Search

Because nerve injury of muscles around the shoulder can be easily disguised by "trick movements" of the trunk, shoulder dysfunction following brachial plexus injury is difficult to quantify with conventional clinical tools. Thus, to evaluate brachial plexus injury and quantify its biomechanical consequences, we used inertial measurement units, which offer the sensitivity required to measure the trunk's subtle movements.We calculated 6 kinematic scores using inertial measurement units placed on the upper arms and the trunk during 9 functional tasks. We used both statistical and machine learning techniques to compare the bilateral asymmetry of the kinematic scores of 15 affected and 15 able-bodied individuals (controls).Asymmetry indexes from several kinematic scores of the upper arm and trunk showed a significant difference (P.05) between the affected and control groups. A bagged ensemble of decision trees trained with trunk and upper arm kinematic scores correctly classified all controls. All but 2 patients were also correctly classified. Upper arm scores showed correlation coefficients ranging from 0.55-0.76 with conventional clinical scores.The proposed wearable technology is a sensitive and reliable tool for objective outcome evaluation of brachial plexus injury and its biomechanical consequences. It may be useful in clinical research and practice, especially in large cohorts with multiple follow-ups.

SUMMARY STATEMENT Culture influences how we communicate, teach, and learn. Debriefings are laden with cultural influences. Without attention to cultural considerations, accepted debriefing techniques might not reach the desired outcome and, in certain cultures, may even harm teacher-learner relationships. We explore cultural considerations in healthcare simulation debriefing and offer guidance for debriefers to gain awareness of potential cultural biases.

OBJECTIVE This qualitative study was an integral part in the development of a multidisciplinary team-led school-based human papillomavirus vaccination health-promotion programme (MDL-SHPVP) aiming to increase HPV vaccine uptake in Hong Kong. Study findings will inform the design of the MDL-SHPVP by drawing on interview data regarding the expectations and needs of key stakeholders and potential programme users. METHODS Eight mother-daughter dyads, four secondary school teachers, two school principals, three social workers and one school nurse were interviewed. All interviews were audio-recorded and transcribed verbatim for thematic analysis. RESULTS Most participants had misconceptions about HPV and the vaccine. Alhough there was no immediate perceived need for the vaccination, most participants had favourable attitudes towards HPV inoculation and vaccines in general. Factors affecting vaccine uptake included perceptions about risk of infection, vaccine availability, and cost. Participants were largely open to suggested MDL-SHPVP components (videos, digital game, and group discussions). CONCLUSION Findings have highlighted knowledge gaps among potential users and key stakeholders and will be used to inform the design of the MDL-SHPVP to ensure that their needs and expectations are addressed. Study findings may also aid future HPV vaccine promotion efforts and boost HPV vaccine uptake among youth in the city.

BackgroundConversations are influenced by cultural perceptions, beliefs and values. Debriefing is a learning conversation. Without cross-cultural engagement or culturally relevant teaching, learning may be compromised and may result in an outcome opposite of that intended.ObjectiveThis systematic review explores cultural considerations in healthcare simulation debriefing. We sought to explore findings that could help debriefers create culturally responsive and inclusive debriefings.Study selectionStudies were included if they were peer-reviewed articles in any language and focused on healthcare simulation debriefing and global cultural considerations. Research study methods included qualitative, quantitative or both. The review included any health-related profession and level of learner.FindingsThree studies met the criteria. The purposes of the three studies were significantly different and did not directly study cultural considerations in debriefing.ConclusionsThe learner–educator relationship is at risk and learning may be negatively impacted without addressing cultural awareness. More studies are needed to fully describe the effect of culture on successful debriefing.

Introduction: Evidence has consistently shown the high efficacy of human papillomavirus (HPV) vaccines in preventing cervical cancers. However, the HPV vaccine uptake rate in Hong Kong is very low. We will develop and evaluate an innovative, theory-based multidisciplinary team-led school-based HPV vaccination health-promotion program (MDL-SHPVP), engaging female adolescents, parents/guardians, and secondary school personnel in multicomponent educational strategies and interactive discussions. Methods and analysis: A cluster randomized controlled trial is proposed. We will recruit 2520 female adolescents and their parents/guardians from 18 secondary day schools. The MDL-SHPVP is underpinned by the Health Belief Model and Precaution Adoption Process Model. Multicomponent interventions will be offered, including education sessions with small group dialogues with a registered nurse and trained healthcare and lay volunteers, and educational computer games. A team of volunteers will be established to raise HPV, cervical cancer, and HPV vaccine awareness. Outcomes include adolescents’ uptake of the HPV vaccine, adolescents’ intention to receive HPV vaccination, vaccine acceptance among parents/guardians, and parents’/guardians’ and adolescents’ HPV knowledge, attitudes, and beliefs. Data will be collected at baseline, 1 month, and 1 year after intervention. The generalized estimating equations analysis will be used for comparing the outcomes between the 2 groups. Ethics and dissemination: Ethical approval was obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (Ref. no.: 2019.055). We will disseminate the study findings via peer-reviewed publications and presentations at relevant events and international and local conferences. Trial registration number: ClinicalTrials.gov NCT04438291

Background Misplacement of the nasogastric tube in the respiratory tract could cause serious complications and even death. Thus, nasogastric tube verification is necessary for optimal patient safety and comfort. Although end-tidal carbon dioxide detection is considered an effective approach to determine nasogastric tube location, there is a paucity of up-to-date evidence. Objectives To review the diagnostic accuracy of end-tidal carbon dioxide detection in determining inadvertent airway intubation and verifying correct placement of nasogastric tubes. Design A systematic review and meta-analysis. Methods We searched clinical trials that evaluated the diagnostic accuracy of colorimetric capnometry or capnography in detecting nasogastric tubes located in the airway and differentiating between inadvertent airway intubation and correct nasogastric tube placement in any adult care setting. Four English language databases - Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and CINAHL - and four Chinese language databases - China Biomedical Literature Database, WanFang Data, China National Knowledge Infrastructure, and Airiti Library - were searched from July 2009 to March 2021. Clinical trial registration databases and reference lists of included studies and relevant reviews were also searched. Two reviewers extracted the data of all included studies using a data extraction form. Two reviewers assessed the methodological quality independently with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. We conducted meta-analysis using the hierarchical bivariate model and estimated the pool sensitivity and specificity of capnography and colorimetric capnometry. Forest plots were generated to display the results. Heterogeneity was investigated by meta-regression. The certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluations framework. Results Of 1,155 records identified, seven new studies were added to this update and a total of 16 studies were analysed in the systematic review. The total absolute number of true positive, false negative, true negative, and false positive observations were 142, 6, 1,500, and 65 respectively. Low to very low certainty of evidence indicated that the use of colorimetric capnometry or capnography is potentially an effective method in differentiating between respiratory and nasogastric tube placement for critically ill adult patients. Pooled results (13 studies, 1,541 intubations) for sensitivity and specificity were 0.96 (95% confidence interval [0.88, 0.99]) and 0.99 (95% confidence interval [0.96, 1.00]), respectively. Conclusions Colorimetric capnometry and capnography may have the potential to be of high sensitivity and specificity for the detection of inadvertent airway nasogastric tube placements in critically ill adults. More evidence is required to generalize the updated findings to different types of patients and settings.

Although there is consensus on the resuscitation of newborns, there is no standardization on how resuscitation equipment should be organized. This might lead to difficulty and inefficiency in retrieval of the right equipment during resuscitation. The neonatal resuscitation carts organized in accordance with the American Academy of Pediatrics (AAP) Neonatal Resuscitation Program (NRP) algorithm might result in more efficient retrieval of resuscitation equipment.To compare user preference and lengths of time required to retrieve standard resuscitation equipment from an NRP Cart versus a generic storage drawer.A prospective, randomized, controlled, and crossover trial was conducted during simulation-based NRP provider courses in the AccidentEmergency Training Centre from September to October 2013. The mean time of accurate equipment retrieval and ease of use, which was rated by the participants using a five-point Likert scale (1=most difficult, 5=easiest to use), were compared using the Wilcoxon signed-rank test because of right skew.A total of 55 individuals participated in this study. The mean length of time required for equipment retrieval from the NRP Cart was significantly less than that from the drawer (Z=-3.90, P0.01, median=36.23 s, interquartile range=97 s). In general, the NRP Cart was 32% faster than the drawer when extensive resuscitation equipment was required. All the participants rated the NRP Cart as easier to use than the drawer, with a median score of 4 for NRP Cart and 3 for the drawer (Z=-4.10, P0.01, interquartile range=2).The NRP Cart was superior to the generic drawer in terms of the speed of equipment retrieval and user acceptability.

Delivery and penetration of chemotherapeutic drugs into neoplasm through the tumor vasculature are essential mechanisms to enhance the efficiency of chemotherapy. "Vascular targeting" strategy focuses on promoting the infiltration of chemotherapeutic drugs into neoplastic tissues. In this study, we achieved a targeted therapy by coupling tumor necrosis factor α (TNFα) with TCP-1, a novel vascular-targeting peptide, in an orthotopic colorectal cancer model in mice. High dose of TCP-1-conjugated TNFα (TCP-1/TNFα: 5μg/mouse) displayed potent antitumor activity by inducing apoptosis and reducing microvessel number in tumors than unconjugated TNFα, with no evidence of increased toxicity. In the combined therapy, the antitumor action of 5-fluorouracil (5-FU) was potentiated when the mice were pretreated with a low dose of TNFα (1ng/mouse) and to a greater extent by the same concentration of TCP-1/TNFα. In this regard, TCP-1/TNFα combined with 5-FU synergistically inhibited the tumor growth, induced apoptosis and reduced cell proliferation. More importantly, TCP-1/TNFα normalized the tumor vasculature and facilitated the infiltration of immune cells to neoplasm as well as attenuated the immunosuppressing effects of TNFα in bone marrow and spleen. At the same time, TCP-1/TNFα significantly improved 5-FU absorption into the tumor mass. Taken together, these findings underscore the therapeutic potential of TCP-1 as a drug carrier in cancer therapy. TCP-1 is a novel vascular-targeting peptide and appears to be a promising agent for drug delivery. TCP-1 fused with TNFα holds great promise for colorectal cancer therapy.

There has been a dramatic rise in preterm births in developed countries owing to changes in clinical practices and greater use of assisted reproductive techniques. However, few studies have examined the growth and outcomes of preterm infants according to the type of feeding (with fortified breast milk or formula). The purpose of this study was to examine the effect of breast milk feedings and formula on the growth and short-term outcomes of preterm infants in Hong Kong. In a single-center retrospective cohort study, we included 642 preterm infants at gestational age

Colorectal cancer (CRC) is the third most common malignancy and the fourth most frequent cause of cancer deaths worldwide. Ligand-mediated diagnosis and targeted therapy would have vital clinical applications in cancer treatment. In this study, an orthotopic model of colorectal cancer was established in mice. In vivo phage library selection was then utilized to isolate peptides specifically recognizing the vasculature of colorectal cancer tissues. A phage (termed TCP-1 phage) was isolated by this manner and it homed to the colorectal cancer tissues by 11- to 94-fold more than other organs. Chemical synthetic peptide (CTPSPFSHC, termed TCP-1) displayed by TCP-1 phage inhibited the homing ability of the phage to the tumor mass when co-injected intravenously with the TCP-1 phage into mice with colon cancer. Meanwhile, immunostaining analysis indicated that TCP-1 phage and peptide localized in the vasculature of the colorectal cancer tissue, but not of normal tissues. Moreover, TCP-1 peptide bound to blood vessels of surgical tissue samples of human colorectal cancer. After intravenous injection of FITC-labeled TCP-1 into the tumor-bearing mice for 20h, there was a strong fluorescent signal in the tumors but not other tissues when observed under blue light. In addition, TCP-1 conjugated with a pro-apoptotic peptide specifically induced apoptosis of tumor-associated blood vessels in vivo. The data define a novel peptide TCP-1 as an effective agent for imaging detection and drug delivery for colorectal cancer.

Background and purpose: Resveratrol, a naturally occurring polyphenolic antioxidant, has been shown to exhibit chemoprophylactic effects on cancer development. Previously, we reported that 2,3′,4,4′,5′-pentamethoxy-trans-stilbene (PMS), a methoxylated resveratrol derivative, exerted a highly potent anti-proliferative effect on human colon cancer cells as compared with its parent compound. In the present study, the chemopreventive effect of PMS was evaluated in a mouse model of colitis-associated colon carcinogenesis. Experimental approach: Seven-week-old Balb/c mice were injected i.p. with 10 mg·kg−1 azoxymethane (AOM). After 1 week, 3% dextran sodium sulphate (DSS) was administered in the drinking water for 7 days followed by 14 days of tap water for recovery, and this cycle was repeated twice. Key results: Intragastric administration of PMS (25, 50 mg·kg−1 body weight) for 16 weeks significantly reduced the multiplicity of colonic neoplasms by 15% and 35% (P < 0.01) respectively. Moreover, PMS at 50 mg·kg−1 inhibited colon cancer cell proliferation and promoted apoptosis. Such changes were accompanied by reduction of Akt (protein kinase B) phosphorylation, inactivation of β-catenin and down-regulation of inducible nitric oxide synthase. In parallel, in vitro studies also demonstrated that PMS inhibited proliferation and induced apoptosis in the murine colon adenocarcinoma cell line Colon26 with concomitant inhibition of Akt phosphorylation and inactivation of β-catenin. Conclusions and implications: PMS effectively suppressed colon carcinogenesis in an AOM/DSS animal model and may merit further clinical investigation as a chemoprophylactic agent against colitis-associated colon cancer in humans.

Aim of the study Dihydrotanshinone is a lipophilic component of the medicinal herb Salvia miltiorrhiza (danshen) belonging to the family of Labiatae. In this study, we have investigated the mechanisms of its relaxant effect on rat-isolated coronary artery. Materials and Methods Rat coronary artery rings were precontracted with 1 μM 5-hydroxytryptamine (5-HT). Involvement of endothelium-dependant mechanisms were investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 μM), a nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 100 μM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a β-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9 H -purine-6-amine (SQ22536, 100 μM), a guanylyl cyclase inhibitor 1 H -[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ,10 μM), and a potassium channel inhibitor tetraethylammonium (TEA, 10 mM). Involvement of Ca 2+ channels was investigated in artery rings incubated with Ca 2+ -free buffer and primed with 1 μM 5-HT for 5 min prior to adding CaCl 2 to elicit contraction. Results Dihydrotanshinone relaxed the 5-HT-precontracted coronary artery rings with an IC50 value of 10.39 ± 1.69 μM. None of the above inhibitors or antagonists tested produced a significant change on the vasorelaxant effect of dihydrotanshinone, except ODQ caused a 50% reduction. Pre-incubation of the artery rings for 10 min with dihydrotanshinone (100 μM) abolished the CaCl 2 -induced vasoconstriction. Conclusions These findings suggest that inhibition of Ca 2+ influx in the vascular smooth muscle cells is important for the vasorelaxant effect of dihydrotanshinone, and it is independent of pathways involving the endothelium, muscarinic receptors, β-adrenoceptors, adenylyl cyclase, and guanylyl cyclase.

This review explores the significance of alpha-2 agonists used clinically in acute pain management.Although alpha-2 agonists have been reported to have an analgesic effect, they are not commonly used clinically for acute pain management. Clinical studies on use of alpha-2 agonists for acute pain management are reviewed and discussed. A literature search was done using Medline with the keywords 'alpha-2 agonist', 'clonidine', 'dexmedetomidine', 'fadolmidine', 'pharmacokinetics', 'pharmacodynamics', 'postoperative analgesia', 'epidural', 'intrathecal', 'peripheral nerve block' and various combinations with these keywords. The years 1977 - 2009 have been included, with particular focus on clinical studies from between 1990 and 2009.This article helps to clarify the clinical use of alpha-2 agonists in acute pain management according to current, up-to-date evidence. Clinically, available alpha-2 agonists, including clonidine and dexmedetomidine, are discussed in detail.Alpha-2 agonists, especially clonidine, seem to be promising with regard to acute postoperative pain management. However, more clinical evidence on dexmedetomidine is necessary to confirm its definite role in acute postoperative pain control.

In this study, we have investigated the actions of cryptotanshinone, an active, lipophilic component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the ethanol-extractable fraction of the herb. Extraction of the ethanol-soluble fraction from danshen provided a yield of 1%. The amount of cryptotanshinone determined in this ethanol extract was 3.682%, and it was 6 times more potent than the extract in relaxing 5-HT-precontracted coronary artery rings; IC(50) values were 2.65+/-0.15 microg/ml and 15.82+/-1.07 microg/ml, respectively. Involvement of endothelium-dependant mechanisms in their dilator effects were investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 microM), a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium; none of these procedures produced a significant change on their dilator actions. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a beta-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 microM), a guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM), and a potassium channel inhibitor tetraethylammonium (TEA, 100 mM); these also produced no change on their dilator actions. The possible involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT for 5 min prior to adding CaCl(2) to elicit contraction. The danshen ethanol extract (100 microg/ml) abolished the CaCl(2)-induced vasoconstriction, whereas, cryptotanshinone (30 microg/ml) produced 59% inhibition. These findings suggest their vasorelaxant effects are independent of pathways mediated by the endothelium, muscarinic receptors, beta-adrenoceptors, adenylyl cyclase, and guanylyl cyclase, whereas, inhibition of Ca(2+) influx in the vascular smooth muscle cells is important for their vasodilator actions. The high vasodilator potency and the quantity of salvianolic acid B contained in danshen ethanolic extract suggest it is an important constituent in this medicinal herb.

In this study, we have investigated the mechanism of action through which salvianolic acid, a constituent of the medicinal herb danshen (Salvia miltiorrhiza), causes relaxation of isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT). The vasorelaxant effects of salvianolic acid B were also compared with the aqueous extract of danshen. Extraction of the water-soluble fraction from danshen provided a yield of 17.5%. The amount of salvianolic acid B determined in this aqueous extract was 3.9%, and the extract was 6.3 times less potent than salvianolic acid B in relaxing 5-HT-precontracted coronary artery rings; IC(50) values were 930.3+/-133.5 microg/ml and 147.9+/-17.4 microg/ml, respectively. Removal of the endothelium did not significantly affect their vasodilator potencies; IC(50) values were 842.1+/-123.8 mictog/ml and 160.3+/-25.9 microg/ml. On the other hand, a potassium channel inhibitor tetraethylammonium (TEA, 10 mM) shifted their concentration-response curves by 1.7 and 2.9 folds. The possible involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT or 60 mM KCl for 5 min prior to adding CaCl(2) to elicit contraction. In 5-HT-primed preparations, 2 mg/ml danshen aqueous extract and 0.72 mg/ml salvianolic acid B abolished the CaCl(2)-induced vasoconstriction, whereas, in KCl-primed preparations, 10 mg/ml danshen aqueous extract and 1.44 mg/ml salvianolic acid B produced 90% inhibition. These findings suggest the vasorelaxant effects of danshen aqueous extract and salvianolic acid B were produced by inhibition of Ca(2+) influx in the vascular smooth muscle cells. The opening of K(+) channels had a minor contribution to their effects, but endothelium-dependent mechanisms were not involved. The high vasodilator potency and the quantity of salvianolic acid B contained in danshen aqueous extract suggest it is an important vasodilator constituent in this medicinal herb.

In this study, we have investigated the actions of danshensu, an active, water-extractable component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the water-extractable fraction of the herb. Extraction of the water-soluble fraction from danshen (S. miltiorrhiza) provided yield of 17.5% (35 g/200 g). The amount of danshensu determined in the crude danshen herb and in its aqueous fraction was 0.45 mg/g (0.045%) and 3.28 mg/g (0.33%). The danshen aqueous extract was 13 times less potent than danshensu in relaxing 5-HT-precontracted coronary artery rings; IC50 values were 930.3+/-133.5 microg/ml and 71.5+/-11.0 microg/ml. Removal of the endothelium did not significantly affect their vasodilator potencies; IC50 values were 842.1+/-123.8 microg/ml and 84.8+/-8.8 microg/ml. On the other hand, a potassium channel inhibitor tetraethylammonium (TEA, 10 mM) shifted their concentration-response curves by 1.7 and 2.2 folds. The possible involvement of Ca2+ channels was investigated in artery rings incubated with Ca2+-free buffer and primed with 1 microM 5-HT or 60 mM KCl for 5 min prior to addition of CaCl2 to elicit contraction. In 5-HT-primed preparations, the CaCl2-induced vasoconstriction was abolished by 2 mg/ml danshen aqueous extract and 200 microg/ml danshensu, whereas, in KCl-primed preparations, 10 mg/ml danshen aqueous extract and 600 microg/ml danshensu were required to abrogate the vasoconstriction. These findings suggest the vasorelaxant actions of danshen aqueous extract and danshensu were produced by inhibition of Ca2+ influx in the vascular smooth muscle cells. The opening of K+ channels had a minor contribution to the response, but endothelium-dependent mechanisms were not involved.

Danggui is a popular traditional Chinese medicinal (TCM) herb which is easily obtained by the public. The effects of Danggui on the pharmacokinetics and pharmacodynamics of warfarin were studied in rabbits. Single subcutaneous doses (2 mg/kg) of warfarin were administered to 6 rabbits with or without 3 days treatment with oral Danggui extracts (2 g/kg twice daily). Plasma warfarin concentrations were measured by high performance liquid chromatography (HPLC) for 72 h after each of the two warfarin doses. The prothrombin time (PT) was measured daily for 3 days both during the Danggui treatment period and after warfarin doses. Danggui treatment did not affect PT on its own, but significantly lowered PT values 3 days after co-treatment with single dose warfarin. No significant variations in the single dose pharmacokinetic parameters of warfarin were observed after Danggui treatment. A separate group of 6 rabbits were given daily subcutaneous doses of warfarin (0.6 mg/kg) to achieve steady state level, followed by 3 day treatment with oral Danggui extract (2 g/kg twice daily). The slight increase in PT was not significant and two rabbits died after day 7 of the treatment period. However, there was no significant difference in steady state concentrations of warfarin after the Danggui treatment. Results indicate that precautionary advice should be given to patients who self-medicate with Danggui or other TCM products while on chronic treatment with warfarin.

1. In 13 of 15 experiments, prostaglandin E2 (PGE2) and sulprostone (a prostanoid EP1/EP3-receptor agonist) contracted isolated rings of human pulmonary artery at low concentrations (> or = 5 and > or = 0.5 nM respectively). Tissue was obtained from patients undergoing surgery mainly for carcinoma of the lung. Characterization of the receptors involved was complicated by loss of sensitivity to the contractile PGE action over the experimental period. In contrast, contractile responses to KCl, phenylephrine and the specific thromboxane (TP-) receptor agonist, U-46619, did not decrease with time. 2. The relative contractile potencies for seven PGE analogues, measured during the first few hours after setting up the preparations, were as follows: sulprostone > misoprostol = gemeprost > or = PGE2 > or = GR 63799X > 17-phenyl-omega-trinor PGE2 > or = 11-deoxy PGE1. This ranking indicates that an EP3-receptor is involved. 3. The contractile action of sulprostone was not blocked by the TP-receptor antagonists, EP 169 and GR 32191, and the EP1-receptor antagonist, AH 6809. 4. In two experiments, PGE2 (50 nM) reduced basal tone and sulprostone was a weak contractile agent. Phenylephrine-induced tone was also inhibited by PGE2 (EC50 = 5-20 nM), 11-deoxy PGE1 and butaprost (a selective EP2-receptor agonist); the latter prostanoids were about 2 and 4 times less potent than PGE2 respectively. Interactions with phenylephrine were different in experiments where PGE2 alone was contractile: PGE2 induced contraction superimposed on the phenylephrine response and 11-deoxy PGE1 induced either further contraction or had no effect. Butaprost produced relaxation at high concentrations;this may not be an EP2 action since preparations were highly sensitive to relaxant actions of prostacyclin (IP-) receptor agonists (cicaprost and TEI-9063).5 The study has shown that in the majority of experiments on the human isolated pulmonary artery,the contractile EP3 system outweighed the relaxant EP2 system. However, in two experiments the reverse was true. It is not clear to what extent these differences are due to disease processes affecting the tissues.The findings are discussed in relation to the adverse cardiovascular responses occasionally encountered during treatment of postpartum haemorrhage with sulprostone, and more generally to the clinical use of EP-receptor agonists in man.

There are no selective agonists for the prostanoid EP4-receptor, and the ones available for the EP2-receptor are either of low potency (e.g. AH 13205) or are C1-methyl esters subject to variable de-esterification within tissues (e.g. butaprost). EP4 vasorelaxant systems are often highly sensitive, with IC50 values for PGE2 as low as 0.1 nM, whereas EP2 systems are usually some 30–100 times less sensitive. Determining whether EP2-receptors co-exist with EP4-receptors is therefore quite difficult. Some information can be gained using the EP4 antagonist AH 23848, but this blocker has a low affinity (pA2= 5.0–5.4), making large dose ratios difficult to obtain. We have recently investigated the utility of a new EP2 agonist, ONO-AE1-259 in this situation. ONO-AE1-259 (free acid) is claimed to be highly selective on the basis of radioligand competition and second messenger measurements on cloned mouse receptors; its EC50 for cyclic AMP production = 1.8 nM for EP2 and >10 μM for EP4-receptors (S. Narumiya; 11th International Conference on Prostaglandins, Florence, 2000). Rings of guinea-pig lateral saphenous vein were set up in a 4-channel Mulvaney myograph system (bath volume = 5 ml) in Krebs-Henseleit solution containing 1 μM indomethacin and 0.2 μM GR 32191 (TP antagonist). Tone was generated with 3 μM phenylephrine and agonists were added cumulatively. PGE2 induced ∼95% relaxation at 5 nM and had an EC50 of about 0.1 nM. ONO-AE1-259 consistently showed small relaxant effects at 1 nM, but its log concentration-response curve was shallower than that of PGE2 and only about 85% relaxation was found at 5 μM (IC50= 20 nM relative to its own maximum). The vein preparation did not contact to sulprostone, and therefore is unlikely to contain opposing EP1 and/or EP3 systems. In the presence of 30 μM AH 23848, the log concentration-response curve for PGE2 was displaced to the right in a parallel manner (dose ratio = 7.6, pA2= 5.3). However, the ONO-AE1-259 curve was only slightly displaced to the right by AH 23848 (dose ratio = 1.6), while at the same time maximum relaxation was reduced by 15%. ONO-AE1-259 was about 25 times more potent than butaprost. It is possible therefore that ONO-AE1-259 is selectively activating a relaxant EP2-receptor in the guinea-pig saphenous vein. The saphenous vein preparation is also highly sensitive to the prostacyclin analogues AFP-07 (IC50= 0.65 nM) and cicaprost (IC50= 7 nM). We are investigating whether these analogues activate IP and/or EP4 receptors, in the light of our recent finding that they are potent and moderately potent EP4 agonists respectively on both piglet and rabbit saphenous veins (Jones & Chan, 2001, Br. J. Pharmacol., in press).

Background Tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) were originally identified to show potent anti-tumor activity and immunomodulatory capability. Unfortunately, several clinical studies of relevant cancer therapy did not observe significant response in maximum tolerated dose whether given alone or in combination. We have identified a tumor vasculature homing peptide (TCP-1 peptide) which targets only the vasculature of colorectal tumors but not normal blood vessels in animals and humans. In the current study, the antitumor effect of TCP-1/TNFα and TCP-1/IFNγ alone or in combination was studied in orthotopic colorectal tumor model. Methods TCP-1/TNFα and TCP-1/IFNγ recombinant proteins were prepared and i.v. injected to study the in vivo anticancer effect in orthotopic colorectal tumor model. Tumor apoptosis was determined by TUNEL staining and cleaved caspase-3 immunofluorescent staining. Tumor infiltrating lymphocytes were analyzed by immunofluorescent staining and flow cytometry. Western-blot was performed to examine the expression of proteins. Cell apoptosis was measured by Annexin V/PI flow cytometry. Results Targeted delivery of TNFα or IFNγ by TCP-1 peptide exhibited better antitumor activity than unconjugated format by inducing more tumor apoptosis and also enhancing antitumor immunity shown by increased infiltration of T lymphocytes inside the tumor. More importantly, combination therapy of TCP-1/TNFα and TCP-1/IFNγ synergistically suppressed tumor growth and alleviated systematic toxicity associated with untargeted therapy. This combination therapy induced massive apoptosis/secondary necrosis in the tumor. Conclusions Taken together, our data demonstrate TCP-1 is an efficient drug carrier for targeted therapy of colorectal cancer (CRC). TCP-1/TNFα combined with TCP-1/IFNγ is a promising combination therapy for CRC. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-0944-3) contains supplementary material, which is available to authorized users.