Publications by authors named "David Dietz"

147 Publications

A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue-induced cocaine craving following prolonged abstinence.

Addict Biol 2021 Jan 25:e13007. Epub 2021 Jan 25.

Department of Pharmacology and Toxicology, Program in Neuroscience, The State University of New York at Buffalo, Buffalo, NY, USA.

Following exposure to drugs of abuse, long-term neuroadaptations underlie persistent risk to relapse. Endocannabinoid signaling has been associated with drug-induced neuroadaptations, but the role of lipases that mediate endocannabinoid biosynthesis and metabolism in regulating relapse behaviors following prolonged periods of drug abstinence has not been examined. Here, we investigated how pharmacological manipulation of lipases involved in regulating the expression of the endocannabinoid 2-AG in the nucleus accumbens (NAc) influence cocaine relapse via discrete neuroadaptations. At prolonged abstinence (30 days) from cocaine self-administration, there is an increase in the NAc levels of diacylglycerol lipase (DAGL), the enzyme responsible for the synthesis of the endocannabinoid 2-AG, along with decreased levels of monoacylglycerol lipase (MAGL), which hydrolyzes 2-AG. Since endocannabinoid-mediated behavioral plasticity involves phosphatase dysregulation, we examined the phosphatase calcineurin after 30 days of abstinence and found decreased expression in the NAc, which we demonstrate is regulated through the transcription factor EGR1. Intra-NAc pharmacological manipulation of DAGL and MAGL with inhibitors DO-34 and URB-602, respectively, bidirectionally regulated cue-induced cocaine seeking and altered the phosphostatus of translational initiation factor, eIF2α. Finally, we found that cocaine seeking 30 days after abstinence leads to decreased phosphorylation of eIF2α and reduced expression of its downstream target NPAS4, a protein involved in experience-dependent neuronal plasticity. Together, our findings demonstrate that lipases that regulate 2-AG expression influence transcriptional and translational changes in the NAc related to drug relapse vulnerability.
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http://dx.doi.org/10.1111/adb.13007DOI Listing
January 2021

DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors.

Cereb Cortex 2020 Nov 24. Epub 2020 Nov 24.

Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.

Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here, we found that male rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory, heightened aggression, and hyperlocomotion, were partially attenuated by Dnmt3a expression in PFC of stressed animals. Finally, we found that there were genome-wide DNA methylation changes and transcriptome alterations in PFC of stressed rats, both of which were enriched at several neural pathways, including glutamatergic synapse and microtubule-associated protein kinase signaling. These results have therefore recognized the potential role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive and emotional processes.
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http://dx.doi.org/10.1093/cercor/bhaa337DOI Listing
November 2020

Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence.

Proc Natl Acad Sci U S A 2020 10 5;117(42):26460-26469. Epub 2020 Oct 5.

Department of Pharmacology and Toxicology, Program in Neuroscience, Jacobs School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214;

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or "incubates") during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-β (TGF-β) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration.
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http://dx.doi.org/10.1073/pnas.2006133117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585028PMC
October 2020

Adding Boost to Standard Neoadjuvant Radiation for Rectal Cancer Improves Likelihood of Complete Response.

J Gastrointest Surg 2020 07 22;24(7):1655-1662. Epub 2020 Apr 22.

Department of Surgery, University Hospitals Research in Surgical Outcomes & Effectiveness Center (UH-RISES), University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, OH, 44106, USA.

Background: Pathologic tumor response is a prognostic factor for survival in patients with rectal cancer. Standard neoadjuvant radiation (nRT) dosing for locally advanced rectal cancer ranges from 4500 to 5400 centigray (cGy), but it is unknown if tumor regression differs as a consequence adding a boost to the tumor bed.

Methods: The National Cancer Database (NCDB) 2006-2016 was used to identify patients 18 years of age and older with clinical stage II and III rectal cancer who received pelvic nRT dosed between 4500 and 5400 cGy. Standard nRT dose (no boost, NB) and dose with boost (DWB) were defined respectively as 4500 and 5040-5400 cGy. Complete pathologic response (pCR) was defined as postoperative pathologic stage of zero. A multivariate logistic regression was performed to evaluate the association between radiation dosing and pCR.

Results: The study cohort was 28,841 patients; the majority received DWB 22,701 (78.7%), while 6140 (21.3%) received NB. pCR was achieved in 3135 (14.4%) patients. On multivariate analysis, patients who received NB were significantly less likely to have complete tumor response (OR 1.41, 95% CI 1.2-1.66, p < 0.001). Other factors significantly associated with pCR included insurance, facility type, tumor characteristics, clinical stage, and time between radiation and surgery.

Conclusions: This is the first investigation demonstrating that standard dose neoadjuvant radiation for rectal cancer was associated with a lower likelihood of pCR compared with standard dose with boost. Past studies demonstrate that rectal cancer patient survival is strongly correlated with pCR. Prospective trials should focus on examining neoadjuvant radiation dosing to evaluate if DWB improves outcomes.
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http://dx.doi.org/10.1007/s11605-020-04594-7DOI Listing
July 2020

Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking.

Science 2020 04;368(6487):197-201

Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.
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http://dx.doi.org/10.1126/science.aaw8806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228137PMC
April 2020

Circumferential Resection Margin as a Hospital Quality Assessment Tool for Rectal Cancer Surgery.

J Am Coll Surg 2020 06 4;230(6):1008-1018.e5. Epub 2020 Mar 4.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: Circumferential resection margin (CRM) status is an important predictor of outcomes after rectal cancer operation, and is influenced not only by operative technique, but also by incorporation of a multidisciplinary treatment strategy. This study sought to develop a risk-adjusted quality metric based on CRM status to assess hospital-level performance for rectal cancer operation.

Study Design: We conducted a retrospective observational cohort study of 58,374 patients with resected stage I to III rectal cancer within 1,303 hospitals who were identified from the National Cancer Database (2010 to 2015). The number of observed cases with a positive CRM (≤ 1 mm) was divided by the risk-adjusted expected number of cases with positive CRM to form the observed-to-expected (O/E) ratio. Secondary endpoint was overall survival.

Results: The overall rate of CRM positivity was 15.9%. Based on the O/E ratio for 1,139 hospitals, 147 (12.9%) and 103 (9.0%) were significantly worse and better performers, respectively. The majority of hospitals (n = 570) performed as expected. Positive CRMs using criteria of 0 mm and 0.1 to 1 mm were associated with a significantly shorter 5-year overall survival of 49% and 63.5% (hazard ratio 1.67; 95% CI, 1.57 to 1.76 and hazard ratio 1.19; 95% CI, 1.12 to 1.26) than negative CRM > 1 mm of 74.1% (all p < 0.001).

Conclusions: CRM-based O/E ratio is a robust hospital-based quality measure for rectal cancer operation. It allows facilities to compare their performance with that of centers of similar characteristics and helps identify underperforming, at-risk, and high-performing centers. National quality-improvement initiatives for rectal cancer should focus on ensuring high-quality data collection and providing ready access to risk-adjusted comparative metrics.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.02.033DOI Listing
June 2020

Sarcopenia is associated with worse overall survival in patients with anal squamous cell cancer.

J Surg Oncol 2020 Jun 4;121(7):1148-1153. Epub 2020 Mar 4.

Department of Surgery, Research in Surgical Outcomes and Effectiveness Center (UH-RISES), University Hospitals Cleveland Medical Center, Cleveland, Ohio.

Background And Objectives: Sarcopenia is associated with poor long-term outcomes in many gastrointestinal cancers, but its role in anal squamous cell carcinoma (ASCC) is not defined. We hypothesized that patients with sarcopenic ASCC experience worse long-term outcomes.

Methods: A retrospective review of patients with ASCC treated at an academic medical center from 2006 to 2017 was performed. Of 104 patients with ASCC, 64 underwent PET/computed tomography before chemoradiation and were included in the analysis. The skeletal muscle index was calculated as total L3 skeletal muscle divided by height squared. Sarcopenia thresholds were 52.4 cm /m for men and 38.5 cm /m for women. Cox regression analysis was performed to assess overall and progression-free survival.

Results: Twenty-five percent of the patients were sarcopenic (n = 16). Demographics were similar between groups. There was no difference in the clinical stage or comorbidities between groups. On multivariate analysis, factors associated with worse overall survival were male gender (hazard ratio [HR] 3.7, P = .022) and sarcopenia (HR 3.6, P = .019). Male gender was associated with worse progression-free survival (HR 2.6, P = .016).

Conclusions: Sarcopenia is associated with worse overall survival in patients with anal cancer. Further studies are indicated to determine if survival can be improved with increased attention to nutritional status in sarcopenic patients.
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http://dx.doi.org/10.1002/jso.25887DOI Listing
June 2020

Disparities in neoadjuvant radiation dosing for treatment of rectal cancer.

Am J Surg 2020 10 13;220(4):987-992. Epub 2020 Jan 13.

Department of Surgery, University Hospitals Research in Surgical Outcomes & Effectiveness Center (UH-RISES), University Hospitals Cleveland Medical Center, Cleveland, OH, USA. Electronic address:

Background: Certain patients are less likely to undergo appropriate cancer treatment, worsening their overall cancer survival. The purpose of this investigation was to identify factors associated with inadequate neoadjuvant radiation for rectal cancer.

Methods: The National Cancer Database was queried for patients with locally advanced rectal cancer who received neoadjuvant radiation 2006-2014. Adequate radiation was considered to be 4,500-5,040 cGy. Demographic, hospital and clinical variables were analyzed for association with inadequate radiation.

Results: The study cohort was 34,391 patients; 1,842(5.4%) received inadequate radiation. On multivariate analysis, female gender, older age, other race, government-provided insurance, lower clinical stage and rural location correlated with inadequate radiation.

Conclusions: Women were 50% less likely than men to receive correct neoadjuvant radiation dosing. Other factors including age, race, insurance, clinical stage, geographic location and neoadjuvant chemotherapy were significantly associated with radiation dosing. These factors should be evaluated to determine if they can be modified to improve outcomes.
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http://dx.doi.org/10.1016/j.amjsurg.2020.01.016DOI Listing
October 2020

Sex-Specific Role for Egr3 in Nucleus Accumbens D2-Medium Spiny Neurons Following Long-Term Abstinence From Cocaine Self-administration.

Biol Psychiatry 2020 06 1;87(11):992-1000. Epub 2019 Nov 1.

Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address:

Background: We previously showed that the transcription factor Egr3 (early growth response 3) is oppositely regulated in nucleus accumbens (NAc) cell subtypes 24 hours following cocaine exposure and bidirectionally mediates cocaine-related behaviors in male rodents. Overexpressing Egr3 in D receptor-containing medium spiny neurons (D2-MSNs) before drug exposure reduces the rewarding and psychomotor sensitization effects of cocaine. However, it is unknown if Egr3 plays a role in long-term neuroadaptations in the NAc and relapse to cocaine seeking.

Methods: We measured EGR3 protein levels in the NAc following 20 days of forced abstinence from intravenous cocaine self-administration in 10-week-old Sprague Dawley rats and C57BL/6 mice. In 8- to 10-week-old A2A-Cre mice, we used virally mediated Egr3 overexpression in NAc D2-MSNs to test the role of Egr3 on operant responding during seeking, extinction, and drug-induced reinstatement of cocaine self-administration. To evaluate if Egr3 contributed to sex differences to cocaine relapse, we conducted these procedures in both male and female rodents.

Results: We found that EGR3 expression was reduced only in female rodents after 20 days of forced abstinence. Additionally, we showed that our self-administration paradigm in mice recapitulated the sex differences in cocaine intake and relapse demonstrated in humans and rats. Finally, whereas Egr3 overexpression in D2-MSNs during forced abstinence facilitated extinction and blunted drug-induced reinstatement in female mice, it had the opposite effect in male mice.

Conclusions: We showed that the immediate early gene Egr3 has long-term effects on drug-related behaviors. Our work suggests that changes in Egr3 expression in D2-MSNs contributes to sex differences in cocaine relapse.
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http://dx.doi.org/10.1016/j.biopsych.2019.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897443PMC
June 2020

Does one size fit all? Risks and benefits of neoadjuvant chemoradiation in patients with clinical stage IIA rectal cancer requiring abdominoperineal resection.

Am J Surg 2020 03 23;219(3):406-410. Epub 2019 Oct 23.

Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, 9500 Euclid Avenue, A-30, Cleveland, OH, 44195, USA. Electronic address:

Background: Neoadjuvant chemoradiotherapy (nCRT) has become the standard of care for locally advanced rectal cancer, decreasing locoregional recurrence, yet with an unclear survival advantage. We aimed to assess the benefit of nCRT on oncologic and perioperative outcomes of patients with clinical stage IIA rectal adenocarcinoma treated with abdominoperineal resection (APR).

Methods: Patients with clinical T3N0 rectal adenocarcinoma that underwent APR between 1995 and 2014 were included. Patients who received nCRT were compared with patients who did not. Multivariate analysis was conducted to compare oncological and perioperative outcomes between the groups.

Results: 127 patients were included, of which 94 received nCRT. Median follow-up was 11.9 years. There was no difference in circumferential margins, postoperative morbidity, and complication rates between the groups. There was no difference in 5-year oncological outcomes between the groups.

Conclusions: No difference was found in 5-year oncological outcomes between patients with clinical T3N0 rectal adenocarcinoma necessitating an APR who received nCRT and those not receiving nCRT, with similar overall complication rates.
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http://dx.doi.org/10.1016/j.amjsurg.2019.10.037DOI Listing
March 2020

A novel role for the actin-binding protein drebrin in regulating opiate addiction.

Nat Commun 2019 09 12;10(1):4140. Epub 2019 Sep 12.

Department of Pharmacology and Toxicology, Program in Neuroscience, Research Institute on Addictions, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.

Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1 subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.
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http://dx.doi.org/10.1038/s41467-019-12122-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742638PMC
September 2019

Outcomes in immunosuppressed anal cancer patients.

Am J Surg 2020 01 19;219(1):88-92. Epub 2019 Aug 19.

University Hospitals Research in Surgical Outcomes & Effectiveness Center (UH-RISES), Department of Surgery, University Hospitals, Cleveland Medical Center, Cleveland, OH, USA. Electronic address:

Background: Immunosuppressed patients have an increased risk of developing anal cancer, but little data exists regarding outcomes of this population.

Methods: A retrospective review of anal cancer patients at a single academic institution from 2006 to 2017 was performed.

Results: 19 (14%) of 136 anal cancer patients were immunosuppressed. Immunosuppressed patients were more likely to be hypoalbuminemic (21% vs. 6%, p = 0.025), less likely to complete chemotherapy (58% vs. 80%, p = 0.031) or exhibit a complete response to chemoradiation (57% vs. 82%, p = 0.037), and more likely to experience recurrence (53% vs. 25%, p = 0.013). Hypoalbuminemia was significantly associated with worse overall (HR 6.4, CI 2.2-19.2, p < 0.001) and progression-free (HR 4.4, CI 1.8-10.4, p < 0.001) survival.

Conclusions: Immunosuppressed patients have poor tolerance of chemotherapy and response to chemoradiation, and an increased rate of recurrence. This finding is possibly due to the relationship between immunosuppression and hypoalbuminemia, which was associated with worse overall and progression-free survival.
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http://dx.doi.org/10.1016/j.amjsurg.2019.08.011DOI Listing
January 2020

Reoperative Surgery in Complex Crohn's Disease.

Clin Colon Rectal Surg 2019 Jul 2;32(4):291-299. Epub 2019 Jul 2.

Department of Surgery-Colorectal, University Hospitals Cleveland Medical Center, Cleveland, Ohio.

This article provides a structured approach to the technical aspects of reoperative surgery for Crohn's disease. Specific indications for surgery including repeat ileocolic resection, Crohn's complications of ileal pouch anal anastomosis and continent ileostomy, completion proctectomy, and the role of small bowel transplant will be discussed.
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http://dx.doi.org/10.1055/s-0039-1683918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606318PMC
July 2019

Synaptic Microtubule-Associated Protein EB3 and SRC Phosphorylation Mediate Structural and Behavioral Adaptations During Withdrawal From Cocaine Self-Administration.

J Neurosci 2019 07 15;39(29):5634-5646. Epub 2019 May 15.

Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029,

Addictive behaviors, including relapse, are thought to depend in part on long-lasting drug-induced adaptations in dendritic spine signaling and morphology in the nucleus accumbens (NAc). While the influence of activity-dependent actin remodeling in these phenomena has been studied extensively, the role of microtubules and associated proteins remains poorly understood. We report that pharmacological inhibition of microtubule polymerization in the NAc inhibited locomotor sensitization to cocaine and contextual reward learning. We then investigated the roles of microtubule end-binding protein 3 (EB3) and SRC kinase in the neuronal and behavioral responses to volitionally administered cocaine. In synaptoneurosomal fractions from the NAc of self-administering male rats, the phosphorylation of SRC at an activating site was induced after 1 d of withdrawal, while EB3 levels were increased only after 30 d of withdrawal. Blocking SRC phosphorylation during early withdrawal by virally overexpressing SRCIN1, a negative regulator of SRC activity known to interact with EB3, abolished the incubation of cocaine craving in both male and female rats. Conversely, mimicking the EB3 increase observed after prolonged withdrawal increased the motivation to consume cocaine in male rats. In mice, the overexpression of either EB3 or SRCIN1 increased dendritic spine density and altered the spine morphology of NAc medium spiny neurons. Finally, a cocaine challenge after prolonged withdrawal recapitulated most of the synaptic protein expression profiles observed at early withdrawal. These findings suggest that microtubule-associated signaling proteins such as EB3 cooperate with actin remodeling pathways, notably SRC kinase activity, to establish and maintain long-lasting cellular and behavioral alterations following cocaine self-administration. Drug-induced morphological restructuring of dendritic spines of nucleus accumbens neurons is thought to be one of the cellular substrates of long-lasting drug-associated memories. The molecular basis of these persistent changes has remained incompletely understood. Here we implicate for the first time microtubule function in this process, together with key players such as microtubule-bound protein EB3 and synaptic SRC phosphorylation. We propose that microtubule and actin remodeling cooperate during withdrawal to maintain the plastic structural changes initially established by cocaine self-administration. This work opens new translational avenues for further characterization of microtubule-associated regulatory molecules as putative drug targets to tackle relapse to drug taking.
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http://dx.doi.org/10.1523/JNEUROSCI.0024-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636087PMC
July 2019

Is Conversion of a Failed IPAA to a Continent Ileostomy a Risk Factor for Long-term Failure?

Dis Colon Rectum 2019 02;62(2):217-222

Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio.

Background: A continent ileostomy may be offered to patients in hopes of avoiding permanent ileostomy. Data on the outcomes of continent ileostomy patients with a history of a failed IPAA are limited.

Objective: This study aimed to assess whether a history of previous failed IPAA had an effect on continent ileostomy survival and the long-term outcomes.

Design: This was a retrospective cohort study.

Settings: This investigation took place in a high-volume, specialized colorectal surgery department.

Patients: Patients who underwent continent ileostomy construction after IPAA failure between 1982 and 2013 were evaluated and compared with patients who have no history of IPAA surgery.

Main Outcome Measures: Functional outcomes and long-term complications were compared.

Results: A total of 67 patients fulfilled the case-matching criteria and were included in the analysis. Requirement of major (52% vs 61%; p = 0.756) and minor (15% vs 19%; p = 0.492) revisions were comparable between patients who had continent ileostomy after a failed IPAA and those who had continent ileostomy without having a previous restorative procedure. Intubations per day (5 vs 5; p = 0.804) and per night (1 vs 1; p = 0.700) were similar in both groups. Our data show no clear relationship between failure of continent ileostomy and history of failed IPAA (p = 0.638). The most common cause of continent ileostomy failure was enterocutaneous/enteroenteric fistula (n = 14). Six patients died during the study period because of other causes unrelated to continent ileostomy.

Limitations: This study was limited by its retrospective and nonrandomized nature.

Conclusions: Converting a failed IPAA to a continent ileostomy did not worsen continent ileostomy outcomes in this selected group of patients. When a redo IPAA is not feasible, continent ileostomy can be offered as an alternative to conventional end ileostomy in highly motivated patients. See Video Abstract at http://links.lww.com/DCR/A803.
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http://dx.doi.org/10.1097/DCR.0000000000001277DOI Listing
February 2019

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial.

Dis Colon Rectum 2018 Oct;61(10):1146-1155

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Adding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response.

Objective: The purpose of this study was to analyze disease-free and overall survival.

Design: This was a nonrandomized phase II trial.

Settings: The study was conducted at multiple institutions.

Patients: Four sequential study groups with stage II or III rectal cancer were included.

Intervention: All of the patients received 50 Gy of radiation with concurrent continuous infusion of fluorouracil for 5 weeks. Patients in each group received 0, 2, 4, or 6 cycles of modified FOLFOX6 after chemoradiation and before total mesorectal excision. Patients were recommended to receive adjuvant chemotherapy after surgery to complete a total of 8 cycles of modified FOLFOX6.

Main Outcome Measures: The trial was powered to detect differences in pathological complete response, which was reported previously. Disease-free and overall survival are the main outcomes for the current study.

Results: Of 259 patients, 211 had a complete follow-up. Median follow-up was 59 months (range, 9-125 mo). The mean number of total chemotherapy cycles differed among the 4 groups (p = 0.002), because one third of patients in the group assigned to no preoperative FOLFOX did not receive any adjuvant chemotherapy. Disease-free survival was significantly associated with study group, ypTNM stage, and pathological complete response (p = 0.004, <0.001, and 0.001). A secondary analysis including only patients who received ≥1 cycle of FOLFOX still showed differences in survival between study groups (p = 0.03).

Limitations: The trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients.

Conclusions: Adding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739.
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http://dx.doi.org/10.1097/DCR.0000000000001207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130918PMC
October 2018

E3 Ubiquitin-Protein Ligase SMURF1 in the Nucleus Accumbens Mediates Cocaine Seeking.

Biol Psychiatry 2018 12 21;84(12):881-892. Epub 2018 Jul 21.

Department of Pharmacology and Toxicology, Program in Neuroscience, Research Institute on Addictions, The State University of New York at Buffalo, Buffalo, New York; Department of Psychology, The State University of New York at Buffalo, Buffalo, New York. Electronic address:

Background: Substance use disorder is a neurobiological disease characterized by episodes of relapse despite periods of withdrawal. It is thought that neuroadaptations in discrete brain areas of the reward pathway, including the nucleus accumbens, underlie these aberrant behaviors. The ubiquitin-proteasome system degrades proteins and has been shown to be involved in cocaine-induced plasticity, but the role of E3 ubiquitin ligases, which conjugate ubiquitin to substrates, is unknown. Here, we examined E3 ubiquitin-protein ligase SMURF1 (SMURF1) in neuroadaptations and relapse behavior during withdrawal following cocaine self-administration.

Methods: SMURF1 and downstream targets ras homolog gene family, member A (RhoA), SMAD1/5, and Runt-related transcript factor 2 were examined using Western blotting (n = 9-11/group), quantitative polymerase chain reaction (n = 6-9/group), co-immunoprecipitation (n = 9-11/group), tandem ubiquitin binding entities affinity purification (n = 5-6/group), and quantitative chromatin immunoprecipitation (n = 3-6/group) (2 rats/sample). Viral-mediated gene transfer (n = 7-12/group) and intra-accumbal microinjections (n = 9-10/group) were used to examine causal roles of SMURF1 and substrate RhoA, respectively, in cue-induced cocaine seeking.

Results: SMURF1 protein expression was decreased, while SMURF1 substrates RhoA and SMAD1/5 were increased, in the nucleus accumbens on withdrawal day 7, but not on withdrawal day 1, following cocaine self-administration. Viral-mediated gene transfer of Smurf1 or constitutive activation of RhoA attenuated cue-induced cocaine seeking, while catalytically inactive Smurf1 enhanced cocaine seeking. Furthermore, SMURF1-regulated, SMAD1/5-associated transcription factor Runt-related transcript factor 2 displayed increased binding at promoter regions of genes previously associated with cocaine-induced plasticity.

Conclusions: SMURF1 is a key mediator of neuroadaptations in the nucleus accumbens following cocaine exposure and mediates cue-induced cocaine seeking during withdrawal.
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http://dx.doi.org/10.1016/j.biopsych.2018.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260585PMC
December 2018

Nationwide Heterogeneity in Hospital-Specific Probabilities of Rectal Cancer Understaging and Its Effects on Outcomes.

Ann Surg Oncol 2018 Aug 30;25(8):2332-2339. Epub 2018 May 30.

Surgical Health Outcomes and Research Enterprise, University of Rochester Medical Center, Rochester, NY, USA.

Background: Rectal cancer patients who are understaged may not be offered the highest quality treatment modalities, which are based on an accurate assessment of preoperative staging. The objective of this study was to evaluate heterogeneity in the probability of being understaged at Commission on Cancer hospitals in the United States and to assess how this variation affects outcomes.

Methods: The 2006-2013 National Cancer Data Base was queried for clinical stage I-III rectal cancer patients who underwent resection. The initial clinical stage was compared with the "gold standard," pathological stage. A Bayesian multilevel logistic regression model was used to characterize variation in hospital-specific probabilities of being understaged (clinical stage < pathologic stage). Separate analyses assessed the impact of being understaged on positive circumferential resection margins (CRM), receipt of adjuvant chemotherapy, and 5-year overall survival.

Results: Among 12,684 patients who did not receive neoadjuvant chemoradiation and treated at 1176 hospitals, 3044 (24%) were understaged. After patient level risk-adjustment, a 24-fold difference in the probability of being understaged was observed between hospitals (range 3-72%, median = 15%). Understaging was independently associated with positive CRM [odds ratio (OR) 1.59, 95% confidence interval (CI) 1.39, 1.92] and receipt of adjuvant chemotherapy (OR 14.22, 95% CI 13.55, 18.88). Despite an increase in the delivery of systemic therapy after surgical resection, understaging was associated with worse survival (hazard ratio = 1.61, 95% CI 1.48, 1.95).

Conclusions: Deficiencies in high-quality rectal cancer management begin with incorrect clinical staging. The risk-adjusted probability of understaging varied widely between hospitals. This institutional failure to provide optimal oncological management at the start of care was associated with worse long-term survival.
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http://dx.doi.org/10.1245/s10434-018-6530-6DOI Listing
August 2018

Modified Pfannenstiel Open Approach as an Alternative to Laparoscopic Total Proctocolectomy and IPAA: Comparison of Short- and Long-term Outcomes and Quality of Life.

Dis Colon Rectum 2018 May;61(5):573-578

Division of Colorectal Surgery, University Hospitals, Cleveland, Ohio.

Background: A laparoscopic approach to total proctocolectomy with IPAA has been suggested to have better short-term outcomes and cosmesis, whereas open surgery by midline incision may result in shorter operative times. We hypothesized that a modified Pfannenstiel open approach would combine the advantages of both techniques.

Objective: The purpose of this study was to compare outcomes of open total proctocolectomy with IPAA using a modified Pfannenstiel incision versus those following the laparoscopic approach.

Design: This was a retrospective study comparing patients submitted to open IPAA using modified Pfannenstiel incision versus laparoscopy from 1998 to 2014.

Settings: The study was conducted at a high-volume tertiary referral center.

Patients: Among 1275 patients, 119 patients underwent the laparoscopic approach and 33 underwent the modified Pfannenstiel approach.

Main Outcome Measures: Short- and long-term outcomes were evaluated, and quality-of-life questionnaires were assessed.

Results: Patients who underwent the modified Pfannenstiel approach were younger, more often women, and had lower BMI and ASA classification compared with those who underwent laparoscopy. Surgical time was lower in Pfannenstiel, and no difference was observed in length of hospital stay. No difference was observed in postoperative complications, pouch failure rate, or quality of life. Patients were then matched 1:1 by diagnosis, sex, age (±5 y) and BMI (±5 kg/m). The Pfannenstiel approach still had a shorter surgical time. No difference was observed in the length of hospital stay, complications, pouch failure, or quality of life. In long-term follow-up, pouchitis symptoms occurred more frequently in Pfannenstiel (mean follow-up = 7.3 y), and seepage was more frequently observed in the laparoscopy group (mean follow-up = 4.2 y). These differences were not observed in matched patients.

Limitations: The study was limited by its retrospective design and inherent selection bias.

Conclusions: The modified Pfannenstiel approach provides equivalent short- and long-term outcomes and similar quality of life compared with laparoscopy but with a significantly shorter operative time. The modified Pfannenstiel approach to total proctocolectomy with IPAA may be the most efficient method in selected patients. See Video Abstract at http://links.lww.com/DCR/A562.
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http://dx.doi.org/10.1097/DCR.0000000000001052DOI Listing
May 2018

Evaluating the Current Status of Rectal Cancer Care in the US: Where We Stand at the Start of the Commission on Cancer's National Accreditation Program for Rectal Cancer.

J Am Coll Surg 2018 05 23;226(5):881-890. Epub 2018 Mar 23.

Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH. Electronic address:

Background: In an effort to improve the quality of rectal cancer care in the US, the American College of Surgeons Commission on Cancer has developed the National Accreditation Program for Rectal Cancer (NAPRC). We aimed to describe the current status of rectal cancer care before implementation of the NAPRC.

Study Design: The 2011-2014 National Cancer Database was queried for non-metastatic rectal cancer patients who underwent proctectomy. The NAPRC process measures evaluated included clinical staging completion, treatment starting fewer than 60 days from diagnosis, CEA level drawn before treatment, tumor regression grading, and margin assessment. The NAPRC performance measures included negative proximal, distal, and circumferential margins, and ≥12 lymph nodes harvested during resection.

Results: There were 39,068 patients identified (mean age 62 years, 61.6% male sex). In >85% of patients, clinical staging was completed, treatment was started within 60 days, and all tumor margins were assessed. Pretreatment CEA level (64.6% complete) was the process measure most often omitted. However, completion of all included process measures occurred in only 28.1% of patients. All pathologic margins were negative in 79.8% of patients and 73.2% of specimens reported ≥12 lymph nodes. Overall, 56.3% of patients achieved all performance measures. Patients treated at high-volume centers (>30 cases/year) had higher odds of meeting all performance measures (odds ratio 1.42; p < 0.001).

Conclusions: Overall, very few patients achieved all of the proposed quality measures for rectal cancer care. It will be important to re-evaluate these data after the implementation of the NAPRC.
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http://dx.doi.org/10.1016/j.jamcollsurg.2018.01.057DOI Listing
May 2018

Role of trace amine-associated receptor 1 in nicotine's behavioral and neurochemical effects.

Neuropsychopharmacology 2018 11 5;43(12):2435-2444. Epub 2018 Feb 5.

Department of Pharmacology and Toxicology; Program in Neuroscience, University at Buffalo, Buffalo, NY, 14214, USA.

Nicotine addiction and abuse remains a global health issue. To date, the fundamental neurobiological mechanism of nicotine addiction remains incompletely understood. Trace amine-associated receptor 1 (TAAR1) is thought to directly modulate dopaminergic system and are thought to be a neural substrate underlying addictive-like behaviors. We aimed to investigate the role of TAAR1 in nicotine addictive-like behaviors. TAAR1 expression after nicotine treatment was evaluated by western blotting. c-Fos immunofluorescence and in vivo fast-scan cyclic voltammetry were used to examine the activation of brain regions and dopamine release, respectively. We then thoroughly and systematically examined the role of TAAR1 in mediating nicotine-induced sensitization, nicotine discrimination, nicotine self-administration, nicotine demand curve, and the reinstatement of nicotine-seeking. Local pharmacological manipulation was conducted to determine the role of TAAR1 in the nucleus accumbens (NAcs) in the reinstatement of nicotine-seeking. We found that the expression of TAAR1 protein was selectively downregulated in the NAc, with no change in either dorsal striatum or prefrontal cortex. TAAR1 activation was sufficient to block nicotine-induced c-Fos expression in the NAc, while also reducing nicotine-induced dopamine release in the NAc. Systemic administration of TAAR1 agonists attenuated the expression and development of nicotine-induced sensitization, nicotine self-administration, the reinstatement of nicotine-seeking, and increased the elasticity of nicotine demand curve, while intra-NAc infusions of a TAAR1 agonist was sufficient to attenuate nicotine reinstatement. Moreover, TAAR1-knockout rats showed augmented cue-induced and drug-induced reinstatement of nicotine-seeking. These results indicated that modulation of TAAR1 activity regulates nicotine addictive-like behaviors and TAAR1 represents a novel target towards the treatment of nicotine addiction.
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http://dx.doi.org/10.1038/s41386-018-0017-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180004PMC
November 2018

Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence.

Neuron 2017 12;96(6):1327-1341.e6

Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Altered brain energy homeostasis is a key adaptation occurring in the cocaine-addicted brain, but the effect of cocaine on the fundamental source of energy, mitochondria, is unknown. We demonstrate an increase of dynamin-related protein-1 (Drp1), the mitochondrial fission mediator, in nucleus accumbens (NAc) after repeated cocaine exposure and in cocaine-dependent individuals. Mdivi-1, a demonstrated fission inhibitor, blunts cocaine seeking and locomotor sensitization, while blocking c-Fos induction and excitatory input onto dopamine receptor-1 (D1) containing NAc medium spiny neurons (MSNs). Drp1 and fission promoting Drp1 are increased in D1-MSNs, consistent with increased smaller mitochondria in D1-MSN dendrites after repeated cocaine. Knockdown of Drp1 in D1-MSNs blocks drug seeking after cocaine self-administration, while enhancing the fission promoting Drp1 enhances seeking after long-term abstinence from cocaine. We demonstrate a role for altered mitochondrial fission in the NAc, during early cocaine abstinence, suggesting potential therapeutic treatment of disrupting mitochondrial fission in cocaine addiction.
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http://dx.doi.org/10.1016/j.neuron.2017.11.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747376PMC
December 2017

A Novel Role for Oligodendrocyte Precursor Cells (OPCs) and Sox10 in Mediating Cellular and Behavioral Responses to Heroin.

Neuropsychopharmacology 2018 05 20;43(6):1385-1394. Epub 2017 Dec 20.

Program in Neuroscience, Department of Pharmacology and Toxicology, The State University of New York at Buffalo, Buffalo, NY, USA.

Opiate abuse and addiction have become a worldwide epidemic with great societal and financial burdens, highlighting a critical need to understand the neurobiology of opiate addiction. Although several studies have focused on drug-dependent changes in neurons, the role of glia in opiate addiction remains largely unstudied. RNA sequencing pathway analysis from the prefrontal cortex (PFC) of male rats revealed changes in several genes associated with oligodendrocyte differentiation and maturation following heroin self-administration. Among these genes changed was Sox10, which is regulated, in part, by the chromatin remodeler BRG1/SMARCA4. To directly test the functional role of Sox10 in mediating heroin-induced behavioral plasticity, we selectively overexpressed Sox10 and BRG1 in the PFC. Overexpression of either Sox10 or BRG1 decreased the motivation to obtain heroin infusions in a progressive ratio test without altering the acquisition or maintenance of heroin self-administration. These data demonstrate a critical, and perhaps compensatory, role of Sox10 and BRG1 in oligodendrocytes in regulating the motivation for heroin.
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http://dx.doi.org/10.1038/npp.2017.303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916371PMC
May 2018

Improving rectal cancer outcomes through advocacy, education, and research: The OSTRiCh Consortium and the new NAPRC.

Bull Am Coll Surg 2016 11;101(11):45-6

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November 2016

Long-term Outcomes After Continent Ileostomy Creation in Patients With Crohn's Disease.

Dis Colon Rectum 2017 May;60(5):508-513

Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio.

Background: Patients with Crohn's disease have a higher failure rate after ileal pouch surgery compared with their counterparts with ulcerative colitis.

Objective: We hypothesized that risk of continent ileostomy failure can be stratified based on the timing of Crohn's disease diagnosis and aimed to assess long-term outcomes.

Design: This was a retrospective cohort study.

Settings: The investigation took place in a high-volume, specialized colorectal surgery department.

Patients: Patients with Crohn's disease who underwent continent ileostomy surgery between 1978 and 2013 were evaluated.

Main Outcome Measures: Functional outcomes, postoperative complications, requirement of revision surgery, and continent ileostomy failure were analyzed.

Results: There were 48 patients (14 male patients) with a median age of 33 years at the time of continent ileostomy creation. Crohn's disease diagnosis was before continent ileostomy (intentional) in 15 or made in a delayed fashion at a median 4 years after continent ileostomy in 33 patients. Median follow-up was 19 years (range, 1-33 y) after index continent ileostomy creation. Major and minor revisions were performed in 40 (83%) and 13 patients (27%). Complications were fistula (n = 20), pouchitis (n = 16), valve slippage (n = 15), hernia (n = 9), afferent limb stricture (n = 9), difficult intubation (n = 8), incontinence (n = 7), bowel obstruction (n = 7), valve stricture (n = 5), leakage (n = 4), bleeding (n = 3), and valve prolapse (n = 3). Median Cleveland global quality-of-life score was 0.8. Continent ileostomy failure occurred in 22 patients (46%). Based on Kaplan-Meier estimates, continent ileostomy survival was 48 % (95% CI, 33%-63%) at 20 years. Continent ileostomy failure was similar regardless of timing of diagnosis of Crohn's disease (p = 0.533).

Limitations: This study was limited by its retrospective and nonrandomized nature.

Conclusions: Outcomes of continent ileostomy in patients with Crohn's disease are poor, regardless of the timing of diagnosis. Very careful consideration should be given by both the surgeon and the patient before undertaking this procedure in patients with Crohn's disease. See Video Abstract at http://links.lww.com/DCR/A327.
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http://dx.doi.org/10.1097/DCR.0000000000000815DOI Listing
May 2017

Activin A is increased in the nucleus accumbens following a cocaine binge.

Sci Rep 2017 03 8;7:43658. Epub 2017 Mar 8.

Department of Pharmacology and Toxicology, Research Institute on Addictions, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY, USA.

Drug addiction is a long-lasting disease characterized by compulsive drug intake mediated in part by neuronal and biological adaptations in key brain areas, such as the nucleus accumbens (NAc). While we previously demonstrated involvement of the activin 2a receptor in drug taking, the role of its ligand, activin A, in cocaine relapse is unknown. Activin A levels in the NAc were assessed via ELISA and immunohistochemistry (in neurons, astrocytes, and microglia) following a cocaine binge paradigm. Cocaine exposure significantly increased the levels of activin A in the NAc of animals that had self-administered cocaine prior to the 14-day withdrawal compared with levels in saline controls. This was accompanied by an increase in the proportion of IBA1 microglia in the NAc that were immunopositive for activin A. In contrast, the proportions of NeuN neurons and GFAP astrocytes that were immunopositive for activin A remained unaltered. In conclusion, these data suggest that increased secretion of activin A, particularly from microglia, in the NAc represents a novel potential target for the treatment of cocaine relapse.
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http://dx.doi.org/10.1038/srep43658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341561PMC
March 2017

WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine.

Proc Natl Acad Sci U S A 2017 02 23;114(6):1395-1400. Epub 2017 Jan 23.

Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;

Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activity-mediated feedback regulation of glutamatergic synapses.
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http://dx.doi.org/10.1073/pnas.1621185114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307471PMC
February 2017

Incidence, Patterns, and Predictors of Locoregional Recurrence in Colon Cancer.

Ann Surg Oncol 2017 Apr 3;24(4):1093-1099. Epub 2016 Nov 3.

Department of Colorectal Surgery, Cleveland Clinic, Digestive Disease Institute, Cleveland, OH, USA.

Background: Locoregional recurrence (LR) in colon cancer is uncommon but often incurable, while the factors associated with it are unclear. The purpose of this study was to identify patterns and predictors of LR after curative resection for colon cancer.

Methods: All patients who underwent colon cancer resection with curative intent between 1994 and 2008 at a tertiary referral center were identified from a prospectively maintained institutional database. The association of LR with clinicopathologic and treatment characteristics was determined using univariable and multivariable analyses.

Results: A total of 1397 patients were included with a median follow-up of 7.8 years; 635 (45%) were female, and the median age was 69 years. LR was detected in 61 (4.4%) patients. Median time to LR was 21 months. On multivariable analysis, the independent predictors of LR were disease stage [hazard ratio (HR) for Stage II 4.6, 95% confidence interval (CI) 1.05-19.9, HR for Stage III 10.8, 95% CI 2.6-45.8], bowel obstruction (HR 3.8, 95% CI 1.9-7.4), margin involvement (HR 4.1, 95% CI 1.9-8.6), lymphovascular invasion (HR 1.9, 95% CI 1.06-3.5), and local tumor invasion (fixation to another structure, perforation, or presence of associated fistula, HR 2.2, 95% CI 1.1-4.5). Adjuvant chemotherapy was not associated with reduced LR in patients with either Stage II or Stage III tumors.

Conclusions: Adherence to oncologic surgical principles in colon cancer resection results in low rates of LR, which is associated with tumor-dependent factors. Recognition of these factors can help to determine appropriate postoperative surveillance.
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http://dx.doi.org/10.1245/s10434-016-5643-zDOI Listing
April 2017

The Disproportionate Effect of Perioperative Complications on Mortality within 1 Year After Colorectal Cancer Resection in Octogenarians.

Ann Surg Oncol 2016 12 26;23(13):4293-4301. Epub 2016 Jul 26.

Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA.

Purpose: Risks and benefits of colorectal cancer resection in octogenarians are not clearly defined. This study aimed to assess the relationship between morbidity and mortality within 1 year after colorectal cancer resection in octogenarians compared with other age groups.

Methods: A single-institution, prospectively maintained database was queried to identify patients with sporadic, pathological stages I-III colorectal adenocarcinoma, electively undergoing radical resection with curative intent between 2000 and 2012. Patients were divided into three age groups: 'octogenarians' if ≥80 years of age; 'intermediate' if ≥65 and <80 years of age; and 'younger' if <65 years of age.

Results: Overall, 2485 patients fulfilled the inclusion criteria-326 in the octogenarian age group, 949 in the intermediate age group, and 1210 in the younger age group. Postoperative morbidity disproportionally increased 1-year mortality in octogenarians when compared with the younger age group (37 vs. 6.5 %; p < 0.001). Anastomotic leak, abdominopelvic abscess, reoperation, and readmission rates were comparable among different age groups, but were associated with a disproportionate risk of 1-year mortality in octogenarians (67, 43, 33, and 41 %, respectively). Multivariate analysis indicated that older age and postoperative complications were the only two independent variables associated with 30- and 90-day mortality. Besides these, American Society of Anesthesiologists (ASA) and pathological stage III were additional independent variables associated with 1-year mortality. An interaction test confirmed that age and postoperative complications were independent variables, with additive effect on 30-day, 90-day, and 1-year mortality.

Conclusions: Age plays an important and independent role in affecting mortality when complications occur following surgery for colorectal cancer. The full magnitude of postoperative risks should be taken into consideration when discussing colorectal cancer surgery in octogenarians.
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http://dx.doi.org/10.1245/s10434-016-5445-3DOI Listing
December 2016