Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer.

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular circadian rhythms in noncancerous and cancerous human breast tissues and their clinical relevance are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For noncancerous breast tissue, inflammatory, epithelial-mesenchymal transition (EMT), and estrogen responsiveness pathways show circadian modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes in circadian organization. Luminal A organoids and informatic ordering of luminal A samples exhibit continued, albeit dampened and reprogrammed rhythms. However, CYCLOPS magnitude, a measure of global rhythm strength, varied widely among luminal A samples. Cycling of EMT pathway genes was markedly increased in high-magnitude luminal A tumors. Surprisingly, patients with high-magnitude tumors had reduced 5-y survival. Correspondingly, 3D luminal A cultures show reduced invasion following molecular clock disruption. This study links subtype-specific circadian disruption in breast cancer to EMT, metastatic potential, and prognosis.

Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment.

Myeloid cell leukemia-1 (Mcl-1) is a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to their resistance to current chemotherapeutics. In this study, more than thirty coumarin derivatives with different substituents were designed and synthesized, and their Mcl-1 inhibitory activities evaluated using a fluorescence polarization-based binding assay. The results showed that the catechol group was a key constituent for Mcl-1 inhibitory activity of the coumarins, and methylation of the catechol group led to decreased inhibitory activity. The introduction of a hydrophobic electron-withdrawing group at the C-4 position of 6,7-dihydroxycoumarin, enhanced Mcl-1 inhibitory capacity, and a hydrophilic group in this position was unbeneficial to the inhibitory potency. In addition, the introduction of a nitrogen-containing group to the C-5 or C-8 position, which allowed an intramolecular hydrogen bond, was also unfavorable for Mcl-1 inhibition. Among all coumarins tested, 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) displayed the most potent inhibitory activity towards Mcl-1 (Ki = 0.21 ± 0.02 µM, IC50 = 1.21 ± 0.56 µM, respectively), for which the beneficial effect on taxol resistance was also validated in A549 cells. A strong interaction between Cpd 4 and Mcl-1 in docking simulations further supported the observed potent Mcl-1 inhibition ability of Cpd 4. 3D-QSAR analysis of all tested coumarin derivatives further provides new insights into the relationships linking the inhibitory effects on Mcl-1 and the steric-electrostatic properties of coumarins. These findings could be of great value for medicinal chemists for the design and development of more potent Mcl-1 inhibitors for biomedical applications.

Discovery of pyrazolones as novel carboxylesterase 2 inhibitors that potently inhibit the adipogenesis in cells.

Carboxylesterase 2 (CES2) is one of the most important Phase I drug metabolizing enzymes in the carboxylesterase family. It plays crucial roles in the bioavailability of oral ester prodrugs and the therapeutic effect of some anticancer drugs such as irinotecan (CPT11) and capecitabine. In addition to the well-known roles of CES2 in xenobiotic metabolism, the enzyme also participates in endogenous metabolism and the production of lipids. In this study, we synthesized a series of pyrazolones and assayed their inhibitory effects against CES2 in vitro. Structure-activity relationship analysis of these pyrazolones reveals that the introduction of 4-methylphenyl unit (R1), 4-methylbenzyl (R2) and cyclohexyl (R3) moieties are beneficial for CES2 inhibition. Guided by these SARs results, 1-cyclohexyl-4-(4-methylbenzyl)-3-p-tolyl-1H- pyrazol-5(4H)-one (27) was designed and synthesized. Further investigations demonstrated that the compound 27 exhibited stronger CES2 inhibition activity with a lower IC50 value (0.13 µM). The inhibition kinetic study demonstrated that compound 27 inhibited the hydrolysis of CES2-fluorescein diacetate (FD) through non-competitive inhibition. In addition, the molecular docking showed that the core of pyrazolone, the cyclohexane moiety, 4-methylbenzyl and 4-methylphenyl groups in compound 27 all played important roles with the amino acid residues of CSE2. Also, compound 27 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. In brief, we designed and synthesized a novel pyrazolone compound with a strong inhibitory ability on CES2 and could inhibit the adipogenesis induced by mouse preadipocytes, which can be served as a promising lead compound for the development of more potent pyrazolone-type CES2 inhibitors, and also used as a potential tool for exploring the biological functions of CES2 in human being.

The effects of labor on airway outcomes with Supreme™ laryngeal mask in women undergoing cesarean delivery under general anesthesia: a cohort study.

BACKGROUND: Pregnancy is associated with higher incidence of failed endotracheal intubation and is exacerbated by labor. However, the influence of labor on airway outcomes with laryngeal mask airway (LMA) for cesarean delivery is unknown. METHODS: This is a secondary analysis of a prospective cohort study on LMA use during cesarean delivery. Healthy parturients who fasted > 4 h undergoing Category 2 or 3 cesarean delivery with Supreme™ LMA (sLMA) under general anesthesia were included. We excluded parturients with BMI > 35 kg/m2, gastroesophageal reflux disease, or potentially difficult airway (Mallampati score of 4, upper respiratory tract or neck pathology). Anesthesia and airway management reflected clinical standard at the study center. After rapid sequence induction and cricoid pressure, sLMA was inserted as per manufacturer's recommendations. Our primary outcome was time to effective ventilation (time from when sLMA was picked up until appearance of end-tidal carbon dioxide capnography), and secondary outcomes include first-attempt insertion failure, oxygen saturation, ventilation parameters, mucosal trauma, pulmonary aspiration, and Apgar scores. Differences between labor status were tested using Student's t-test, Mann-Whitney U test, or Fisher's exact test, as appropriate. Quantitative associations between labor status and outcomes were determined using univariate logistic regression analysis. RESULTS: Data from 584 parturients were analyzed, with 37.8% in labor. Labor did not significantly affect time to effective ventilation (mean (SD) for labor: 16.0 (5.75) seconds; no labor: 15.3 (3.35); mean difference: -0.65 (95%CI: - 1.49 to 0.18); p = 0.1262). However, labor was associated with increased first-attempt insertion failure and blood on sLMA surface. No reduction in oxygen saturation or pulmonary aspiration was noted. CONCLUSIONS: Although no significant increase in time to effective ventilation was noted, labor may increase the number of insertion attempts and oropharyngeal trauma with sLMA use for cesarean delivery in parturients at low risk of difficult airway. Future studies should investigate the effects of labor on LMA use in high risk parturients. TRIAL REGISTRATION: The study was prospectively registered at clinicaltrials.gov ( NCT02026882 ) on 3 January 2014.

Comparison of Supreme laryngeal mask airway versus endotracheal intubation for airway management during general anesthesia for cesarean section: a randomized controlled trial.

BACKGROUND: The obstetric airway is a significant cause of maternal morbidity and mortality. Endotracheal intubation is considered the standard of care but the laryngeal mask airway (LMA) has gained acceptance as a rescue airway and has been incorporated into the obstetric airway management guidelines. In this randomized controlled equivalence trial, we compared the Supreme LMA (SLMA) with endotracheal intubation (ETT) in managing the obstetric airway during cesarean section. METHODS: Parturients who underwent elective cesarean section under general anesthesia were randomized to receive either an SLMA or ETT as their airway device. Our primary outcome was first-attempt insertion success. Successful insertion was defined as adequate bilateral air entry with auscultation and the presence of end-tidal carbon dioxide on the capnogram. The first-attempt insertion success rate was compared using the Chi-Square test. Secondary outcomes included time-to-ventilation, seal pressure, ventilation/hemodynamic parameters, occurrence of clinical aspiration, fetal outcomes, and maternal side effects associated with the airway device. RESULTS: We recruited 920 parturients (460 SLMA, 460 ETT) who underwent elective cesarean section under general anesthesia. Patient characteristics were similar between the groups. First attempt success was similar (Odds Ratio--ORSLMA/ETT: 1.00 (95%CI: 0.25, 4.02), p = 1.0000). SLMA was associated with reduced time to effective ventilation (Mean Difference--MD -22.96; 95%CI: - 23.71, - 22.21 s) compared to ETT group (p <  0.0001). Ventilation parameters, maternal and fetal outcomes were similar between the groups, and there was no aspiration. CONCLUSIONS: SLMA could be an alternative airway management technique for a carefully selected low-risk obstetric population, with similar insertion success rates, reduced time to ventilation and less hemodynamic changes compared with ETT. Our findings are consistent with the airway guidelines in recommending the second-line use of LMA in the management of the obstetric airway. TRIAL REGISTRATION: The study was registered at http://www.clinicaltrials.gov , identifier: NCT01858467 , retrospectively registered. Date of registration: May 21, 2013.

Association of Mallampati scoring on airway outcomes in women undergoing general anesthesia with Supreme™ laryngeal mask airway in cesarean section.

BACKGROUND: Obstetric dfficult airway is a leading cause of maternal morbidity and mortality. The laryngeal mask airway (LMA) is often used as a rescue airway device after failed intubation, however, little is known about predictors of difficult LMA insertion, particularly in obstetrics. Since Mallampati scores of III/IV has been associated with difficult tracheal intubation, our present study aims to investigate if Mallampati score (MP) could predict airway outcomes for LMA use in obstetrics. METHODS: This prospective cohort study was performed at a single-center: Quanzhou Women's and Children's Hospital, Fujian Province, China. Five hundred and eighty-four parturients undergoing elective cesarean section under general anesthesia were recruited. The primary outcome was time to effective ventilation, and secondary outcomes included first attempt insertion success, seal pressure, ventilation and hemodynamic parameters, occurrence of clinical aspiration, and maternal and fetal outcomes. RESULTS: The parturients were classified into two groups based on MP of III/IV (High MP: 61) versus I/II (Low MP: 523). BMI was higher in the High MP group than in the Low MP group (mean (SD) 29.3 (7.0) vs 26.8 (3.1), p <  0.0001). There was no difference in maternal age, ASA status and gestational age. There was similar time to effective ventilation (mean (SD) High MP: 14.9 (4.5) vs Low MP: 15.7 (4.4) seconds, p = 0.2172), and first attempt success rate, seal pressure, and peak airway pressure. No clinical aspiration was noted. The incidence of blood on SLMA was higher in the High MP group than in Low MP (4 (6.6%) vs 4 (0.8%), p = 0.001). There was no difference in sore throat, voice hoarseness, maternal satisfaction and fetal outcomes. CONCLUSION: High MP was not associated with reduced SLMA airway outcomes in cesarean section under general anesthesia, but may increase the risk of blood found on SLMA upon removal. TRIAL REGISTRATION: This study was registered at http://www.clinicaltrials.gov , identifier: NCT02026882 , retrospectively registered. Date of registration: December 31, 2013.

An Optimized Two-Photon Fluorescent Probe for Biological Sensing and Imaging of Catechol-O-Methyltransferase.

A practical two-photon fluorescent probe was developed for highly sensitive and selective sensing of the activities of catechol-O-methyltransferase (COMT) in complex biological samples. To this end, a series of 3-substituted 7,8-dihydroxycoumarins were designed and synthesized. Among them, 3-BTD displayed the best combination of selectivity, sensitivity, reactivity, and fluorescence response following COMT-catalyzed 8-O-methylation. The newly developed two-photon fluorescent probe 3-BTD can be used for determining the activities of COMT in complex biological samples and bio-imaging of endogenous COMT in living cells and tissue slices with good cell permeability, low cytotoxicity, and high imaging resolution. All these findings suggest that 3-BTD holds great promise for developing therapeutic molecules that target COMT, as well as for exploring COMT-associated biological processes and its biological functions in living systems. Furthermore, the strategy also sheds new light on the development of fluorescent probes for other conjugative enzymes.

Supreme™ laryngeal mask airway use in general Anesthesia for category 2 and 3 Cesarean delivery: a prospective cohort study.

BACKGROUND: The Supreme™ laryngeal mask airway (SLMA) is a single-use LMA with double lumen design that allows separation of the respiratory and the alimentary tract, hence potentially reducing the gastric volume and risk of aspiration. The purpose of this prospective cohort study is to evaluate the the role of the SLMA as an airway technique for women undergoing category 2 and 3 Cesarean delivery under general anesthesia. METHODS: We recruited 584 parturients who underwent category 2 or 3 Cesarean delivery under general anesthesia, in which 193 parturients underwent category 2 and 391 parturients underwent category 3 Cesarean delivery. The primary outcome was insertion success rate at 1st attempt in SLMA insertion. The secondary outcomes included anaesthetic, obstetric outcomes and maternal side effects associated with airway device. RESULTS: The 1st attempt insertion success rate was 98.3%, while the overall insertion success rate was 100%. The mean (Standard deviation) time to effective ventilation was 15.6 (4.4) seconds. Orogastric tube insertion was successful at the 1st attempt in all parturients. There was no clinical evidence of aspiration or regurgitation. No episodes of hypoxemia, laryngospasm or bronchospasm were observed intra-operatively. The incidence of complications was low and with good maternal satisfaction reported. CONCLUSIONS: The SLMA could be an alternative effective airway in category 2 and 3 parturients emergency Cesarean Delivery under general anesthesia in a carefully-selected obstetric population. TRIAL REGISTRATION: Clinical Trials Registration: Clinicaltrials.gov Registration NCT02026882 . Registered on December 31, 2013.

Highly selective and efficient biotransformation of linarin to produce tilianin by naringinase.

OBJECTIVES: To develop a practical method to prepare tilianin by highly selective and efficient hydrolysis of the C-7 rhamnosyl group from linarin. RESULTS: Naringinase was utilized to selectively catalyze the formation of tilianin using linarin as the starting material. The reaction conditions, including temperature, pH, metal ions, substrate concentration and enzyme concentration, were optimized. At 60 °C, naringinase showed enhanced α-L-rhamnosidase activity while the ß-D-glucosidase activity was abrogated. The addition of Mg(2+), Fe(2+) and Co(2+) was also beneficial for selective biotransformation of linarin to tilianin. Under the optimized conditions (pH 7.0 at 60 °C), linarin could be nearly completely transformed to tilianin with excellent selectivity (>98.9 %), while that of the by-product acacetin was less than 1.1 %. In addition, the structure of target product tilianin was fully characterized by HR-MS and (1)H-NMR. CONCLUSION: A highly selective and efficient biotransformation of linarin to tilianin was developed by the proper control of incubation temperature, which enhanced the α-L-rhamnosidase activity of naringinase and blocked its ß-D-glucosidase activity.

Identification and characterization of naturally occurring inhibitors against UDP-glucuronosyltransferase 1A1 in Fructus Psoraleae (Bu-gu-zhi).

As an edible traditional Chinese herb, Fructus psoraleae (FP) has been widely used in Asia for the treatment of vitiligo, bone fracture and osteoporosis. Several cases on markedly elevated bilirubin and acute liver injury following administration of FP and its related proprietary medicine have been reported, but the mechanism in FP-associated toxicity has not been well investigated yet. This study aimed to investigate the inhibitory effects of FP extract and its major constituents against human UDP-glucuronosyltransferase 1A1 (UGT1A1), the key enzyme responsible for metabolic elimination of bilirubin. To this end, N-(3-carboxy propyl)-4-hydroxy-1,8-naphthalimide (NCHN), a newly developed specific fluorescent probe for UGT1A1, was used to evaluate the inhibitory effects of FP extract or its fractions in human liver microsomes (HLM), while LC-UV fingerprint and UGT1A1 inhibition profile were combined to identity and characterize the naturally occurring inhibitors of UGT1A1 in FP. Our results demonstrated that both the extract of FP and five major components of FP displayed evident inhibitory effects on UGT1A1 in HLM. Among these five identified naturally occurring inhibitors, bavachin and corylifol A were found to be strong inhibitors of UGT1A1 with the inhibition kinetic parameters (Ki) values lower than 1 µM, while neobavaisoflavone, isobavachalcone, and bavachinin displayed moderate inhibitory effects against UGT1A1 in HLM, with the Ki values ranging from 1.61 to 9.86µM. These findings suggested that FP contains natural compounds with potent inhibitory effects against human UGT1A1, which may be one of the important reasons for triggering FP-associated toxicity, including elevated bilirubin levels and liver injury.

Enzymatic hydrolysis of 7-xylosyltaxanes by an extracellular xylosidase from Cellulosimicrobium cellulans.

OBJECTIVES: To find extracellular biocatalysts that can specifically and efficiently remove the C-7 xylosyl group from 7-xylosyltaxanes. RESULTS: A Cellulosimicrobium cellulans strain F16 that can remove the C-7 xylosyl group from 7-xylosyltaxanes was isolated from the root soil of an old Taxus yunnanensis tree. Using corn cob as sole carbon source, the maximum 7-xylosyl-10-deacetylpaclitaxel ß-xylosidase activity of 9.6 U l(-1) was achieved. The ß-xylosidase could be trapped by a ceramic tubular membrane (pore size 50 nm), and exhibited an apparent molecular weight much greater than 500 kDa. Under optimized conditions, 3.75 l cell-free culture medium transformed 2 grams 7-xylosyltaxane mixtures to their corresponding aglycones within 3 h, with a conversion >98%. CONCLUSION: This is the first report that C. cellulans can produce extracellular ß-xylosidases capable of removing the C-7 xylosyl group from 7-xylosyltaxanes.

The N-terminal 20-amino acid region of guanine nucleotide exchange factor Vav1 plays a distinguished role in T cell receptor-mediated calcium signaling.

Vav1 is a guanine nucleotide exchange factor (GEF) specifically expressed in hematopoietic cells. It consists of multiple structural domains and plays important roles in T cell activation. The other highly conserved isoforms of Vav family, Vav2 and Vav3, are ubiquitously expressed in human tissues including lymphocytes. All three Vav proteins activate Rho family small GTPases, which are involved in a variety of biological processes during T cell activation. Intensive studies have demonstrated that Vav1 is indispensable for T cell receptor (TCR)-mediated signal transduction, whereas Vav2 and Vav3 function as GEFs that overlap with Vav1 on TCR-induced cytoskeleton reorganization. T cells lacking Vav1 exhibited severe defect in TCR-mediated calcium elevation, indicating that the co-existing Vav2 and Vav3 did not compensate Vav1 in calcium signaling. What is the functional particularity of Vav1 in lymphocytes? In this study, we identified the N-terminal 20 amino acids of Vav1 in the calponin homology (CH) domain to be essential for its interaction with calmodulin (CaM) that leads to TCR-induced calcium mobilization. Substitution of the 1-20 amino acids of Vav1 with those of Vav2 or Vav3 abolished the association with CaM, and the N-terminal mutations of Vav1 failed to potentiate normal TCR-induced calcium mobilization, that in turn, suspended nuclear factor of activated T cells (NFAT) activation and IL-2 production. This study highlights the importance of the N-terminal 20 aa of Vav1 for CaM binding, and provides new insights into the distinguished and irreplaceable role of Vav1 in T cell activation and signal transduction.

A new classification for epidemiological study of mechanical eye injuries.

OBJECTIVE: Considering the difficulty in classifying some cases with eye trauma by Birmingham Eye Trauma Terminology (BETT) in our epidemiological study, we introduce a new classification for epidemiological study of mechanical eye injuries based on BETT. METHODS: A retrospective investigation was carried out in 31 hospitals from January 2005 to December 2010. All medical records of inpatients with eye injuries were reviewed. A total of 10 718 patients (11 227 eyes) were diagnosed as mechanical eye injuries. All mechanical eye injuries were tried to be classified using BETT. While some eye injuries were difficult to categorize. We recorded the injury type and case number. A new classification based on BETT was also used for the same project. RESULTS: Of 10 718 patients (11 227 eyes) with mechanical eye injuries, the following cases cannot be classified by BETT: 1 488 patients (1 559 eyes) with merely orbital or ocular adnexa injury, 1 961 (2 054) globe injuries associated with orbital or ocular adnexa injury, 271 (284) ocular surface foreign body (OSFB) or ocular wall foreign body (OWFB), 77 (89) contusion, 9 (11) lamellar laceration associated with OSFB or OWFB, 29 (30) rupture associated with OSFB, OWFB or intraocular foreign body and 60 (62) lace- ration associated with OSFB or OWFB. While according to our new classification, all eye injuries can be categorized without any difficulty. CONCLUSION: Difficulty in classifying some eye injuries in epidemiological study by BETT brings some trouble to our study, which can be solved by our new eye injury classification to some extent. It is hoped that other ophthalmologists present better ones to make the classification more perfect.

[Comparative a nimble of monitoring indicator, explore the superiority about Supreme dual-chamber laryngeal mask used for cesarean section anesthesia].

OBJECTIVE: Explore the feasibility and superiority about Supreme double-lumen laryngeal mask airway for cesarean section anesthesia. METHODS: From March 2011 to March 2012, a total of 300 patients with American Society of Anesthesiologists (ASA) I or II foot of cesarean section in full-term pregnant women for the first time production of Quanzhou Women's and Children's Hospital were recruited, authenticated by Hospital Ethics Committee, they were randomly divided into three groups (Random number table), dual-chamber in the LMA group (A group of 100 cases), tracheal intubation group (B group of 100 cases) and spinal anesthesia group (C group of 100 cases). ECG, SpO2, MAP, heart rate, Narcotrend and Apgar scores were observed. RESULTS: Before and after the LMA group inserted laryngeal mask HR,MAP no significant change in the performance of Narcotrend value remained at the level of anesthesia, intubation before and after HR, MAP significantly increased performance of Narcotrend values significantly increased, both compared to the obvious statistical difference (P < 0.05). The ventilation indicators of two groups compared to no significant difference (P > 0.05). LMA group cover required intubation time was significantly shorter than the time required for intubation of endotracheal intubation group (P < 0.01). Three groups of patient administration to the fetus at all times is in 5-10 min.Three groups similar to the Apgar score was no significant difference (P > 0.05). CONCLUSION: The dual-chamber laryngeal mask airway for caesarean section anesthesia, fetal Apgar scores, feasibility, and its operation is easy, safe and comfortable anesthesia, compared tracheal intubation has obvious superiority.

[Hemodynamic variations during tracheal intubation with intubating laryngeal mask airway versus direct laryngoscope in hypertensive patients].

OBJECTIVE: To compare the variations of cardiovascular responses and vascular angiotensin II (AngII) in hypertensive patients during tracheal intubation with intubating laryngeal mask airway (ILMA) versus direct laryngoscope (DLS). METHODS: A total of 120 hypertensive patients undergoing abdominal surgery were randomly divided into 2 groups, i.e.intubating laryngeal mask airway (Group I) and direct laryngoscope (Group D).Variations of invasive arterial blood pressure and angiotensin II were compared between two groups before and after intubation. RESULTS: The variations of cardiovascular responses and vascular angiotensin II (AngII) during tracheal intubation used of ILMA (T4) and DLS (T4) in an instant, tracheal intubation were immediately accomplished in two groups (T5). The variations of group I were significantly lower than those of group D (P < 0.05). And statistical significance existed between two groups. CONCLUSION: Tracheal intubation with intubating laryngeal mask airway (ILMA) can significantly reduce violent cardiovascular reactions and avoid cardiovascular accidents.

Endoscopic and pathological characteristics of de novo colorectal cancer: Retrospective cohort study.

BACKGROUND: Endoscopy has rapidly developed in recent years and has enabled further investigation into the origin and features of intestinal tumors. The small size and concealed position of these tumors make it difficult to distinguish them from nonneoplastic polyps and carcinoma in adenoma (CIA). The invasive depth and metastatic potential determine the operation regimen, which in turn affects the overall survival and distant prognosis. The previous studies have confirmed the malignant features and clinicopathological features of de novo colorectal cancer (CRC). AIM: To provide assistance for diagnosis and treatment, but the lack of a summary of endoscopic features and assessment of risk factors that differ from the CIA prompted us to conduct this retrospective study. METHODS: In total, 167 patients with small-sized CRCs diagnosed by endoscopy were reviewed. The patients diagnosed as advanced CRCs and other malignant cancers or chronic diseases that could affect distant outcomes were excluded. After screening, 63 cases were excluded, including 33 de novo and 30 CIA cases. Patient information, including their follow-up information, was obtained from an electronic His-system. The characteristics between two group and risk factors for invasion depth were analyzed with SPSS 25.0 software. RESULTS: Nearly half of the de novo CRCs were smaller than 1 cm (n = 16, 48.5%) and the majority were located in the distal colon (n = 26, 78.8%). The IIc type was the most common macroscopic type of de novo CRC. In a Pearson analysis, the differential degree, Sano, JNET, and Kudo types, surrounding mucosa, and chicken skin mucosa (CSM) were correlated with the invasion depth (P < 0.001). CSM was a significant risk factor for deep invasion and disturbed judgment of endoscopic ultrasound. A high degree of tumor budding and tumor-infiltrating lymphocytes are accompanied by malignancy. Finally, de novo CRCs have worse outcomes than CIA CRCs. CONCLUSION: This is the first comprehensive study to analyze the features of de novo CRCs to distinguish them from nonneoplastic polyps. It is also the first study paying attention to CSM invasive depth measurement. This study emphasizes the high metastatic potential of de novo CRCs and highlights the need for more research on this tumor type.

Comparative study on inhibitory effects of ginsenosides on human pancreatic lipase and porcine pancreatic lipase: structure-activity relationships and inhibitory mechanism.

The inhibitory effects of twenty-six ginsenosides on human pancreatic lipase (hPL) and porcine pancreatic lipase (pPL) were studied. Study reveals that nine ginsenosides have moderate inhibitory effects against hPL, and good selectivity over pPL. By contrast, (S)-Rh2 showed good inhibitory effects on pPL over hPL. SAR analysis indicated that introduction of the O-glycosyl group(s) at C-3/C-7 site is unbeneficial for hPL inhibition, ginsenosides with A-skeleton is more beneficial than ginsenosides with B-/C-skeleton. Inhibition kinetic analysis indicated that Rg3 and (S)-Rh2 inhibited hPL-catalyzed DDAO-ol hydrolysis in a mixed manner. Molecular docking studies have confirmed that Rg3 and (S)-Rh2 inhibit hPL via many Pi-hydrogen interactions and hydrogen bonds with catalytic residues of hPL. These results indicated that pPL as an enzyme source could not fully represent the inhibitory effect of the tested compounds on hPL, and hPL should be used as far as possible to evaluate the inhibitory effect of PL.

Subtype-specific circadian clock dysregulation modulates breast cancer biology, invasiveness, and prognosis.

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular rhythms in non-cancerous and cancerous human breast tissues are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For non-cancerous tissue, the inferred order of core-circadian genes matches established physiology. Inflammatory, epithelial-mesenchymal transition (EMT), and estrogen responsiveness pathways show circadian modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes in circadian organization. Luminal A organoids and informatic ordering of Luminal A samples exhibit continued, albeit disrupted rhythms. However, CYCLOPS magnitude, a measure of global rhythm strength, varied widely among Luminal A samples. Cycling of EMT pathway genes was markedly increased in high-magnitude Luminal A tumors. Patients with high-magnitude tumors had reduced 5-year survival. Correspondingly, 3D Luminal A cultures show reduced invasion following molecular clock disruption. This study links subtype-specific circadian disruption in breast cancer to EMT, metastatic potential, and prognosis.

Ginsenoside-Rd potentiates apoptosis induced by hydrogen peroxide in basilar artery smooth muscle cells through the mitochondrial pathway.

Our previous studies showed that ginsenoside-Rd, a purified component from Panax notoginseng, inhibited cell proliferation and reversed basilar artery remodeling. The aim of this study was to investigate whether ginsenoside- Rd influences H(2)O(2)-induced apoptosis in basilar artery smooth muscle cells (BASMCs). The results showed that ginsenoside-Rd significantly potentiated H(2)O(2)-induced cell death and cell apoptosis. This resulted in a concentration-dependent reduction of the cell viability. Ginsenoside-Rd further increased cytochrome C release and caspase-9/caspase-3 activations, and reduced the stability of mitochondrial membrane potential (MMP) and the ratio of Bcl-2/Bax. Cyclosporine A, an inhibitor of mitochondrial-permeability transition, inhibited alteration of mitochondrial permeability induced by H(2)O(2) and reversed the effect of ginsenoside-Rd on MMP. Our data strongly suggest that ginsenoside-Rd potentiated H(2)O(2)-induced apoptosis of BASMCs through the mitochondria-dependent pathway.

Simvastatin attenuated cerebrovascular cell proliferation in the development of hypertension through Rho/Rho-kinase pathway.

The cerebrovascular remodeling is a prominent feature of hypertension and considered as a major risk of stroke. Statins may suppress the activation of the Rho/Rho-kinase pathway and have pleiotropic actions against the development of vascular remodeling. We hypothesized that the inhibition of the Rho/Rho-kinase pathway by simvastatin during hypertension could recuperate the pathological changes of basilar artery through the downregulation of cell proliferation. To resolve the problem, we used 2-kid, 2-clip rat as a hypertension model and evaluated the effect of simvastatin on the Rho/Rho-kinase pathway. In addition, we assessed the changes of the proliferation rate by CCK-8 assay in basilar artery smooth muscle cells. Our results from this study showed that a continuous increase in the plasma endothelin-1 (ET-1) concentration and the Rho/Rho-kinase activity was positively correlated with changes in blood pressure in the hypertensive rat. Simvastatin ameliorated the upregulated Rho/Rho-kinase activity and cell proliferation during hypertension. Moreover, simvastatin, the RhoA inhibitor C3, and the RhoA-kinase inhibitor Y27632 all attenuated the proliferation rate induced by ET-1 in basilar artery smooth muscle cells via the Rho/Rho-kinase signaling pathway. In conclusion, simvastatin attenuated ET-1-induced proliferation through the Rho/Rho-kinase signaling pathway in hypertensive rat basilar artery, and it may be an excellent reagent to protect vascular remodeling and stroke.