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Intraabdominal adhesions develop after abdominal surgery as part of the normal healing processes that occur after damage to the peritoneum. Over the last 2 decades, much research has gone into understanding the biochemical and cellular processes that lead to adhesion formation. The early balance between fibrin deposition and degradation seems to be the critical factor in adhesion formation. Although adhesions do have some beneficial effects, they also cause significant morbidity, including adhesive small bowel obstruction, infertility and increased difficulty with reoperative surgery. Several strategies have been employed over the years to prevent adhesion formation while not interfering with wound healing. This article summarizes much of our current understanding of adhesion formation and strategies that have been employed to prevent them. 相似文献
3.
Gennady Bratslavsky Stephanie Gleicher Joseph M. Jacob Thomas H. Sanford Oleg Shapiro Dimitra Bourboulia Laurie M Gay Julie Andrea Elvin Jo-Anne Vergilio James Suh Shakti Ramkissoon Eric Allan Severson Jonathan Keith Killian Alexa Betzig Schrock Jon H. Chung Vincent A. Miller Mehdi Mollapour Jeffrey S. Ross 《Urologic oncology》2021,39(6):367.e1-367.e5
Introduction and ObjectiveUnlike clear cell renal cell carcinoma (CCRCC), collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are rare tumors that progress rapidly and appear resistant to current systemic therapies. We queried comprehensive genomic profiling to uncover opportunities for targeted therapy and immunotherapy.Material and MethodsDNA was extracted from 40 microns of formalin-fixed, paraffin-embedded specimen from relapsed, mCDC (n = 46), mRMC (n = 24), and refractory and metastatic (m) mCCRCC (n = 626). Comprehensive genomic profiling was performed, and Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated. We analyzed all classes of genomic alterations.ResultsmCDC had 1.7 versus 2.7 genomic alterations/tumor in mCCRCC ( = 0.04). Mutations in VHL (P < 0.0001) and TSC1 (P = 0.04) were more frequent in mCCRCC. SMARCB1 (P < 0.0001), NF2 (P = 0.0007), RB1 (P = 0.02) and RET (P = 0.0003) alterations were more frequent in mCDC versus mCCRCC. No VHL alterations in mRMC and mCDC were identified. SMARCB1 genomic alterations were significantly more frequent in mRMC than mCDC (P = 0.0002), but were the most common alterations in both subtypes. Mutations to EGFR, RET, NF2, and TSC2 were more frequently identified in mCDC versus mRMC. The median TMB and MSI-High status was low with <1% of mCCRC, mCDC, and mRMC having ≥ 20 mut/Mb.ConclusionGenomic alteration patterns in mCDC and mRMC differ significantly from mCCRCC. Targeted therapies for mCDC and mRMC appear limited with rare opportunities to target alterations in receptor tyrosine kinase and MTOR pathways. Similarly, TMB and absence of MSI-High status in mCDC and mRMC suggest resistance to immunotherapies. 相似文献
4.
David Phong Nguyen Britt Klein Denny Meyer David William Austin Jo-Anne M Abbott 《Journal of medical Internet research》2015,17(9)
Background
Internet-based assessment has the potential to assist with the diagnosis of mental health disorders and overcome the barriers associated with traditional services (eg, cost, stigma, distance). Further to existing online screening programs available, there is an opportunity to deliver more comprehensive and accurate diagnostic tools to supplement the assessment and treatment of mental health disorders.Objective
The aim was to evaluate the diagnostic criterion validity and test-retest reliability of the electronic Psychological Assessment System (e-PASS), an online, self-report, multidisorder, clinical assessment and referral system.Methods
Participants were 616 adults residing in Australia, recruited online, and representing prospective e-PASS users. Following e-PASS completion, 158 participants underwent a telephone-administered structured clinical interview and 39 participants repeated the e-PASS within 25 days of initial completion.Results
With structured clinical interview results serving as the gold standard, diagnostic agreement with the e-PASS varied considerably from fair (eg, generalized anxiety disorder: κ=.37) to strong (eg, panic disorder: κ=.62). Although the e-PASS’ sensitivity also varied (0.43-0.86) the specificity was generally high (0.68-1.00). The e-PASS sensitivity generally improved when reducing the e-PASS threshold to a subclinical result. Test-retest reliability ranged from moderate (eg, specific phobia: κ=.54) to substantial (eg, bulimia nervosa: κ=.87).Conclusions
The e-PASS produces reliable diagnostic results and performs generally well in excluding mental disorders, although at the expense of sensitivity. For screening purposes, the e-PASS subclinical result generally appears better than a clinical result as a diagnostic indicator. Further development and evaluation is needed to support the use of online diagnostic assessment programs for mental disorders.Trial Registration
Australian and New Zealand Clinical Trials Registry ACTRN121611000704998; http://www.anzctr.org.au/trial_view.aspx?ID=336143 (Archived by WebCite at http://www.webcitation.org/618r3wvOG). 相似文献5.
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Celine Valant Lauren T. May Luigi Aurelio Chung Hui Chuo Paul J. White Jo-Anne Baltos Patrick M. Sexton Peter J. Scammells Arthur Christopoulos 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(12):4614-4619
The concepts of allosteric modulation and biased agonism are revolutionizing modern approaches to drug discovery, particularly in the field of G protein-coupled receptors (GPCRs). Both phenomena exploit topographically distinct binding sites to promote unique GPCR conformations that can lead to different patterns of cellular responsiveness. The adenosine A1 GPCR (A1AR) is a major therapeutic target for cardioprotection, but current agents acting on the receptor are clinically limited for this indication because of on-target bradycardia as a serious adverse effect. In the current study, we have rationally designed a novel A1AR ligand (VCP746)—a hybrid molecule comprising adenosine linked to a positive allosteric modulator—specifically to engender biased signaling at the A1AR. We validate that the interaction of VCP746 with the A1AR is consistent with a bitopic mode of receptor engagement (i.e., concomitant association with orthosteric and allosteric sites) and that the compound displays biased agonism relative to prototypical A1AR ligands. Importantly, we also show that the unique pharmacology of VCP746 is (patho)physiologically relevant, because the compound protects against ischemic insult in native A1AR-expressing cardiomyoblasts and cardiomyocytes but does not affect rat atrial heart rate. Thus, this study provides proof of concept that bitopic ligands can be designed as biased agonists to promote on-target efficacy without on-target side effects.G protein-coupled receptors (GPCRs) are the largest family of cell surface proteins and tractable drug targets (1, 2). Unfortunately, there remains a high attrition rate associated with traditional GPCR-based drug discovery that, in part, reflects an emphasis on the endogenous agonist binding (orthosteric) site as the predominant means of achieving selective GPCR drug targeting (3). Over the last decade, substantial breakthroughs have occurred in the exploitation of topographically distinct GPCR allosteric sites as a means for attaining greater selectivity, especially in those instances where there is high sequence similarity in the orthosteric site across GPCR subtypes (4–6). However, there are increasing examples where both the therapeutic effect and adverse effects are mediated by the same GPCR target (7). In these situations, the desired selectivity needs to be attained at the level of the intracellular signaling pathways linked to a given receptor subtype.GPCRs are highly dynamic proteins, fluctuating between different conformations; these conformations can be linked to different cellular outcomes (8). Thus, chemically distinct ligands, interacting with either orthosteric or allosteric sites, have the potential to stabilize different interaction networks within a GPCR to promote a subset of signaling pathways linked to the receptor at the expense of others. This phenomenon has been termed biased agonism (7, 9, 10). The overall promise of biased agonism is the ability to design GPCR ligands that selectively engage therapeutically relevant signaling pathways while sparing pathways that contribute to undesirable side effects mediated by the same target.The adenosine receptor (AR) family is an important class of physiologically and therapeutically relevant GPCRs that can benefit substantially from more selective drug targeting. Although all four AR subtypes are expressed in the mammalian heart (11, 12), the well-known protective effects of adenosine in this tissue are predominantly mediated by the adenosine A1 receptor (A1AR) subtype, especially under conditions of ischemia and reperfusion injury (13–17). Unfortunately, the transition of A1AR agonists into the clinic has been severely hindered because of high doses causing on-target bradycardia, atrioventricular block, and hypotension (13, 18). As a consequence, clinical trials of AR agonists have had limited success because of the suboptimal dose of agonist that can be used (19–22). It is possible that this problem may be overcome through the exploitation of biased agonism at the A1AR.Although no study has identified biased orthosteric A1AR ligands, we recently showed that the 2-amino-3-benzoylthiophene allosteric modulator (VCP171) could promote biased signaling in the activity of the prototypical orthosteric agonist, R(-)N6-(2-phenylisopropyl) adenosine (R-PIA) (23). Thus, we hypothesized that the rational design of a bitopic ligand (i.e., a class of hybrid molecule containing both orthosteric and allosteric pharmacophores) (24–26) may be able to achieve high efficacy and biased agonism at the A1AR in a single molecule. Herein, we report proof of concept that it is possible to use this approach as a means to dissociate on-target efficacy from on-target side effects. 相似文献
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8.
Scott Worley MD BScPT Jeff Pike MD David Anderson MD Jo-Anne Douglas BSc Kara Thompson BSc MSc 《The journal of spinal cord medicine》2013,36(4):379-387
Background: When venous thromboembolism (VTE) includes deep-vein thrombosis (DVT) and pulmonary embolism (PE), patients with acute traumatic spinal cord injury (SCI) have the highest incidence of VTE among all hospitalized groups, with PE the third most common cause of death. Although low-molecular-weight heparin (LMWH) outperforms low-dose unfractionated heparin (LDUH) in other patient populations, the evidence in SCI remains less robust.Objective: To determine whether the efficacy for LMWH shown in previous SCI surveillance studies (eg, routine Doppler ultrasound) would translate into real-world effectiveness in which only clinically evident VTE is investigated (ie, after symptoms or signs present).Methods: A retrospective cohort study was conducted of 90 patients receiving LMWH dalteparin (5,000 U daily) or LDUH (5,000 U twice daily) for VTE prophylaxis after acute traumatic SCI. The incidence of radiographically confirmed VTE was primarily analyzed, and secondary outcomes included complications of bleeding and heparin-induced thrombocytopenia.Results: There was no statistically significant association (p = 0.7054) between the incidence of VTE (7.78% overall) and the type of prophylaxis received (LDUH 3/47 vs dalteparin 4/43). There was no significant differences in complications, location of VTE, and incidence of fatal PE. Paraplegia (as opposed to tetraplegia) was the only risk factor identified for VTE.Conclusions: There continues to be an absence of definitive evidence for dalteparin (or other LMWH) over LDUH as the choice for VTE prophylaxis in patients with SCI. Novel approaches to VTE prophylaxis are urgently required for this population, whose risk of fatal PE has not decreased over the last 25 years. 相似文献
9.
Richard S.P. Huang Xinyan Li James Haberberger Ethan Sokol Eric Severson Daniel L. Duncan Amanda Hemmerich Claire Edgerly Erik Williams Julia Elvin Jo-Anne Vergilio Jonathan Keith Killian Douglas Lin Matthew Hiemenz Jinpeng Xiao Deborah McEwan Oliver Holmes Natalie Danziger Rachel Erlich Garrett Frampton Michael B. Cohen Kimberly McGregor Prasanth Reddy Dawn Cardeiro Rachel Anhorn Jeffrey Venstrom Brian Alexander Charlotte Brown Lajos Pusztai Jeffrey S. Ross Shakti H. Ramkissoon 《The oncologist》2020,25(11):943-953
10.
Anne E McCarthy Noni E MacDonald Stephen Feder Jo-Anne A Doherty Lisa McAvoy Baldwin Toye 《Paediatrics & child health》1999,4(6):395-399