of detection of the GB HDV Ab kit is approximately 100-fold lower than that of the other two commercial kits. Conclusions The GB HDV Ab kit, which presented equivalent sensitivity and specificity compared to both certified anti-HDV kits, would be a suitable kit for HDV diagnosis in Taiwan.

Low-density lipoprotein receptor-related protein 8 (LRP8) is involved in the development of multiple tumors, including lung cancer. However, the exact mechanism by which LRP8 exerts its oncogenic role in non-small cell lung cancer (NSCLC) remains elusive. Hence, in this study, we aimed to unravel the expression and role of LRP8 in the progression of NSCLC. We used online bioinformatics databases to identify the expression of LRP8 in multiple types of lung cancer. We validated LRP8 expression in NSCLC cell lines and tissues by Western blotting and immunohistochemistry. The functions of LRP8 in NSCLC carcinogenesis and progression were determined using

This paper described our efforts to develop dianilinopyrimidines as novel EGFR inhibitors. All the target compounds were tested for inhibitory effects against wild type EGFR (EGFRwt) and three tumour cells, including A549, PC-3, and HepG2. Some of the compounds performed well in antitumor activities. Especially, compound 4c 2-((2-((4-(3-fluorobenzamido)phenyl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)amino)-N-methylthiophene-3-carboxamide showed higher anti-tumour activities than Gefitinib. The IC50 values of compound 4c against A549, PC-3, and HepG2. reached 0.56 μM, 2.46 μM, and 2.21 μM, respectively. In addition, further studies indicated that compound 4c could induce apoptosis against A549 cells and arrest A549 cells in the G2/M phase. Molecular docking studies showed that compound 4c could closely interact with EGFR. Generally, compound 4c was the potential for developing into an anti-tumour drug.

Fluorine is a necessary element for human, which is closely related to life activities, such as metabolism of teeth and bone tissue. A small amount of fluoride ions can promote the strengthen of our body. However, a large amount of fluoride ions will damage the human immune system to produce organ diseases. Sensitive and rapid detection of fluoride ions has attracted great interests for researchers. In this work, a reactive fluorescent probe SCP for detection of fluoride ions with high quantum yield was designed and synthesized based on the carbazole ring. Subsequently, the photophysical properties of the probe SCP were carefully studied. At last, SCP performed 62.8% quantum yield in physiological condition, excellent ability of quantitative analysis, well selectivity, and distinguishing features for HepG2 cell imaging.

ObjectiveTo determine the effect of gender of reciprocal chromosomal translocation on blastocyst formation and pregnancy outcome in preimplantation genetic testing, including different parental ages.MethodsThis was a retrospective cohort study that enrolled 1034 couples undergoing preimplantation genetic testing-structural rearrangement on account of a carrier of reciprocal chromosomal translocation from the Reproductive Medicine Center of the First Affiliated Hospital of Zhengzhou University from January 2015 to December 2019. Group A represented 528 couples in which the man was the carrier of reciprocal translocation and group B represented 506 couples in which the woman was the carrier of reciprocal translocation. All patients were divided into two groups according to their age: female ageResultsThe blastocyst formation rate of group A (55.3%) is higher than that of group B (50%) and the results were statistically significant (PConclusionWhen the carrier of reciprocal translocation is male, the blastocyst formation rate is higher than that of female carrier. While there is no significant difference between the two in terms of fertilization rate, aeuploidy rate, clinical pregnancy rate, miscarriage rate and live birth rate.

Anhedonia, or the inability to experience pleasure, is a key clinical feature of many mental disorders such as depression and schizophrenia. Although various valid measurements of anhedonia and pleasure experience exist, no scales exist that quantify smell and taste pleasure experiences. The Chemosensory Pleasure Scale (CPS) was therefore designed to assess the hedonic capacity for smell and taste pleasure. We examined the reliability and validity of the CPS in our study. First, we conducted exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) to identify and examine the structure of the CPS. Second, the CPS’s validity and test-retest stability were investigated. The CPS was correlated with other measurements of anhedonia and pleasure experience. Furthermore, the empirical validity of CPS was also examined in our study. The results indicated that the CPS is a reliable and valid measure for assessing an individual’s hedonic capacity for smell and taste pleasure in nonclinical samples. Further application of the CPS for various populations is also discussed herein, especially for patients with mental disorders such as depression, schizophrenia, and autism.

Skp2 is overexpressed in multiple cancers and plays a critical role in tumor development through ubiquitin/proteasome‐dependent degradation of its substrate proteins. Drugs targeting Skp2 have exhibited promising anticancer activity. Here, we identified a plant‐derived Skp2 inhibitor, betulinic acid (BA), via high‐throughput structure‐based virtual screening of a phytochemical library. BA significantly inhibited the proliferation and migration of non–small cell lung cancer (NSCLC) through targeting Skp2‐SCF E3 ligase both in vitro and in vivo. Mechanistically, BA binding to Skp2, especially forming H‐bonds with residue Lys145, decreases its stability by disrupting Skp1‐Skp2 interactions, thereby inhibiting the Skp2‐SCF E3 ligase and promoting the accumulation of its substrates; that is, E‐cadherin and p27. In both subcutaneous and orthotopic xenografts, BA significantly inhibited the proliferation and metastasis of NSCLC through targeting Skp2‐SCF E3 ligase and upregulating p27 and E‐cadherin protein levels. Taken together, BA can be considered a valuable therapeutic candidate to inhibit metastasis of NSCLC., By screening a phytochemical library via high‐throughput molecular docking, we identified that betulinic acid is capable of binding to Skp2 at residue Lys145, leading to decreased protein stability of Skp2 and the accumulation of its substrate protein p27 and E‐cadherin. Betulinic acid significantly inhibited the proliferation and migration of NSCLC through downregulating Skp2 both in vitro and in vivo.

INTRODUCTION GammaTile intracranial brachytherapy (cesium-131 seeds) has demonstrated encouraging safety and local control results, and recently received Food and Drug Administration clearance for newly diagnosed and recurrent brain tumors. The authors present the first reported case of GammaTile intraoperative brachytherapy performed during an awake craniotomy. METHODS A 50-year-old man had a biopsy-proven, 2.8 cm left lateral frontal glioblastoma lesion nearing Broca's area on MRI. Despite several interventions (craniotomy, adjuvant chemoradiation, tumor treating fields) tumor progression occurred near the left parietal resection cavity. Re-resection was planned with awake craniotomy and language mapping. A preoperative planning session involving Radiation Oncology and Neurosurgery identified the area of the expected postoperative bed, and consequently five GammaTiles were ordered, each containing 4 cesium-131 3.5 U seeds. RESULTS During surgery, tumor mapping and bipolar stimulation were performed while the patient spoke in complete sentences. Speech arrest occurred upon stimulation at the posterior edge of the gyrus, indicative of language cortex. Microsurgical maximal safe resection subsequently occurred, and areas at risk for residual/recurrence disease were determined in consultation with Radiation Oncology. Subsequently, Neurosurgery placed all five GammaTiles (20 cesium-131 seeds total) after which closure was completed and radioactive surveys of the room remained within state statue. Postoperative dosimetry yielded excellent coverage. CONCLUSIONS The first reported case of GammaTile intraoperative brachytherapy during awake craniotomy supports the safety and feasibility of this treatment strategy. This case indicates that for patients with tumors adjacent to eloquent cortex, awake craniotomy can allow for custom implantation of intraoperative brachytherapy following maximum safe resection.

In this paper, two new Cu(II) complexes, [Cu(Gluc)(HPB)(H2O)]Gluc (CuG1) and [Cu(Gluc)(HPBC)(H2O)]Gluc (CuG2) (where HPB = 2-(2′-pyridyl)benzimidazole, HPBC = 5-chloro-2-(2′-pyridyl)benzimidazole, Gluc = d -Gluconic acid), with good water solubility were synthesized and characterized. These complexes exhibited a five-coordinated tetragonal pyramidal geometry. The DNA binding and cleavage properties of the complexes were investigated using multi-spectroscopy, viscosity measurement, molecular docking and gel electrophoresis analysis methods. The results showed that the complexes could interact with DNA by insertion and groove binding, and cleave CT-DNA through a singlet oxygen-dependent pathway in the presence of ascorbic acid. The studies on antibacterial and anticancer activities in vitro demonstrated that both complexes had good inhibitory activity against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Listeria monocytogenes) and one Gram-negative bacterium (Escherichia coli) and good cytotoxic activity toward the tested cancer cells (A549, HeLa and SGC-7901). CuG2 showed higher antimicrobial and cytotoxic activities than CuG1, which was consistent with their binding strength and cleavage ability to DNA, indicating that their antimicrobial and cytotoxic activities may be related to the DNA interaction. Moreover, the cell-based mechanism studies have indicated that CuG1 and CuG2 could arrest the cell cycle at G2/M phase, elevate the levels of intracellular reactive oxygen species (ROS) and decrease the mitochondrial membrane potential (MMP). The results showed that the complexes could induce apoptosis through DNA-damaged and ROS-mediated mitochondrial dysfunction pathways. Finally, the in vivo antitumor study revealed that CuG2 inhibited tumor growth by 50.44%, which is better than that of cisplatin (40.94%).

Purpose Low-dose-rate brachytherapy is a highly effective treatment modality for prostate carcinoma, but postimplant dosimetry quality is essential and correlated with likelihood of treatment success. Registered ultrasound and fluoroscopy (iRUF) can facilitate real-time intraoperative monitoring and plan adaptation, with the aim of attaining superior dosimetric outcomes. The purpose of this research was to compare clinical postimplant dosimetric results of iRUF-guided brachytherapy against brachytherapy using standard ultrasound-guided intraoperative dosimetry methods. Methods and Materials We analyzed postimplant dosimetry in 292 patients treated with Pd-103 between January 2007 and December 2018. All patients had postimplant dosimetry measured on day 0 to 1 using fused magnetic resonance/computed tomography assessment. Fifty-two patients were treated in 2 prospective clinical trials using iRUF intraoperative dosimetry, including 6 patients in a pilot study and 46 treated in a phase 2 study. Postimplant dosimetry in iRUF-treated patients was compared with dosimetry from 240 patients treated using standard (real-time ultrasound) intraoperative seed tracking. Results For every parameter measuring dose coverage to the prostate, iRUF patients had significantly higher values, irrespective of adjustment for year of treatment. In adjusted analyses, parameters of dose to urethra and rectum were not significantly higher among iRUF-treated patients. Conclusions Use of iRUF intraoperative dosimetry was associated with improved postimplant dose coverage in prostate, without associated increases in doses to urethra or rectum.

Mountain-agarwood plays an important role in ethnic medicine in China for its pharmaceutical value. Modern pharmacological researches demonstrated that mountain-agarwood was effective for its anti-myocardial ischemia, antibacterial, anti-inflammatory, antitumor and analgesic effects. Mountain-agarwood derives from the peeled roots, stems or twigs of Syringa pinnatifolia which belongs to Syringa genus. It often depends on the purple substance and fragrance to estimate the formation of mountain-agarwood. However, the mechanism of mountain-agarwood formation has not been reported. To observe the microcosmic change in the process during the formation of mountain-agarwood, this study described the microscopic and histochemical characteristics of mountain-agarwood formation through histochemical staining. Our results showed that a significant difference of the distribution of tyloses existed during mountain-agarwood formation. It was observed that inchoate mountain-agarwood had more starch granules and viable cells than mountain-agarwood formed with high level or low level. The amount of polysaccharide and degree of lignification were increased during the mountain-agarwood formation. The results indicated that the mountain-agarwood, which meets the quality requirements for pharmaceutical use, contained the following characteristics: a large amount of purple tyloses in heartwood; yellow-brown tyloses distributing in heartwood and sapwood which were less in the latter; lignification with high level; a few viable cells; lots of polysaccharide and few starch granules in xylem rays cell. This study is aimed to reveal the change of histochemical characteristics during mountain-agarwood formation, and lay the foundation for exploring the mechanism of mountain-agarwood formation.

Objective: To study the risk factors for recurrent ectopic pregnancy (REP) in patients undergoing in vitro fertilization (IVF).Methods: This was a 1:4 matched case-control study that enrolled 227 REP patients and 908 matched intrauterine pregnancy (IUP) patients from the assisted reproductive technology (ART) center of the First Affiliated Hospital of Zhengzhou University from January 2012 to November 2019. Univariate analysis was carried out between the two groups for the occurrence of REP. Multivariate logistic regression analysis was used to explore the risk factors of REP after IVF.Results: The results of univariate analysis showed that there were significant differences in previous treatment of EP, stage of embryo and the number of embryos transferred between the two groups (all P < 0.05). The other factors did not have a significant effect on the probability of developing REP. Multivariate logistic regression analysis showed that after adjusting for confounders, previous treatment of EP, type of embryos transferred and stage of embryo were related to the occurrence of REP (all P < 0.05).Conclusion: Conservative treatment, frozen-thawed embryo transfer and cleavage embryo transfer were independent risk factors for REP after ART treatment.

Objective To observe the early interventions of traditional Chinese Medicine (TCM) on the conversion time of nucleic acid in patients with coronavirus disease 2019 (COVID-19), and find possible underlying mechanisms of action. Methods A retrospective cohort study was conducted on 300 confirmed COVID-19 patients who were treated with TCM, at a designated hospital in China. The patients were categorized into three groups: TCM1, TCM2 and TCM3, who respectively received TCM interventions within 7, 8–14, and greater than 15 days of hospitalization. Different indicators such as the conversion time of pharyngeal swab nucleic acid, the conversion time of fecal nucleic acid, length of hospital stay, and inflammatory markers (leukocyte count, and lymphocyte count and percentage) were analyzed to observe the impact of early TCM interventions on these groups. Results The median conversion times of pharyngeal swab nucleic acid in the three groups were 5.5, 7 and 16 d (P

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that has no effective treatment. The tumor microenvironment (TME) of PDA employs a multitude of immune derangement strategies to protect PDA from immune elimination. Tumor-associated macrophages (TAMs) have been implicated in the pathogenesis of immune suppression of the PDA TME; however, its underlying mechanisms remained largely unknown. Using primary patient samples, our studies showed that, in comparison with macrophages isolated from normal pancreatic tissues, the phagocytosis activity of the PDA TAMs was significantly reduced. We found that the expression of homeobox protein VentX, a master regulator of macrophage plasticity, was significantly decreased in the PDA TAMs. We demonstrated that VentX was required for phagocytosis and that restoration of VentX expression in PDA TAMs promoted phagocytosis through the regulation of the signaling cascades involved in the process. Using an ex vivo culture model of primary human PDA, we showed that VentX-modulated TAMs transformed the PDA TME from a protumor milieu to an antitumor microenvironment by rectifying differentiation, proliferation, and activation of PDA-infiltrating immune cells. Using NSG-PDX models of primary human PDAs, we showed that VentX-modulated TAMs exerted strong inhibition on PDA tumorigenesis in vivo. Taken together, our data revealed a central mechanism underlying immune evasion of PDA and a potential novel venue to improve PDA prognosis.

Background The value of this report is the identification of late recurrence with an extremely unusual combination of malignant transformation. In particular, the retroconversion of immature to mature teratoma as well as a somatic-type malignant transformation were both observed postchemotherapeutically in our case. Case presentation We report the case of a 20-year-old girl who completed fertility-sparing surgery and chemotherapy under the diagnosis of ovarian mixed germ cell tumor (immature teratoma and yolk sac tumor) and experienced subsequent recurrence 4 years after a second debulking surgery with a somatic type malignant transformation (teratoma with melanoma and leiomyosarcoma). Multiple metastases developed after a third debulking surgery, and the patient survived for 18 additional months. Conclusions Recurrent disease after repeated cytoreduction and chemotherapy hints a poor outcome despite a generally excellent long-term survival rate among ovarian germ cell malignancies. It is important for clinicians to distinguish those at risk of poorer outcomes and establish individualized postoperative surveillance. Fertility-compromising surgery may be considered in selected patients.

STUDY OBJECTIVE Previous studies suggest female-to-male transgender men tend to choose less invasive procedures, but the superior route of hysterectomy for them remains undetermined. DESIGN A retrospective study (Canadian Task Force Classification II-3). SETTING An academic tertiary hospital. PATIENTS Fifty-six female-to-male transsexuals received total vaginal hysterectomy (VH) with bilateral salpingo-oophorectomy (BSO) between April 2008 and August 2016 at Taipei Veterans General Hospital, Taipei, Taiwan. INTERVENTIONS The patients underwent natural orifice transluminal endoscopic surgery (NOTES) (n = 14) or the conventional approach (n = 42). MEASUREMENTS AND MAIN RESULTS Medical charts and surgical records were reviewed retrospectively. The general characteristics of the patients were similar in both groups. There were no statistically significant differences in operative time, estimated blood loss, intraoperative and immediate postoperative complications, or length of hospital stay between the 2 groups. However, postoperative pain was significantly reduced in the NOTES group compared with the conventional group as evidenced by lower mean scores on the visual analog scale (4.9 ± 3.0 vs 7.1 ± 1.4 at 2 hours, p = .008; 1.5 ± 1.2 vs 3.0 ± 1.7 at 48 hours, p = .001; and 1.7 ± 1.0 vs 2.7 ± 1.1 at 72 hours, p

Two water-soluble copper(II) complexes of 6-(pyrazin-2-yl)-1,3,5-triazine-2,4-diamine (pzta) and amino acids, [Cu(pzta)(L-ArgH)(H2O)](ClO4)2 (1) and [Cu(pzta)(L-Met)(H2O)]ClO4·3H2O (2) (L-ArgH: protonated L-Argininate; L-Met: L-Methioninate), were synthesized and characterized. The determined X-ray crystallographic structures of 1 and 2 exhibited distorted square-pyramidal coordination geometries. Their binding properties toward calf thymus DNA (CT-DNA) and human serum protein (HSA) were measured by spectroscopic (UV-Vis, fluorescence, circular dichroism (CD)), calorimetric (isothermal titration calorimetry (ITC)) and molecular docking technology. DNA binding experiments showed that the complexes bound to DNA through a groove binding mode, the positive ΔH and ΔS values indicated that the hydrophobic interaction was the main force in the binding between the complexes and DNA. Besides, the complexes caused the fluorescence quenching of HSA through a static quenching procedure, changed the secondary structure and microenvironment of the Trp-214 residue, and preferably bound to subdomain IIA of HSA driven by hydrophobic and hydrogen-bond interactions. These results were further verified by the molecular docking technology. Furthermore, the in vitro cytotoxicities of the complexes against three human carcinoma cell lines (A549, PC-3 and HeLa) were evaluated, which confirmed that the complexation improved the anticancer activity of the pzta ligand significantly.

Immune suppression in the tumor microenvironment (TME) is a central obstacle to effective immunotherapy. Tumor-associated macrophages (TAMs) are key components of the TME. Although TAMs have been viewed as an ideal target of intervention to steer immunity in cancer treatment, the approach has been hampered by the lack of knowledge of how TAM plasticity is controlled by cell intrinsic factors. VentX is a homeobox protein implicated in proliferation and differentiation of human hematopoietic and immune cells. Using clinical samples obtained from cancer patients, we find that VentX expression is drastically reduced in TAMs. We show here that VentX promotes M1 differentiation of TAMs, and that VentX-regulated TAMs, in turn, revert immune suppression at the TME. Using a NSG mouse model of human colon cancers, we demonstrate that VentX regulates TAM function in tumorigenesis in vivo. Our findings suggest a mechanism underlying immune suppression at TME and potential applications of VentX-regulated TAMs in cancer immunotherapy., Tumour associated macrophages (TAMs) polarize into either pro-tumor or anti-tumor phenotypes. Here the authors show that the homeobox protein VentX is downregulated in clinical samples of colorectal cancer and regulates TAMs plasticity with its forced re-expression converting TAMs into an anti-tumor phenotype.

In the search for more effective anticancer drugs with less toxic side effects, dipeptides were introduced into the Cu(II) complex of 5-methyl-2-(2′-pyridyl)benzimidazole (HPBM). Analytical and spectroscopic techniques were employed to thoroughly characterize complexes [Cu(Gly-gly)(HPBM)(H2O)]ClO4·0.5H2O (1) and [Cu(Gly-L-leu)(HPBM)(H2O)]ClO4 (2) (where Gly-gly = Glycyl-glycine anion, Gly-L-leu = Glycyl- l -leucine anion). The solution stability studies performed by ultraviolet–visible (UV–Vis) spectroscopy confirmed the stability of the complexes in the buffer solutions. The DNA binding affinity was evaluated using multi-spectroscopy, viscosity measurement and molecular docking methods and further quantified by Kb and Kapp values, revealing an intercalative mode. Moreover, gel electrophoresis analysis revealed that the complexes could damage CT DNA through a hydroxyl radical pathway in the presence of ascorbic acid. All the complexes displayed favorable antimicrobial and cytotoxic activities toward the tested microorganisms (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa) and cancer cells (A549, HeLa and PC-3). Most importantly, the possible anticancer mechanism of the complexes was explored by determining the cells morphological changes, intracellular reactive oxygen species (ROS) levels, location in mitochondria, mitochondrial membrane potentials and the expression of Bcl-2 family proteins. The results showed that the complexes could induce apoptosis in HeLa cells through an ROS-mediated mitochondrial dysfunction pathway, which was accompanied by the regulation of Bcl-2 family proteins.

Purpose Interest in prostate dose reduction or focal treatment exists due to expected reductions in treatment morbidity. Prior analyses have not generally corroborated relationships between prostate or urethral dose and urinary toxicity after brachytherapy, but such analyses have been performed on cohorts all receiving the same prescribed dose. We analyzed patients treated to differing prescription doses to assess acute urinary morbidity with dose reduction. Methods and Materials Patients treated with Pd-103 to either 125 Gy or 90–100 Gy were compared using the International Prostate Symptom Score (IPSS) at 1-month postimplant. Patients in the 90–100 Gy cohort began external beam radiation therapy after their 1-month assessment; thus, toxicities were measured before contribution from external beam radiation therapy. Patient/treatment characteristics were compared to verify subgroup homogeneity. Dose and change in IPSS 1 month after treatment were assessed using a multivariate linear regression model. Results One hundred ninety-one and 41 patients were treated with 125 Gy versus 90–100 Gy, respectively. Preimplant and postimplant prostate volumes and initial IPSS were similar between groups. Higher prescription dose and increased pretreatment IPSS were independent predictors of increased 1-month IPSS. In addition, every 10 percentage point additional prostate volume receiving a given dose was associated with increase in IPSS after treatment for the same level of pretreatment IPSS. Conclusion Lower prescription dose and decreased volume of high-dose regions to the prostate correlated with reduced acute urinary morbidity after brachytherapy. Our findings suggest that focal treatment approaches with modest dose reductions to subregions of the prostate may reduce acute morbidity and potentially expand the number of patients eligible for brachytherapy.

Objective: Nail change after chemotherapy is relatively unfamiliar with gynecological oncologist. It often occurs after docetaxel treatment. For gynecological tract cancers, paclitaxel might be most frequently used but nail change after paclitaxel treatment is seldom reported before. Case report: Two patients treated with the postoperative dose-dense weekly schedule of paclitaxel 80 mg/m2 plus cisplatin 20 mg/m2 every three weeks were complicated with nail problems during the treatment. They included onycholysis, subungual hemorrhage, proximal white subungual collections of pus obscuring the lunula (onychophosis), dystrophy, Beau's lines, pigmentation, and melanonychia. Topical use of anti-fugal cream and oral antibiotics stopped the nail disease progression and both patients had completed their chemotherapy without interruption. Conclusion: Clinicians should be aware of paclitaxel-induced nail toxicities. Adequate information, detailed preventive intervention, and early use of prophylactic and/or therapeutic agents to minimize the occurrence of severe morbidity, such as cellulitis and subsequent sepsis is important for women who need the continuous dose-dense paclitaxel chemotherapy. Keywords: Dermatological problems, Dose-dense chemotherapy, Nail, Paclitaxel

Brainstem metastases offer a unique challenge in cancer treatment, yet stereotactic radiosurgery (SRS) has proven to be an effective modality in treating these tumors. This report discusses the clinical outcomes of patients with brainstem metastases treated at Indiana University with Gamma Knife (GK) radiosurgery from 2008 to 2016. 19 brainstem metastases from 14 patients who had follow-up brain imaging were identified. Median tumor volume was 0.04 cc (range: 0.01–2.0 cc). Median prescribed dose was 17.5 Gy to the 50% isodose line (range: 14–22 Gy). Median survival after GK SRS treatment to brainstem lesion was 17.2 months (range: 2.8–45.6 months). The experience at Indiana University confirms the safety and efficacy of range of GK SRS prescription doses (14–22 Gy) to brainstem metastases.

Objective By exploring the exposure-response relationships between meteorological factors and rupture of intracranial aneurysm (IA) to reveal the influence of meteorological variation on IA rupture under the specific climate in Fujian, China. Method 7515 cases of IA rupture from several municipal medical institutions in Fujian Province as well as local meteorological data during the same period were collected from 2013 to 2017. Poisson regression and Spearman correlation analysis were applied to explore the distribution characteristics of IA rupture and how it is associated with meteorological parameters. Poisson generalized additive model was established to further analyze the exposure-response relationships between meteorological factors and IA rupture, and its hysteresis effects. Result The IA rupture exhibited a negative correlation with temperature (rs = −0.323, 95% CI: −0.539 ~ −0.068) and a positive correlation with atmospheric pressure (rs = 0.397, 95% CI: 0.152–0.597) or pressure difference (rs = 0.296, 95% CI: 0.038–0.517), 21.05 ℃ and 1000.14 hPa were the risk thresholds for the onset ascribed to variation in temperature and atmospheric pressure, respectively. Temperature and atmospheric pressure also exerted hysteresis effects on IA rupture. Cold will increase the rupture risk in the subsequent 1–3 days, and high pressure will raise the morbidity in the next 1–2 days. Besides, drastic variations in temperature and atmospheric pressure were also associated with the higher risk of IA rupture in the next 2 days and 1 day, respectively. Conclusion Temperature and atmospheric pressure have a negative and positive correlation with IA rupture in Fujian, China, respectively. Variation in temperature and atmospheric pressure exert different degrees of hysteresis effects on IA rupture.

Beta-lactams (BL), the most commonly prescribed class of antibiotics, are recommended as the first-line therapy for multiple indications in infectious disease guidelines. Meropenem (MERO) is frequently used in intensive care units (ICU) to treat bacterial infections with or without sepsis. The pharmacokinetics of MERO display a large variability in patients admitted to ICUs due to altered pathophysiology. The aim of this study was to perform an external evaluation of published population pharmacokinetic models of MERO in order to test their predictive performance in a cohort of ICU adult patients. A literature search in PubMed/Medline database was made following the PRISMA statement. External evaluation was performed using NONMEM software, and the bias and inaccuracy values were calculated. An external validation dataset from the Timone Hospital in Marseille, France, included 84 concentration samples from 27 patients. Four models of MERO were identified according to the inclusion criteria of the study. None of the models presented acceptable values of bias and inaccuracy. While performing external evaluations on some populations may confirm a model’s suitability to diverse groups of patients, there is still some variability that cannot be explained nor solved by the procedure. This brings to light the difficulty to develop only one model for ICU patients and the need to develop one specific model to each population of critically ill patients.

BACKGROUND Sepsis-induced myopathy (SIM) is a complication of sepsis that results in prolonged mechanical ventilation, long-term functional disability, and increased patient mortality. This study aimed to use bioinformatics analysis to identify hub genes and molecular pathways involved in SIM, to identify potential diagnostic or therapeutic biomarkers. MATERIAL AND METHODS The Gene Expression Omnibus (GEO) database was used to acquire the GSE13205 expression profile. The differentially expressed genes (DEGs) in cases of SIM and healthy controls, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the limma R/Bioconductor software package and clusterProfiler package in R, respectively. The protein-protein interaction (PPI) network data of DEGs was retrieved using the STRING database and analyzed using the Molecular Complex Detection (MCODE) Cytoscape software plugin. RESULTS A total of 196 DEGs were obtained in SIM samples compared with healthy samples, including 93 upregulated genes. The DEGs were significantly upregulated in mineral absorption, and the interleukin-17 (IL-17) signaling pathway and 103 down-regulated genes were associated with control of the bile secretion signaling pathway. A protein-protein interaction (PPI) network was constructed with 106 nodes and 192 edges. The top two important clusters were selected from the PPI by MCODE analysis. There were 16 hub genes with a high degree of connectivity in the PPI network that were selected, including heme oxygenase 1 (HMOX1), nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (NQO1), and metallothionein (MT)-1E. CONCLUSIONS Bioinformatics network analysis identified key hub genes and molecular mechanisms in SIM.

Hemodialysis patients are vulnerable to infectious diseases and frequent receipt of antimicrobial agents. The aim of this study was to describe the prevalence and characteristics of infections and antimicrobials use among hemodialysis outpatients. We utilized the dialysis event surveillance protocol developed by the National Healthcare Safety Network to conduct a prospective multicenter study in Anhui, China. A total of 41 dialysis centers involving 7393 outpatients were included. Fistula was the most common type of vascular access (85.3%), followed by tunneled central line (12.7%), and non-tunneled central line (1.2%). There were 118 dialysis events with an overall pooled events rate of 1.60 per 100 patient-months. Intravenous antimicrobial start, positive blood culture, and pus, redness, or increased swelling at the vascular access site were detected at rates of 0.91, 0.23, and 0.46 per 100 patient-months, respectively. The prevalence of dialysis events was commonly higher in patients with a central line, and lower in patients with a fistula. Hemodialysis outpatients also had the noteworthy risks of nonaccess infections. Older age, female gender, and having a central line were associated with the increased risk of dialysis events. Findings recommend that regular monitoring and improvement strategies are warranted in management of infections among hemodialysis outpatients.

Objective The climatic characteristics of aneurysmal subarachnoid hemorrhage (aSAH) have been reported, but consensus has not yet been reached. It is of great significance to elucidate the relationships between meteorological variation and aSAH in regions with specific climate patterns. We analyzed the occurrence of aSAH in the capital city of Fujian Province, China, through a multicenter, 5-year study, and aimed to reveal the meteorological influences on aSAH in the coastal city of eastern Fujian under the subtropical marine monsoon condition. Methods A total of 2555 consecutive patients with aSAH in Fuzhou were collected using specialized stroke admission database from January 2013 to December 2017. Meteorological parameters including temperature, atmospheric pressure, and humidity were obtained from China Surface Meteorological Station during the same period. Poisson regression was used to explore the association between meteorological parameters and aSAH to calculate the incidence rate ratios (IRRs) with corresponding 95% confidence intervals (CIs). Generalized additive model analysis further revealed the nonlinear relationships between weather and aSAH. Results Daily minimum temperature (IRR 0.976, 95% CI 0.958–0.996) and maximum pressure (IRR 1.022, 95% CI 1.001–1.042) were independently correlated with the onset of aSAH. Low temperature (below 16°C) and excessive atmospheric pressure (above 1008 hPa) increased the risk of aSAH. In addition, March in spring and December in winter were the 2 ictus peaks in Fuzhou throughout the year. Conclusions Cold and excessive atmospheric pressure are triggers for the occurrence of aSAH; March in spring and December in winter are the predominant onset periods in Fuzhou.

Oxidative stress is implicated in the pathogenesis of neurodegeneration and other aging-related diseases. Previous studies have found that the whole herb of Centipeda minima has remarkable antioxidant activities. However, there have been no reports on the neuroprotective effects of C. minima, and the underlying mechanism of its antioxidant properties is unclear. Here, we examined the underlying mechanism of the antioxidant activities of the ethanol extract of C. minima (ECM) both in vivo and in vitro and found that ECM treatment attenuated glutamate and tert-butyl hydroperoxide (tBHP)-induced neuronal death, reactive oxygen species (ROS) production, and mitochondria dysfunction. tBHP-induced phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinases (JNK) was reduced by ECM, and ECM sustained phosphorylation level of extracellular signal regulated kinase (ERK) in SH-SY5Y and PC12 cells. Moreover, ECM induced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the upregulation of phase II detoxification enzymes, including heme oxygenase-1 (HO-1), superoxide dismutase-2 (SOD2), and NAD(P)H quinone oxidoreductase-1 (NQO-1) in both two cell types. In a D-galactose (D-gal) and aluminum muriate (AlCl3)-induced neurodegenerative mouse model, administration of ECM improved the learning and memory of mice in the Morris water maze test and ameliorated the effects of neurodegenerative disorders. ECM sustained the expression level of postsynaptic density 95 (PSD95) and synaptophysin (SYN), activated the Nrf2 signaling pathway, and restored the levels of cellular antioxidants in the hippocampus of mice. In addition, four sesquiterpenoids were isolated from C. minima to identify the bioactive components responsible for the antioxidant activity of C. minima; 6-O-angeloylplenolin and arnicolide D were found to be the active compounds responsible for the activation of the Nrf2 signaling pathway and inhibition of ROS production. Our study examined the mechanism of C. minima and its active components in the amelioration of oxidative stress, which holds the promise for the treatment of neurodegenerative disease.

IMPORTANCE: There is no current consensus on the role of chemotherapy in addition to radiation for postoperative adjuvant treatment of patients with early-stage cervical cancer with adverse pathological factors. OBJECTIVE: To evaluate the clinical benefits of sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT) compared with radiation alone (RT) as a postoperative adjuvant treatment in early-stage cervical cancer. DESIGN, SETTING, AND PARTICIPANTS: After radical hysterectomy at 1 of 8 participating hospitals in China, patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IIA cervical cancer with adverse pathological factors were randomized 1:1:1 to receive adjuvant RT, CCRT, or SCRT. Data were collected from February 2008 to December 2018. INTERVENTIONS: Patients received adjuvant RT (total dose, 45-50 Gy), CCRT (weekly cisplatin, 30-40 mg/m(2)), or SCRT (cisplatin, 60-75 mg/m(2), plus paclitaxel, 135-175 mg/m(2)) in a 21-day cycle, given 2 cycles before and 2 cycles after radiotherapy, respectively. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of disease-free survival (DFS) at 3 years. RESULTS: A total of 1048 women (median [range] age, 48 [23-65] years) were included in the analysis (350 in the RT group, 345 in the CCRT group, and 353 in the SCRT group). Baseline demographic and disease characteristics were balanced among the treatment groups except that the rate of lymph node involvement was lowest in the RT group (18.3%). In the intention-to-treat population, SCRT was associated with a higher rate of DFS than RT (3-year rate, 90.0% vs 82.0%; hazard ratio [HR], 0.52; 95% CI, 0.35-0.76) and CCRT (90.0% vs 85.0%; HR, 0.65; 95% CI, 0.44-0.96). Treatment with SCRT also decreased cancer death risk compared with RT (5-year rate, 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95) after adjustment for lymph node involvement. However, neither DFS nor cancer death risk was different among patients treated with CCRT or RT. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, conducted in a postoperative adjuvant treatment setting, SCRT, rather than CCRT, resulted in a higher DFS and lower risk of cancer death than RT among women with early-stage cervical cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00806117

// Hong Gao 1, 2, * , Bin Wu 1, 3, * , Yi Le 1 , Zhenglun Zhu 1 1 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA 2 Current address: Department of Medicine, Tufts Medical Center, Boston, 02115, Massachusetts, USA 3 Current address: Department of Gastroenterology, Third Hospital, Sun Yat-Sen University, Guangzhou, 510630, China * These authors contributed equally to this work Correspondence to: Zhenglun Zhu, e-mail: zzhu@partners.org Keywords: ventX, apoptosis, p53, caspase-3, PARP Received: December 18, 2015 Accepted: April 24, 2016 Published: May 09, 2016 ABSTRACT Identifying novel tumor suppressors holds promise for improving cancer treatment. Our recent studies identified VentX, a homeobox transcriptional factor, as a putative tumor suppressor. Here we demonstrate that VentX exerts strong inhibitory effects on the proliferation and survival of cancer cells, but not primary transformed cells, such as 293T cells. Mechanistically, both in vitro and in vivo data showed that VentX induces apoptosis of cancer cells in a p53-independent manner. We found that VentX expression can be induced by chemotherapeutic agents. Taken together, our findings suggest that VentX may function as a novel therapeutic target in cancer treatment.

The recognition and association between Ca2+/calmodulin-activated protein kinase II-α (CaMKIIα) and multi-PDZ domain protein 1 (MUPP1) plays an important role in sperm acrosome reaction and human fertilization, which is mediated by the binding of CaMKIIα’s C-terminal tail to one or more PDZ domains of the scaffolding protein MUPP1. In this study, we attempt to identify the CaMKIIα-interacting MUPP1 PDZ domains and to design peptide ligands that can potently target and then competitively disrupt such interaction. Here, a synthetic biology approach was proposed to systematically characterize the structural basis, energetic property, dynamic behavior and biological implication underlying the intermolecular interactions between the C-terminal peptide of CaMKIIα and all the 13 PDZ domains of MUPP1. These domains can be grouped into four clusters in terms of their sequence, structure and physiochemical profile; different clusters appear to recognize different classes of PDZ-binding motifs. The cluster 3 includes two members, i.e. MUPP1 PDZ 5 and 11 domains, which were suggested to bind class II motif Φ-X-Φ–COOH of the C-terminal peptide SGAPSV–COOH of CaMKIIα. Subsequently, the two domains were experimentally measured as the moderate- and high-affinity binders of the peptide by using fluorescence titration (dissociation constants K d = 25.2 ± 4.6 and 0.47 ± 0.08 µM for peptide binding to PDZ 5 and 11, respectively), which was in line with theoretical prediction (binding free energies ΔG total = −7.6 and −9.2 kcal/mol for peptide binding to PDZ 5 and 11, respectively). A systematic mutation of SGAPSV–COOH residues suggested few favorable amino acids at different residue positions of the peptide, which were then combined to generate a number of potent peptide mutants for PDZ 11 domain. Consequently, two peptides (SIAPNV–COOH and SIVMNV–COOH) were identified to have considerably improved affinity with K d increase by ~tenfold relative to wild type peptide. Thus, the two peptides are considered as promising lead entities to develop therapeutic molecular agents with high efficacy and specificity to target CaMKIIα–MUPP1 interaction. Other five designed peptides (SILPSV–COOH, SGLPNV–COOH, SIVMSV–COOH, SIVPNV–COOH and SIAMNV–COOH) possessed comparable affinity with the wild type, and they may be further optimized to obtain higher potency.

Objectives Heart failure (HF) is a common and potentially fatal condition. In 2015, HF affected approximately 40 million people globally. Evidence showing that the use of nitrates can improve clinical outcomes in patients with HF is limited. This study aimed to assess the effect of nitrates on functional capacity and exercise time in patients with HF. Methods PubMed, Cochrane Library, and Embase databases were reviewed for articles on the use of nitrates and other treatments for patients with HF. The primary endpoints were the 6-minute walk test distance, exercise time, and quality of life. Secondary endpoints were all-cause mortality, arrhythmia, hospitalization, and worsening HF. The weighted mean difference, risk ratio, and 95% confidence interval were calculated. Results A total of 14 related studies that comprised 26,321 patients were included. No significant differences were found in the 6-minute walk test distance, exercise time, and quality of life between the nitrate and control treatment groups. There were also no differences in all-cause mortality, the incidence of arrhythmia, hospitalization, and worsening HF between these two groups. Conclusion Patients with HF who receive nitrate treatment do not have better quality of life or exercise capacity compared with controls.

Purpose Dosimetric assessment following permanent prostate brachytherapy (PPB) commonly involves seed localization using CT and prostate delineation using coregistered MRI. However, pelvic CT leads to additional imaging dose and requires significant resources to acquire and process both CT and MRI. In this study, we propose an automatic postimplant dosimetry approach that retains MRI for soft-tissue contouring, but eliminates the need for CT and reduces imaging dose while overcoming the inconsistent appearance of seeds on MRI with three projection x rays acquired using a mobile C-arm. Methods Implanted seeds are reconstructed using x rays by solving a combinatorial optimization problem and deformably registered to MRI. Candidate seeds are located in MR images using local hypointensity identification. X ray-based seeds are registered to these candidate seeds in three steps: (a) rigid registration using a stochastic evolutionary optimizer, (b) affine registration using an iterative closest point optimizer, and (c) deformable registration using a local feature point search and nonrigid coherent point drift. The algorithm was evaluated using 20 PPB patients with x rays acquired immediately postimplant and T2-weighted MR images acquired the next day at 1.5 T with mean 0.8 × 0.8 × 3.0 mm 3 voxel dimensions. Target registration error (TRE) was computed based on the distance from algorithm results to manually identified seed locations using coregistered CT acquired the same day as the MRI. Dosimetric accuracy was determined by comparing prostate D90 determined using the algorithm and the ground truth CT-based seed locations. Results The mean ± standard deviation TREs across 20 patients including 1774 seeds were 2.23 ± 0.52 mm (rigid), 1.99 ± 0.49 mm (rigid + affine), and 1.76 ± 0.43 mm (rigid + affine + deformable). The corresponding mean ± standard deviation D90 errors were 5.8 ± 4.8%, 3.4 ± 3.4%, and 2.3 ± 1.9%, respectively. The mean computation time of the registration algorithm was 6.1 s. Conclusion The registration algorithm accuracy and computation time are sufficient for clinical PPB postimplant dosimetry.

Background We tested the hypothesis that high-density lipoprotein (HDL) is associated with intracranial aneurysm growth and rupture. Methods We used an observational cohort study design. Age, sex, admission systolic blood pressure (SBP), diabetes, hypertension, coronary artery disease, aneurysmal rupture, apolipoprotein (APO)-A1, APO-B, HDL, low-density lipoprotein, triglycerides, cholesterol, and aneurysm location and size were recorded. Aneurysms Results The data from 581 patients with intracranial aneurysms were analyzed. The predictive factors for small size of aneurysms were female sex (odds ratio [OR], 0.630; 95% confidence interval [CI], 0.428–0.927; P = 0.019) and higher HDL (OR, 0.327; 95% CI, 0.159–0.672; P = 0.0002). In the subgroup of male patients, lower HDL was the only risk factor for large size (P = 0.015). The predictors of aneurysmal rupture were small size (OR, 0.875; 95% CI, 0.842–0.910; P = 0.000), higher HDL (OR, 3.716; 95% CI, 1.623–8.509; P = 0.002), no coronary artery disease (OR, 4.736; 95% CI, 1.528–14.681; P = 0.007), lower APO-A1 (OR, 0.202; 95% CI, 0.064–0.641; P = 0.007), and higher admission SBP (OR, 1.024; 95% CI, 1.015–1.032; P = 0.000). An HDL/aneurysm size ratio >0.31 was associated with a 46.2-fold increased likelihood of aneurysmal rupture (OR, 46.214; 95% CI, 13.386–159.548; P = 0.002). Conclusions The HDL level was inversely associated with intracranial aneurysm growth, especially in men. Higher HDL levels and small aneurysm size contributed to a greater risk of aneurysmal rupture. An HDL/size ratio >0.31 was a valuable predictor of intracranial rupture.

Introduction The aim of this study was to summarize evidence on the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and odds of preterm delivery and placental abruption. Material and Methods PubMed, EMBASE, CBM (Chinese Biomedical Database) and CNKI (Chinese National Knowledge Infrastructure) were searched to identify eligible studies published in English or Chinese before 12 August 2014. The pooled odds ratios (ORs) with 95% confidence intervals were estimated for the association of MTHFR C677T polymorphism with preterm delivery and placental abruption using random effects models. Results A total of 22 studies that met inclusion and exclusion criteria were included in this meta-analysis. Regardless of the genetic model tested we found no statistically significant association of MTHFR C677T polymorphism with preterm delivery or placental abruption. Funnel plots inspections, Begg's test and Egger's test did not show evidence of publication bias. Conclusions This meta-analysis demonstrated that overall there was no association of MTHFR C677T polymorphism with preterm delivery or placental abruption.

Objective To systematically evaluate the efficacy and safety of Modified Tongxie Yaofang (M-TXYF) for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D). Method Electronic databases including PubMed, Springer Link, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature (CBM), Wanfang, and Chinese Scientific Journals Database (VIP) were conducted from their inception through May 11, 2017 without language restrictions. Primary and secondary outcomes were estimated by 95% confidence intervals (CI). RevMan 5.3 and the Cochrane Collaboration’s risk of bias tool were analyzed for this meta-analysis. Results Twenty-three literatures with a total of 1972 patients were included for the meta-analysis. The overall risk of bias evaluation was low. The pooled odds ratio showed that M-TXYF was significantly superior to routine pharmacotherapies (RP) in clinical therapeutic efficacy (OR 4.04, 95% CI 3.09, 5.27, P < 0.00001, therapeutic gain = 17.6%, number needed to treat (NNT) = 5.7). Moreover, compared with RP, M-TXYF showed that it can significantly reduce the scores of abdominal pain (standardized mean difference (SMD) -1.27; 95% CI -1.99, -0.56; P = 0.0005), abdominal distention (SMD -0.37; 95% CI -0.73, -0.01; P = 0.09), diarrhea (SMD -1.10; 95% CI -1.95, -0.25; P = 0.01), and frequency of defecation (SMD -1.42; 95% CI -2.19, -0.65; P = 0.0003). The differences of the adverse events between experiment and control groups had no statistical significance. Conclusion This meta-analysis indicated that M-TXYF could be a promising Chinese herbal formula in treating IBS-D. However, considering the lack of higher quality of randomized controlled trials (RCTs), highly believable evidences should be required.

Two new Cu(II)–dipeptide complexes of 2-(4′-thiazolyl)benzimidazole, [Cu(Gly-Gly)(TBZ)(Cl)]·4H2O (1) and [Cu(Gly- l -Leu)(TBZ)(Cl)]·H2O (2) (Gly-Gly = glycyl-glycine anion, Gly- l -Leu = glycyl- l -leucine anion and TBZ = 2-(4′-thiazolyl)benzimidazole) have been synthesized and characterized by elemental analyses, molar conductance measurements and spectroscopy methods (IR, UV–visible, electrospray ionization mass spectra (ESI-MS) and EPR). The DNA binding and cleavage properties of the complexes monitored by multi-spectroscopic techniques (UV absorption, fluorescence and circular dichroism), viscosity determination and agarose gel electrophoresis indicated that the complexes bound to calf thymus (CT)-DNA via a partial intercalative mode with considerable intrinsic binding constants (Kb = 1.64 × 105 M− 1 for 1 and 2.59 × 105 M− 1 for 2), and cleaved pBR322 DNA efficiently in the mediation of ascorbic acid (AA), probably via an oxidative damage mechanism induced by OH. The antioxidant activities of the complexes have been evaluated by means of modified nitroblue tetrazolium (NBT) photoreduction and cellular antioxidant activity (CAA) assays using HepG2 cells as a model, and it was found that IC50 values of 1 and 2 for dismutation of O2− were 0.172 and 0.247 μM, respectively, and the CAA50 values were 10.57 and 10.74 μM. In addition, the complexes were subjected to in vitro cytotoxicity against three human carcinoma cell lines (HeLa, A549 and HepG2), which revealed that the complexes exhibited effective cytotoxicity (IC50 values varying from 33.17 to 100 μM) and selective inhibition toward HeLa cell lines. These findings indicate that the complexes have the potential to act as effective metallopeptide chemotherapeutic agents.

Bronchiolitis is a common respiratory illness and is a leading cause of hospitalisation in infancy. We aimed to appraise three recent national bronchiolitis guidelines produced by the Australasian Paediatric Research in Emergency Departments International Collaborative, the National Institute for Health and Care Excellence in the UK and the American Academy of Pediatrics.A group of final-year medical students and one senior clinician used the AGREE II tool to appraise each guideline in two stages. First, two students appraised each guideline independently and presented their results. Second, two self-selected students met with the senior clinicians to review all scores to ensure completeness of the appraisal and consistency of AGREE II application.The guidelines scored well overall, with particular strengths in the domains of clarity of presentation, scope and purpose and rigour of development. Comparison of the recommendations across each guideline demonstrated a high degree of consistency. Notable differences included recommendations for the role of palivizumab in prevention of bronchiolitis, the use of continuous pulse oximetry monitoring in the hospitalised patient and the value of respiratory virus testing.Our appraisal of bronchiolitis guidelines from three high-income countries demonstrated that they were of high quality, with substantial areas of agreement. Most aspects of clinical practice should be uniform for this common paediatric condition. Areas of guideline weakness were in the domains of applicability and editorial independence. We identified three areas of controversy where further research is needed to support stronger evidence-based recommendations.

The dorsal cell fate determination factor β-catenin and its antagonist, the ventral cell fate determination factor Xom, are expressed and distributed in a polarized fashion during early vertebrate embryogenesis. Ubiquitin-mediated proteolysis has been shown to control the abundance of both β-catenin and Xom. However, the mechanism of ubiquitin-mediated proteolysis in regulating dorsoventral patterning remains largely unclear. Our current study shows that Xom induces proteolysis of β-catenin through GSK3-mediated phosphorylation of Ser33/37 of β-catenin. Our findings reveal a novel pathway that regulates β-catenin stability, and suggest, for the first time, a critical function of ubiquitin-mediated proteolysis in balancing the integration of dorsal-ventral signals and the polarized distribution of β-catenin and Xom during dorsoventral axis formation.

The recognition and association between the Ca2+/calmodulin-activated protein kinase II-α (CaMKIIα) and the multi-PDZ domain protein 1 (MUPP1) plays an important role in the sperm acrosome reaction and human fertilization. Previously, we have demonstrated that the MUPP1 PDZ11 domain is the primary binding partner of the CaMKIIα C-terminal tail, which can be targeted by a rationally designed sia peptide with nanomolar affinity. Here, we further introduced an orthogonal noncovalent interaction (ONI) system between a native hydrogen bond and a designed halogen bond across the complex interface of the PDZ11 domain with the sia [Asn-1Phe] peptide mutant, where the halogen bond was formed by substituting the o-hydrogen atom of the benzene ring of the peptide Phe-1 residue with a halogen atom (F, Cl, Br or I). Molecular dynamics simulations and high-level theoretical calculations suggested that bromine (Br) is a good compromise between the halogen-bonding strength and steric hindrance effect due to introduction of a bulkier halogen atom into the tightly packed complex interface. Fluorescence spectroscopy assays revealed that the resulting o-Br-substituted peptide (Kd = 18 nM) exhibited an ∼7.6-fold affinity increase relative to its native counterpart (Kd = 137 nM). In contrast, the p-Br-substituted peptide, a negative control that is unable to establish the ONI according to structure-based analysis, has decreased affinity (Kd = 210 nM) upon halogenation.

A new ternary copper(II)-dipeptide complex [Cu(glygly)(HPB)(Cl)]⋅2H2O (glygly=glycylglycine anion, HPB=2-(2'-pyridyl)benzimidazole) has been synthesized and characterized. The DNA interaction of the complex was studied by spectroscopic methods, viscosity, and electrophoresis measurements. The antioxidant activity was also investigated using the pyrogallol autoxidation assay. Besides, the interaction of the complex with human serum albumin (HSA) in vitro was examined by multispectroscopic techniques. The complex partially intercalated to CT-DNA with a high binding constant (Kb=7.28×10(5) M(-1)), and cleaved pBR322 DNA efficiently via an oxidative mechanism in the presence of Vc, with the HO· and O2(-) as the active species, and the SOD as a promoter. Furthermore, the complex shows a considerable SOD-like activity with the IC50 value of 3.8386 μM. The complex exhibits desired binding affinity to HSA, in which hydrogen bond or vander Waals force played a major role. The alterations of HSA secondary structure induced by the complex were confirmed by UV-visible, CD, synchronous fluorescence and 3D fluorescence spectroscopy.

Background Hemoglobin (Hb) gene disorders are common hereditary disorders in Taiwan, and α- and β-thalassemias are among the well-known Hb disorders here. Our study provides a primary reference for designing a locally relevant antenatal diagnostic test to control the spread of thalassemia. Methods Between 1998 and 2011, prenatal diagnoses for identifying thalassemia and hemoglobinopathies were performed on 1240 fetuses at risk for α-hydrops and β-thalassemia major. Results Of 1240 specimens analyzed, 1082 (87%) were obtained by amniocentesis; 125 (10%), by chorionic villus sampling; and 33 (3%), by cordocentesis. Prenatal diagnoses revealed that 21.5% of these fetuses as thalassemia major (including α-thalassemia hydrops, β-thalassemia major, and Hb E/β-thalassemia); 50.2%, for thalassemia minor (include α-thalassemia carrier, β-thalassemia carrier, and α-thalassemia combined β-thalassemia carrier); and 28.3% for normal type (include non-α, β-thalassemia). The most common α-hydrops were SEA (Southeast Asian) and Philippine type (frequencies of 74.91 and 5.24%, respectively). The frequency of the IVS-II-654 combined codons 41/42 mutation, the most common β-thalassemia major mutation in this region, was 5.24%. Two fetuses were found with E/β-thalassemia (HbE/IVS-II-654 and HbE/codons 41/42, respectively). Since 1993, Taiwan's Department of Health adopted a national program for screening pregnancies to control spread of thalassemia. In the last 10 years, less than 3 such cases have occurred per year. After 2003, this number was 0 for a total of 4 years (2003, 2004, 2007, and 2008). Conclusion In Taiwan, incidence and frequency of thalassemia genotypes were similar to those previously reported. The national program for screening pregnancies to control spread of thalassemia that resulted in a marked decline in the number of newborns with thalassemia major. Interestingly, prenatal diagnoses revealed 21.5% for thalassemia major, 50.2% for thalassemia minor, 28.3% normal comparison of thalassemia type distribution showed normal type increasing by 13.2% and major type decreasing by 14%. This unique and significant finding needs further clinical studies and discussion to explain such a phenomenon.

Background and purpose Intraoperative transrectal ultrasound dosimetry during low-dose-rate prostate brachytherapy is imprecise due to sonographic distortion caused by seed echoes and needle tracks that obscure seed positions or create false signals as well as traumatic edema. Here we report the results of a pilot study comparing a combined ultrasound and fluoroscopy-based seed localization method (iRUF) to standard ultrasound-based dosimetry (USD). Material and methods Eighty patients undergoing permanent Pd-103 seed implantation for prostate cancer were prospectively enrolled. Seed implantation was performed using standard USD for intraoperative dose tracking. Upon implant completion, six X-ray images were intraoperatively acquired using a mobile C-arm and transverse ultrasound images of the implanted prostate were also acquired. Three-dimensional seed locations were reconstructed from X-ray images and registered to the ultrasound for iRUF dosimetry. Day 1 CT/MRI scans were performed for post-implant dosimetry. Prostate and urethral dosimetric parameters were separately calculated for analysis on iRUF, USD, and CT/MRI data sets. Differences and similarities between dosimetric values measured by iRUF, USD, and CT/MRI were assessed based on root mean squared differences, intraclass correlation coefficients (ICC), and Wilcoxon signed rank test. Results Data from 66 eligible patients were analyzed. Compared to CT/MRI, iRUF dosimetry showed higher correlation with overall ICC of 0.42 (0.01 for USD) and significantly smaller root mean squared differences (overall 16.5 vs 21.5 for iRUF and USD) than USD for all prostate and urethral dosimetric parameters examined. USD demonstrated a tendency to overestimate dose to the prostate when compared to iRUF. Conclusions iRUF approximated post-implant CT/MRI prostate and urethral dosimetry to a greater degree than USD. A phase II trial utilizing iRUF for intraoperative dynamic plan modification is underway, with the goal to confirm capability to minimize and correct for prostate underdosage not otherwise detected.

Two new mononuclear mixed ligand copper(II) complexes [Cu(PBO)(Gly-gly)(H2O)]·ClO4·1.5H2O (1) and [Cu(PBO)(Gly-L-leu)(H2O)]·ClO4 (2) (PBO is 2-(2′-pyridyl)benzoxazole, Gly-gly and Gly-L-leu are Glycyl-glycine anion and Glycyl-L-leucine anion, respectively), have been prepared and characterized by various analytical and spectral techniques. The interactions of the complexes with DNA were investigated using multi-spectroscopic methods (absorption, emission, circular dichroism), viscometry and electrochemical titration as well as molecular docking technique. The results indicated that 1 and 2 are bound to calf thymus DNA (CT-DNA) through an intercalative mode. The thermodynamic analyses revealed that the reactions between the Cu(II) complexes with DNA are spontaneous with negative Gibbs free energy (ΔG). The positive changes of enthalpy (ΔH) and entropy (ΔS) suggested that the binding processes are dominated by hydrophobic interaction accompanying with endothermic. Also, the complexes exhibited efficient oxidative cleavage of pBR322 plasmid DNA in the presence of ascorbic acid, probably induced by •OH as reactive oxygen species. In addition, 1 and 2 displayed excellent antioxidant activities with the IC50 values of 0.112 and 0.191 μM, respectively, using the mean of nitroblue tetrazolium (NBT) photochemical reduction under a nonenzymatic condition. Moreover, the complexes were screened for their in vitro cytotoxicity against three human carcinoma cell lines (HeLa, PC-3 and A549), in which 2 owns higher cytotoxicity, which was consistent with DNA binding and cleavage ability order of the complexes. This results showed the in vitro biochemical potentials of the Cu(II)-dipeptide complexes with aromatic heterocyclic, viz. effective metallopeptide-nucleases, SOD mimics and non-platinum chemotherapeutic metallopharmaceuticals and their structure-activity relationship, which may contribute to the rational molecular design of new metallopeptide based chemotherapeutic agents.

Human mitogen-activated protein kinase (MAPK) family members JNK and p38 are two homologous protein-serine/threonine kinases but play distinct roles in the pathological process of neurological disorders. Selective targeting of JNK over p38 has been established as a potential therapeutic approach to epilepsy and other nervous system diseases. Herein, we describe an integrated in vitro–in silico protocol to rationally design kinase–peptide interaction specificity based on crystal structure data. In the procedure, a simulated annealing (SA) iteration optimization strategy is described to improve peptide selectivity between the two kinases. The optimization accepts moderate compromise in peptide affinity to JNK in order to maximize the affinity difference between peptide interactions with JNK and p38. The structural basis, energetic properties and dynamic behavior of SA-improved peptides bound with the peptide-docking sites of JNK and p38 kinase domains are investigated in detail using atomistic molecular dynamics (MD) simulations and post binding free energy analysis. The theoretical findings and computational designs are then confirmed by fluorescence polarization assays. Using the integrated protocol we successfully obtain three decapeptide ligands, namely RLHPSMTDFL, RAKLPTSVDY and KPSRPWNLEI, that exhibit both potent affinity to JNK (KJNKd = 8.0, 5.4 and 12.1 μM, respectively) and high selectivity for JNK over p38 (Kp38d/KJNKd = 9.2, 17.9 and 6.3 fold, respectively). We also demonstrate that a JNK-over-p38 selective peptide should have a positively charged N-terminus, a polar central region and a negatively charged C-terminus, in which a number of hydrophobic residues distribute randomly along the peptide sequence. In particular, the residue positions 1, 6 and 9 play a crucial role in shaping peptide selectivity; the presence of, respectively, Arg, Thr and Asp at the three positions confers high specificity to kinase–peptide interactions.

Leukemic stem cells (LSCs) play the central role in the relapse and refractory of acute myeloid leukemia (AML) and highlight the critical need for the new therapeutic strategies to directly target the LSC population. However, relatively little is known about the unique molecular mechanisms of drug and natural killer cells (NK)-killing resistance of LSCs because of very small number of LSCs in bone marrow. In this study, we investigated whether established leukemia cell line contains LSCs. We showed that KG1a leukemia cell line contained leukemic stem-like cells, which have been phenotypically restricted within the CD34(+)CD38(-) fractions. CD34(+)CD38(-) cells could generate CD34(+)CD38(+) cells in culture medium and had renewal function. Moreover, CD34(+)CD38(-) cells had self-renewal potential. We found that leukemic stem-like cells from KG1a cells were resistant to chemotherapy and NK-mediated cytotoxicity. NKG2D ligands involve in protecting LSCs from NK-mediated attack. Taken together, our studies provide a novel cell model for leukemic stem cells research. Our data also shed light on mechanism of double resistant to chemotherapy and NK cell immunotherapy, which was helpful for developing novel effective strategies for LSCs.