Publications by authors named "Jennifer Heim"

17 Publications

  • Page 1 of 1

Pubic Symphysis Separation and Regression in Vaginal versus Cesarean Delivery.

J Obstet Gynaecol Can 2021 Aug 18. Epub 2021 Aug 18.

Department of Orthopaedic Surgery, Regions Hospital, St. Paul, MN; Department of Obstetrics, Gynecology and Women's Health, Health partners, St. Paul, MN. Electronic address:

Objective: To quantify the association of pubic symphysis separation with mode of delivery and follow the resolution of this physiologic separation in the postpartum period.

Methods: Prospective observational cohort study that recruited two cohorts of primiparous women: those undergoing vaginal and cesarean delivery (45 and 46 patients, respectively). Chart review collected intrapartum factors. Patients were followed with serial anterior-posterior radiographs within 48 hours of delivery and at 6, 12, and 24 weeks postpartum, to evaluate the extent of pubic symphysis separation. Differences between the two cohorts in intrapartum factors were assesses as was pubic symphysis separation at each time point.

Results: Mean age of women was 25.8 (SD 5.1) years, and 56% were White. Mean birth weight was 3.5 (SD 0.52) kg. Mean immediate postpartum pubic symphysis separation was 7.6 (SD 2.2) mm and did not differ between groups, at 7.18 mm for vaginal delivery versus 8.04 mm for cesarean delivery (CD; P = 0.08). Pubic symphysis separation was not significantly different for CD with and without labour. Black race and obesity were associated with increased pubic symphysis separation. No intrapartum events were related to extent of separation. Normalization of pregnancy pubic symphysis separation to 4-5 mm occurred by 6 weeks postpartum. Separation of >10mm and <15mm occurred in 10 of the 91 women and occurred after vaginal and cesarean delivery. The widest pubic symphysis separation was observed in 3 patients after vaginal delivery.

Conclusion: Physiological pubic symphysis separation occurs during pregnancy and regresses postpartum with minimal effects from labour and delivery. Cesarean delivery does not prevent physiological pubic symphysis separation.
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http://dx.doi.org/10.1016/j.jogc.2021.07.015DOI Listing
August 2021

Mutation in Leads to Hypotonic Cerebral Palsy, Autism, Epilepsy, and Intellectual Disability.

Neurol Genet 2021 Aug 29;7(4):e602. Epub 2021 Jul 29.

Pediatric Movement Disorders Program (S.A.L., S.B., J.H., J.L., S.R.P.-L., M.C.K.), Barrow Neurological Institute, Phoenix Children's Hospital; Departments of Child Health, Neurology, Genetics and Cellular & Molecular Medicine (S.A.L., S.B., J.L., S.R.P.-L., M.C.K.), University of Arizona College of Medicine; Division of Neuroradiology (P.C.), Department of Radiology, Phoenix Children's Hospital, AZ; Programs in Neuroscience and Molecular & Cellular Biology (A.H., A.M.), Arizona State University, Tempe; and Department of Genetics (S.C.J.), Washington University, St. Louis, MO; Department of Genetics (K.B.), Yale University, New Haven, CT.

Objective: To determine whether mutations reported for can cause mixed neurodevelopmental disorders, we performed both functional studies on variant pathogenicity and ZDHHC15 function in animal models.

Methods: We examined protein function of 4 identified variants in ZDHHC15 in a yeast complementation assay and locomotor defects of loss-of-function genotypes in a model.

Results: Although we assessed multiple patient variants, only 1 (p.H158R) affected protein function. We report a patient with a diagnosis of hypotonic cerebral palsy, autism, epilepsy, and intellectual disability associated with this bona fide damaging X-linked variant. Features include tall forehead with mild brachycephaly, down-slanting palpebral fissures, large ears, long face, facial muscle hypotonia, high-arched palate with dental crowding, and arachnodactyly. The patient had mild diminished cerebral volume, with left-sided T2/FLAIR hyperintense periatrial ovoid lesion. We found that loss-of-function mutations in orthologs of this gene cause flight and coordinated movement defects in .

Conclusions: Our findings support a functional expansion of this gene to a role in motor dysfunction. Although mutations represent a rare cause of neurodevelopmental disability, candidate variants need to be carefully assessed before pathogenicity can be determined.
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http://dx.doi.org/10.1212/NXG.0000000000000602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323736PMC
August 2021

Opsoclonus-myoclonus-ataxia syndrome in children.

J Neurol 2021 Mar 29. Epub 2021 Mar 29.

Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children's Hospital, 1919 E Thomas Rd, Phoenix, AZ, 85016, USA.

Opsoclonus-myoclonus-ataxia syndrome is a rare neuroimmunologic disorder typically presenting in previously healthy infants and toddlers. It is characterized by a clinical triad of (1) erratic saccadic intrusions; (2) myoclonus and/or ataxia; (3) behavioral features, typified by developmental plateauing, irritability and insomnia. About half of cases are associated with an underlying neuroblastoma and diagnostic imaging is essential once OMAS is suspected. A thorough workup, including serum, urine, and cerebrospinal fluid studies is critical to identify underlying biomarkers of OMAS itself or neuroblastoma. Historically, many children had relatively poor long-term outcomes, with residual neurologic and/or neuropsychiatry sequelae typical. More recent concepts have emphasized combined immunotherapy regimens that offer hope for better outcomes in children with this remarkable, challenging disease.
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http://dx.doi.org/10.1007/s00415-021-10536-3DOI Listing
March 2021

Cataplexy in Patients Harboring the KCNMA1 p.N999S Mutation.

Mov Disord Clin Pract 2020 Oct 21;7(7):861-862. Epub 2020 Aug 21.

Pediatric Movement Disorders Program, Barrow Neurological Institute Phoenix Children's Hospital Phoenix Arizona USA.

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http://dx.doi.org/10.1002/mdc3.13024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533972PMC
October 2020

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

Nat Genet 2020 10 28;52(10):1046-1056. Epub 2020 Sep 28.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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http://dx.doi.org/10.1038/s41588-020-0695-1DOI Listing
October 2020

Recessivity of pyrethroid resistance and limited interspecies hybridization across Hyalella clades supports rapid and independent origins of resistance.

Environ Pollut 2020 Nov 26;266(Pt 1):115074. Epub 2020 Jun 26.

Center for Fisheries, Aquaculture, and Aquatic Sciences, Department of Zoology, Southern Illinois University Carbondale, IL, USA. Electronic address:

Several populations of the amphipod, Hyalella azteca, have developed resistance to pyrethroid insecticides due to non-target exposure, but the dominance of the resistance trait is unknown. The current study investigated the dominance level of point mutations in natural populations of insecticide-resistant H. azteca and determined whether H. azteca from different clades with and without resistant alleles can hybridize and produce viable offspring. A parent generation (P) of non-resistant homozygous wild type H. azteca was crossbred with pyrethroid-resistant homozygous mutant animals and the tolerance of the filial 1 (F) generation to the pyrethroid insecticide, permethrin, was measured. Then the genotypes of the F generation was examined to assure heterozygosity. The resistant parents had permethrin LC values that ranged from 52 to 82 times higher than the non-resistant animals and both crossbreeding experiments produced heterozygous hybrid offspring that had LC values similar to the non-resistant H. azteca parent. Dominance levels calculated for each of the crosses showed values close to 0, confirming that the L925I and L925V mutations were completely recessive. The lack of reproduction by hybrids of the C x D breeding confirmed that these clades are reproductively isolated and therefore introgression of adaptive alleles across these clades is unlikely. Potential evolutionary consequences of this selection include development of population bottlenecks, which may arise leading to fitness costs and reduced genetic diversity of H. azteca.
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http://dx.doi.org/10.1016/j.envpol.2020.115074DOI Listing
November 2020

Biallelic mutations of TBC1D24 in exercise-induced paroxysmal dystonia.

Mov Disord 2020 02 10;35(2):372-373. Epub 2020 Jan 10.

Molecular Neurosciences, Developmental Neurosciences, University College London (UCL) Great Ormond Street Institute of Child Health, London, United Kingdom.

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http://dx.doi.org/10.1002/mds.27981DOI Listing
February 2020

Non-human Papillomavirus Cervical Mucinous Adenocarcinoma in a Phenotypic Male with Congenital Adrenal Hyperplasia.

Cureus 2018 Nov 18;10(11):e3607. Epub 2018 Nov 18.

Obstetrics and Gynecology, University of Minnesota, Minneapolis, USA.

A majority of cervical cancers are caused by human papillomavirus (HPV); however, HPV-negative cervical cancers exist and, though rare, are more aggressive. No prior reports examine HPV-negative cancer of the cervix in a female pseudohermaphrodite with congenital adrenal hyperplasia (CAH). This is a case of a 78-year-old phenotypic male with hypospadias and absent testicles who presented with urinary retention and urosepsis. He was diagnosed with a pelvic mass on imaging and with a female mosaic karyotype (45,X/47,XXX/46 XX). He was taken to the operating room and found to have a rare form of HPV-negative cervical cancer: gastric-type adenocarcinoma (GAS). This study examines the presentation, management, and outcome of a GAS cervical cancer in a patient with a known lack of HPV exposure secondary to the unique anatomy of female pseudohermaphrodism.
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http://dx.doi.org/10.7759/cureus.3607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338395PMC
November 2018

Genomic Analyses of Acute Flaccid Myelitis Cases among a Cluster in Arizona Provide Further Evidence of Enterovirus D68 Role.

mBio 2019 01 22;10(1). Epub 2019 Jan 22.

Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA

Enteroviruses are a common cause of respiratory and gastrointestinal illness, and multiple subtypes, including poliovirus, can cause neurologic disease. In recent years, enterovirus D68 (EV-D68) has been associated with serious neurologic illnesses, including acute flaccid myelitis (AFM), frequently preceded by respiratory disease. A cluster of 11 suspect cases of pediatric AFM was identified in September 2016 in Phoenix, AZ. To determine if these cases were associated with EV-D68, we performed multiple genomic analyses of nasopharyngeal (NP) swabs and cerebrospinal fluid (CSF) material from the patients, including real-time PCR and amplicon sequencing targeting the EV-D68 VP1 gene and unbiased microbiome and metagenomic sequencing. Four of the 11 patients were classified as confirmed cases of AFM, and an additional case was classified as probable AFM. Real-time PCR and amplicon sequencing detected EV-D68 virus RNA in the three AFM patients from which NP swabs were collected, as well as in a fourth patient diagnosed with acute disseminated encephalomyelitis, a disease that commonly follows bacterial or viral infections, including enterovirus. No other obvious etiological causes for AFM were identified by 16S or RNA and DNA metagenomic sequencing in these cases, strengthening the likelihood that EV-D68 is an etiological factor. Herpes simplex viral DNA was detected in the CSF of the fourth case of AFM and in one additional suspect case from the cluster. Multiple genomic techniques, such as those described here, can be used to diagnose patients with suspected EV-D68 respiratory illness, to aid in AFM diagnosis, and for future EV-D68 surveillance and epidemiology. Enteroviruses frequently result in respiratory and gastrointestinal illness; however, multiple subtypes, including poliovirus, can cause severe neurologic disease. Recent biennial increases (i.e., 2014, 2016, and 2018) in cases of non-polio acute flaccid paralysis have led to speculations that other enteroviruses, specifically enterovirus D68 (EV-D68), are emerging to fill the niche that was left from poliovirus eradication. A cluster of 11 suspect cases of pediatric acute flaccid myelitis (AFM) was identified in 2016 in Phoenix, AZ. Multiple genomic analyses identified the presence of EV-D68 in the majority of clinical AFM cases. Beyond limited detection of herpesvirus, no other likely etiologies were found in the cluster. These findings strengthen the likelihood that EV-D68 is a cause of AFM and show that the rapid molecular assays developed for this study are useful for investigations of AFM and EV-D68.
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http://dx.doi.org/10.1128/mBio.02262-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343034PMC
January 2019

Salivary beta amyloid protein levels are detectable and differentiate patients with Alzheimer's disease dementia from normal controls: preliminary findings.

BMC Neurol 2018 Sep 26;18(1):155. Epub 2018 Sep 26.

Aurin Biotech, Vancouver, BC, USA.

Background: Peripheral diagnostics for Alzheimer's disease (AD) continue to be developed. Diagnostics capable of detecting AD before the onset of symptoms are particularly desirable, and, given the fact that early detection is imperative for alleviating long-term symptoms of the disease, methods which enable detection in the earliest stages are urgently needed. Saliva testing is non-invasive, and saliva is easy to acquire. A simple, non-invasive saliva test can potentially be used as an adjunct to diagnose AD during its earliest stages.

Methods: Salivary levels of beta amyloid 42 (Aβ) were quantitated with enzyme-linked immunosorbent-type assays. Fifteen AD patients (7 men, mean age 77.8 ± 1.8 years, mean Mini-Mental State Examination [MMSE] score 19.0 ± 1.3) and 7 normal controls (2 men, mean age 60.4 ± 4.7 years, mean MMSE 29.0 ± 0.4) were enrolled.

Results: Salivary Aβ levels were significantly higher in AD patients than in controls (51.7 ± 1.6 pg/mL for AD and 21.1 ± 0.3 pg/mL for controls, p < 0.001). Based on these results, saliva testing appears to be a promising method for detecting AD during its critical early stages.
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http://dx.doi.org/10.1186/s12883-018-1160-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158897PMC
September 2018

Environmental risk assessment of biocidal products: identification of relevant components and reliability of a component-based mixture assessment.

Environ Sci Eur 2018 18;30(1). Epub 2018 Jan 18.

German Environment Agency, Woerlitzer Platz 1, 06844 Dessau-Roßlau, Germany.

Background: Biocidal products are mixtures of one or more active substances (a.s.) and a broad range of formulation additives. There is regulatory guidance currently under development that will specify how the combined effects of the a.s. and any relevant formulation additives shall be considered in the environmental risk assessment of biocidal products. The default option is a component-based approach (CBA) by which the toxicity of the product is predicted from the toxicity of 'relevant' components using concentration addition. Hence, unequivocal and practicable criteria are required for identifying the 'relevant' components to ensure protectiveness of the CBA, while avoiding unnecessary workload resulting from including by default components that do not significantly contribute to the product toxicity. The present study evaluated a set of different criteria for identifying 'relevant' components using confidential information on the composition of 21 wood preservative products. Theoretical approaches were complemented by experimentally testing the aquatic toxicity of seven selected products.

Results: For three of the seven tested products, the toxicity was underestimated for the most sensitive endpoint (green algae) by more than factor 2 if only the a.s. were considered in the CBA. This illustrated the necessity of including at least some additives along with the a.s. Considering additives that were deemed 'relevant' by the tentatively established criteria reduced the underestimation of toxicity for two of the three products. A lack of data for one specific additive was identified as the most likely reason for the remaining toxicity underestimation of the third product. In three other products, toxicity was overestimated by more than factor 2, while prediction and observation fitted well for the seventh product. Considering all additives in the prediction increased only the degree of overestimation.

Conclusions: Supported by theoretical calculations and experimental verifications, the present study developed criteria for the identification of CBA-relevant components in a biocidal product. These criteria are based on existing criteria stated in the regulation for classification, labelling and packaging of substances. The CBA was found sufficiently protective and reliable for the tested products when applying the here recommended criteria. The lack of available aquatic toxicity data for some of the identified relevant components was the main reason for underestimation of product toxicity.
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http://dx.doi.org/10.1186/s12302-017-0130-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773622PMC
January 2018

Are there fitness costs of adaptive pyrethroid resistance in the amphipod, Hyalella azteca?

Environ Pollut 2018 Apr 20;235:39-46. Epub 2017 Dec 20.

Center for Fisheries, Aquaculture and Aquatic Sciences and Department of Zoology, Southern Illinois University, Carbondale, IL 62901, USA. Electronic address:

Pyrethroid-resistant Hyalella azteca with voltage-gated sodium channel mutations have been identified at multiple locations throughout California. In December 2013, H. azteca were collected from Mosher Slough in Stockton, CA, USA, a site with reported pyrethroid (primarily bifenthrin and cyfluthrin) sediment concentrations approximately twice the 10-d LC50 for laboratory-cultured H. azteca. These H. azteca were shipped to Southern Illinois University Carbondale and have been maintained in pyrethroid-free culture since collection. Even after 22 months in culture, resistant animals had approximately 53 times higher tolerance to permethrin than non-resistant laboratory-cultured H. azteca. Resistant animals held in culture also lacked the wild-type allele at the L925 locus, and had non-synonymous substitutions that resulted in either a leucine-isoleucine or leucine-valine substitution. Additionally, animals collected from the same site nearly three years later were again resistant to the pyrethroid permethrin. When resistant animals were compared to non-resistant animals, they showed lower reproductive capacity, lower upper thermal tolerance, and the data suggested greater sensitivity to, 4, 4'-dichlorodiphenyltrichloroethane (DDT), copper (II) sulfate, and sodium chloride. Further testing of the greater heat and sodium chloride sensitivity of the resistant animals showed these effects to be unrelated to clade association. Fitness costs associated with resistance to pyrethroids are well documented in pest species (including mosquitoes, peach-potato aphids, and codling moths) and we believe that H. azteca collected from Mosher Slough also have fitness costs associated with the developed resistance.
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http://dx.doi.org/10.1016/j.envpol.2017.12.043DOI Listing
April 2018

Evaluation of the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator in Gynecologic Oncology Patients Undergoing Minimally Invasive Surgery.

J Minim Invasive Gynecol 2017 01 24;24(1):48-54. Epub 2016 Oct 24.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, Minnesota.

Study Objective: To evaluate the ability of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) surgical risk calculator to predict discharge to postacute care and perioperative complications in gynecologic oncology patients undergoing minimally invasive surgery (MIS).

Design: A retrospective chart review (Canadian Task Force classification II-1).

Setting: A university hospital.

Patients: All patients undergoing MIS on the gynecologic oncology service from January 1, 2009, to December 30, 2013.

Interventions: Surgical procedures were reviewed, and appropriate Common Procedural Terminology codes were assigned. Twenty-one preoperative risk factors were abstracted from the chart and entered into the ACS NSQIP surgical risk calculator. The predicted risk of discharge to postacute care and 8 additional postoperative complications were calculated and recorded. Actual postoperative complications were abstracted from the medical record. The association between the calculated risk and the actual outcome was determined using logistic regression. The ability of the calculator to accurately predict a particular event was assessed using the c-statistic and Brier score.

Measurements And Main Results: Of the 876 patients reviewed, a majority underwent hysterectomy (71.6%), with almost half of those patients undergoing additional cancer staging procedures (34.8%). Although the calculator was a poor predictor of postoperative complications, it was a strong predictor for discharge to postacute care (c-statistic = 0.91, Brier score = 0.02) with an odds ratio of 2.31 (95% confidence interval, 1.65-3.25; p < .0001).

Conclusion: The ACS NSQIP surgical risk calculator does not accurately predict postoperative complications or length of stay in gynecologic oncology patients undergoing MIS. Although it was a strong predictor of need for discharge to postacute care, it vastly overestimated the number of patients requiring this service. Therefore, the calculator's risk score for discharge to postacute care may be considered during preoperative counseling but should not be a predictor of whether or not the patient should proceed with surgery.
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http://dx.doi.org/10.1016/j.jmig.2016.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614862PMC
January 2017

Do pyrethroid-resistant Hyalella azteca have greater bioaccumulation potential compared to non-resistant populations? Implications for bioaccumulation in fish.

Environ Pollut 2017 Jan 15;220(Pt A):375-382. Epub 2016 Oct 15.

Center for Fisheries, Aquaculture and Aquatic Sciences and Department of Zoology, Southern Illinois University, Carbondale, IL 62901, USA. Electronic address:

The recent discovery of pyrethroid-resistant Hyalella azteca populations in California, USA suggests there has been significant exposure of aquatic organisms to these terrestrially-applied insecticides. Since resistant organisms are able to survive in relatively contaminated habitats they may experience greater pyrethroid bioaccumulation, subsequently increasing the risk of those compounds transferring to predators. These issues were evaluated in the current study following toxicity tests in water with permethrin which showed the 96-h LC50 of resistant H. azteca (1670 ng L) was 53 times higher than that of non-resistant H. azteca (31.2 ng L). Bioaccumulation was compared between resistant and non-resistant H. azteca by exposing both populations to permethrin in water and then measuring the tissue concentrations attained. Our results indicate that resistant and non-resistant H. azteca have similar potential to bioaccumulate pyrethroids at the same exposure concentration. However, significantly greater bioaccumulation occurs in resistant H. azteca at exposure concentrations non-resistant organisms cannot survive. To assess the risk of pyrethroid trophic transfer, permethrin-dosed resistant H. azteca were fed to fathead minnows (Pimephales promelas) for four days, after which bioaccumulation of permethrin and its biotransformation products in fish tissues were measured. There were detectable concentrations of permethrin in fish tissues after they consumed dosed resistant H. azteca. These results show that bioaccumulation potential is greater in organisms with pyrethroid resistance and this increases the risk of trophic transfer when consumed by a predator. The implications of this study extend to individual fitness, populations and food webs.
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http://dx.doi.org/10.1016/j.envpol.2016.09.073DOI Listing
January 2017

RNA-seq Identification of RACGAP1 as a Metastatic Driver in Uterine Carcinosarcoma.

Clin Cancer Res 2016 Sep 27;22(18):4676-86. Epub 2016 Apr 27.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York. Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York.

Purpose: Uterine carcinosarcoma is a rare aggressive malignancy frequently presenting at advanced stage of disease with extrauterine metastases. Median survival is less than 2 years due to high relapse rates after surgery and poor response to chemotherapy or radiotherapy. The goal of this study was to identify novel therapeutic targets.

Experimental Design: We applied RNA-seq analysis to prospectively collected uterine carcinosarcoma tumor samples from patients undergoing primary surgical resection and for comparison, normal endometrial tissues from postmenopausal women undergoing hysterectomy for benign indications. Functional assays were done in primary carcinosarcoma cell lines developed from patients and in established cell lines, as well as a cell line-derived xenograft model. Validation was done by analysis of an independent cohort of patients with uterine carcinosarcoma from The Cancer Genome Atlas (TCGA).

Results: Rac GTPase-activating protein 1 (RACGAP1) was identified to be highly upregulated in uterine carcinosarcoma. Functional assays showed that RACGAP1 mediates motility and invasion via regulation of STAT3 phosphorylation and survivin expression. RACGAP1 depletion or survivin inhibition abrogated motility and invasiveness of carcinosarcoma cells, while RACGAP1 overexpression conferred invasiveness to endometrial adenocarcinoma cells. In the TCGA cohort, RACGAP1 expression correlated with survivin expression and extrauterine spread of disease.

Conclusions: The RACGAP1-STAT3-survivin signaling pathway is required for the invasive phenotype of uterine carcinosarcoma and is a newly identified therapeutic target in this lethal disease. Clin Cancer Res; 22(18); 4676-86. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2116DOI Listing
September 2016

The alpha subunit of the G protein G13 regulates activity of one or more Gli transcription factors independently of smoothened.

J Biol Chem 2011 Sep 11;286(35):30714-30722. Epub 2011 Jul 11.

Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104. Electronic address:

Smoothened (Smo) is a seven-transmembrane (7-TM) receptor that is essential to most actions of the Hedgehog family of morphogens. We found previously that Smo couples to members of the G(i) family of heterotrimeric G proteins, which in some cases are integral although alone insufficient in the activation of Gli transcription factors through Hedgehog signaling. In response to a report that the G(12/13) family is relevant to Hedgehog signaling as well, we re-evaluated the coupling of Smo to one member of this family, G(13), and investigated the capacity of this and other G proteins to activate one or more of forms of Gli. We found no evidence that Smo couples directly to G(13). We found nonetheless that Gα(13) and to some extent Gα(q) and Gα(12) are able to effect activation of Gli(s). This capacity is realized in some cells, e.g. C3H10T1/2, MC3T3, and pancreatic cancer cells, but not all cells. The mechanism employed is distinct from that achieved through canonical Hedgehog signaling, as the activation does not involve autocrine signaling or in any other way require active Smo and does not necessarily involve enhanced transcription of Gli1. The activation by Gα(13) can be replicated through a G(q)/G(12/13)-coupled receptor, CCK(A), and is attenuated by inhibitors of p38 mitogen-activated protein kinase and Tec tyrosine kinases. We posit that G proteins, and perhaps G(13) in particular, provide access to Gli that is independent of Smo and that they thus establish a basis for control of at least some forms of Gli-mediated transcription apart from Hedgehogs.
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http://dx.doi.org/10.1074/jbc.M111.219279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162432PMC
September 2011
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