Publications by authors named "Cynthia Jackson"

27 Publications

  • Page 1 of 1

SHP2 regulates the development of intestinal epithelium by modifying OSTERIX crypt stem cell self-renewal and proliferation.

FASEB J 2021 Jan 9;35(1):e21106. Epub 2020 Nov 9.

Department of Orthopedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, RI, USA.

The protein tyrosine phosphatase SHP2, encoded by PTPN11, is ubiquitously expressed and essential for the development and/or maintenance of multiple tissues and organs. SHP2 is involved in gastrointestinal (GI) epithelium development and homeostasis, but the underlying mechanisms remain elusive. While studying SHP2's role in skeletal development, we made osteoblast-specific SHP2 deficient mice using Osterix (Osx)-Cre as a driver to excise Ptpn11 floxed alleles. Phenotypic characterization of these SHP2 mutants unexpectedly revealed a critical role of SHP2 in GI biology. Mice lacking SHP2 in Osx cells developed a fatal GI pathology with dramatic villus hypoplasia. OSTERIX, an OB-specific zinc finger-containing transcription factor is for the first time found to be expressed in GI crypt cells, and SHP2 expression in the crypt Osx+ cells is critical for self-renewal and proliferation. Further, immunostaining revealed the colocalization of OSTERIX with OLFM4 and LGR5, two bona fide GI stem cell markers, at the crypt cells. Furthermore, OSTERIX expression is found to be associated with GI malignancies. Knockdown of SHP2 expression had no apparent influence on the relative numbers of enterocytes, goblet cells or Paneth cells. Given SHP2's key regulatory role in OB differentiation, our studies suggest that OSTERIX and SHP2 are indispensable for gut homeostasis, analogous to SOX9's dual role as a master regulator of cartilage and an important regulator of crypt stem cell biology. Our findings also provide a foundation for new avenues of inquiry into GI stem cell biology and of OSTERIX's therapeutic and diagnostic potential.
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http://dx.doi.org/10.1096/fj.202001091RDOI Listing
January 2021

Aggressive CD4/CD8 Double-Negative Primary Cutaneous T-Cell Lymphoma With Dural Invasion: A Rare Presentation of Mycosis Fungoides?

Am J Dermatopathol 2021 Jan;43(1):63-66

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI.

Abstract: Mycosis fungoides (MF) is primarily characterized by epidermotropic CD3+/CD4+/CD45RO+ memory T cells. CD4/CD8 double-negative MF is an uncommon variant with no presumed prognostic significance. Despite the variability in the clinical course and presentation of MF, most cases behave indolently. About 5% of patients, however, advance to stage IV with visceral organ involvement. Central nervous system metastasis in MF is rare with no known cases of direct central nervous system invasion by MF to date. We report an exceedingly rare locally aggressive case of CD4/CD8 double-negative MF with direct dural invasion and underline pertinent diagnostic challenges encountered in our case.
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http://dx.doi.org/10.1097/DAD.0000000000001725DOI Listing
January 2021

Analysis of Intestinal Metaplasia Without Dysplasia in the Urinary Bladder Reveal Only Rare Mutations Associated With Colorectal Adenocarcinoma.

Appl Immunohistochem Mol Morphol 2020 Nov/Dec;28(10):786-790

Departments of Pathology.

Intestinal metaplasia (IM) is a rare finding in urinary bladder specimens. It is unclear whether IM without dysplasia is a precursor of malignancy in the urinary system. We retrospectively selected 9 cases of IM of bladder (1 case harboring high-grade dysplasia), and performed mutation analysis for genes frequently mutated in colon cancer including BRAF, APC, KRAS, MET, NRAS, PIK3CA, CTNNB1, FBXW7, and TP53 using validated clinical tests. Control groups included 7 colonic tubular adenomas, 10 high-grade papillary urothelial carcinomas. One IM case revealed an APC mutation and another showed an NRAS mutation. Among the tubular adenomas cases, 6 of 7 (85.7%) harbored KRAS mutations and 3 of 7 (42%) APC mutations. Among urothelial carcinomas cases, 1 revealed a KRAS mutation, 2 had PIK3CA mutations, and all cases were negative for APC mutations. Clinical follow-up for the IM patients was available with a median follow-up of 70 months. One patient-without any mutation in the genes investigated-developed invasive bladder adenocarcinoma with intestinal differentiation with metastasis to the liver and lung. Neither of the 2 patients harboring mutations developed any malignancy. In conclusion, a minority of cases with IM without dysplasia bear mutations in the genes commonly associated with colonic adenocarcinoma, suggesting a premalignant potential for such lesions possibly following the classic multistep chromosomal instability pathway of carcinogenesis. A larger cohort of patients with longer follow-up is needed to better establish whether close follow-up is warranted for mutation-harboring IM of the bladder.
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http://dx.doi.org/10.1097/PAI.0000000000000812DOI Listing
December 2019

Surgical resection of breast cancers: Molecular analysis of cancer stem cells in residual disease.

Surgery 2019 05 15;165(5):1008-1013. Epub 2019 Feb 15.

Division of Surgical Oncology, Department of Surgery, Oregon Health & Science University, Portland.

Background: Approximately 70% of breast cancer patients have residual disease after neoadjuvant chemotherapy. This study was designed to determine whether breast cancer cells with stemlike properties are present in residual disease after neoadjuvant chemotherapy and whether they exhibit oncogenic mutations. The presence of breast cancer cells with stemlike properties with specific mutations may help explain the poor prognosis associated with residual disease.

Methods: A total of 68 breast cancer specimens were collected at the time of mastectomy or lumpectomy. A total of 44 were chemotherapy naïve and 24 were collected as residual disease after neoadjuvant chemotherapy. Tumor cells were collected by fluorescence-activated cell sorting, with breast cancer cells with stemlike properties specifically identified using breast stem cell associated antibodies. Whole tumor specimens and fluorescence-activated cell sorting breast cancer cells with stemlike properties were analyzed for genetic mutations, including PIK3CA.

Results: Breast cancer cells with stemlike properties, demonstrating EpCAM-positive, CD44-positive, CD49f, CD24 expression were present in chemotherapy-naïve tumors and residual disease. In both chemotherapy-naïve and residual disease specimens the highest frequency of PIK3CA mutations were detected in CD49f-CD24+ BCSCs (39% and 33%, respectively). PIK3CA mutations were detected in all stages of breast cancer (35%), in both chemotherapy naïve (39%) and residual disease (29%) and in both estrogen receptor positive (41%) and negative tumors (14%) (P = ns). Various PIK3CA mutations were identified in chemotherapy-naïve specimens versus residual disease specimens in both patient-paired and unpaired breast cancers.

Conclusion: Breast cancer cells with stemlike properties with mutations in PIK3CA were present in chemotherapy-naïve breast cancers and residual disease after neoadjuvant chemotherapy. These results demonstrate that neoadjuvant chemotherapy does not completely eradicate PIK3CA-defective breast cancer cells with stemlike properties. Although these findings may help explain the poor clinical outcomes in patients with residual disease, they also identify breast cancer cells with stemlike-property targets for therapies.
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http://dx.doi.org/10.1016/j.surg.2019.01.001DOI Listing
May 2019

Endometrial Adenocarcinomas With Significant Mucinous Differentiation: A Characterization of Intratumoral Heterogeneity of KRAS Mutations in Mucinous and Endometrioid Histologic Components.

Int J Gynecol Cancer 2018 02;28(2):241-247

Objective: KRAS mutations are frequently seen in malignancies with mucinous morphology. In our previous study, mucinous endometrial carcinomas were associated with a significantly higher frequency of KRAS mutations as compared with matched conventional endometrioid carcinomas. This study expands our previous report by exploring possible intratumoral heterogeneity for KRAS gene mutations in the mucinous components of mucinous carcinomas (MCs) and endometrioid carcinomas with significant mucinous differentiation (ECSMD) versus their associated "usual" endometrioid components.

Materials And Methods: KRAS-positive cases from our previous report were studied, including 10 MCs and 10 ECSMDs. The specimens were microscopically dissected to separately isolate morphologically mucinous and endometrioid components. Direct DNA sequencing for KRAS mutations at codons 12 and 13 using capillary electrophoresis were performed.

Results: KRAS mutations were detected in the endometrioid components of 8 (80%) of 10 MCs and 3 (30%) of 10 ECSMDs. The endometrioid component of the ECSMD group was less frequently associated with KRAS mutation than the endometrioid component of the MC group, even when the mucinous component of the same tumor contained a mutation; the difference is statistically significant (P < 0.05).

Conclusions: Our current study shows that intratumoral heterogeneity for KRAS gene mutation was associated with ECSMD, but less frequently with MC. It is possible that when the mucinous component predominates, qualifying for an MC, KRAS mutations appear to be widespread, irrespective of the mucinous or nonmucinous differentiation of the tumor cells. The findings suggest that multiple samples for KRAS tests may be useful, especially in endometrioid carcinoma with significant mucinous differentiation.
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http://dx.doi.org/10.1097/IGC.0000000000001168DOI Listing
February 2018

Refining a Church-Based Lifestyle Intervention Targeting African-American Adults at Risk for Cardiometabolic Diseases: A Pilot Study.

Open J Epidemiol 2017 May 21;7(2):96-114. Epub 2017 Apr 21.

Department of Internal Medicine, Meharry Medical College, Nashville, TN, USA.

Objective: The pilot study was intended to test the feasibility of a multiple-component lifestyle intervention targeting African American adults in a weight control and cardiometabolic risk reduction program on diet, activity, and stress, using community-engagement principles.

Methods: Applying mixed qualitative and quantitative measures, the intervention had a two-part sequential study design consisting of 12 weekly small group sessions that provided individual and group counseling in nutrition, exercise, and mindfulness, while incorporating focus group and interactive techniques to learn about barriers and acceptable practices for this population. The program was implemented at an African-American church in Nashville, Tennessee.

Results: Thirty-four participants (aged 56.1 ± 11 years, body mass index (BMI) 36.7 ± 6.6 kg/m) completed the intervention. Lifestyle changes after the 12 weekly sessions showed some positive trends including reduced sodium intake (from 2725.3 ± 326.5 to 2132 ± 330, mg/day, P = 0.008), increased walking steps (from 4392.1 ± 497.2 to 4895.3 ± 497.9, steps/day, not significant), and slightly decreased Perceived Stress Scale (PSS) scores (from 13.7 ± 1.4 to 12.4 ± 1.5, not significant). Body fat % among male participants decreased significantly (from 33.8 ± 2.6 to 28 ± 2.6, %, P = 0.043). Among cardiometabolic risk biomarkers, hemoglobin A1c (HbA1c) decreased significantly (from 6.6 ± 0.2 to 6.1 ± 0.2, %, P < 0.001). The baseline PSS score was positively associated with baseline adiposity levels (e.g., weight, = 2.4, P = 0.006). Twenty-one participants took part in focus groups during the program to identify barriers to healthy lifestyle changes. Primary barriers reported were price, time for preparing healthy meals, unfamiliarity with mindfulness activities, their health condition, and daily schedule available for physical activities.

Conclusions: This church-based pilot intervention was proven feasible by showing modest progress in reducing adiposity and decreasing HbA1c levels. The focus group and interactive methods facilitated program direction. Future full-scale studies are warranted to identify key strategies that provide more personalized approaches and supportive environments to sustain a healthy lifestyle among these at risk minorities with limited resources.
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http://dx.doi.org/10.4236/ojepi.2017.72009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808719PMC
May 2017

Pragmatic trial of an intervention to increase human papillomavirus vaccination in safety-net clinics.

BMC Public Health 2017 02 2;17(1):158. Epub 2017 Feb 2.

Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Human papillomavirus (HPV) infection has been causally linked to six cancers, and many disproportionately affect minorties. This study reports on the development and effectiveness of an intervention aimed at increasing HPV vaccine uptake among African American and Hispanic pediatric patients in safety-net clinics.

Methods: Formative research, community engagement, and theory guided development of the intervention. A clustered, non-randomized controlled pragmatic trial was conducted in four clinics providing healthcare for the underserved in Tennessee, U.S., with two intervention sites and two usual care sites. Patients aged 9-18 years (N = 408) and their mothers (N = 305) enrolled, with children clustered within families. The intervention consisted of two provider/staff training sessions and provision of patient education materials, consisting of a video/flyer promoting HPV vaccine. Medical records were reviewed before/after the initial visit and after 12 months.

Results: At the initial visit, provision of patient education materials and provider recommendation were higher at intervention sites versus usual care sites, and receipt of HPV vaccine was higher at intervention sites (45.4% versus 32.9%) but not significantly after adjusting for patient's age and mother's education. Provider recommendation, but not education materials, increased the likelihood of vaccine receipt at the initial visit, although over one-third of intervention mothers cited the flyer/video as motivating vaccination. Completion of the 3-dose series at follow-up was lower in the intervention arm.

Conclusions: Future interventions should combine patient education, intensive provider/staff education, and patient reminders. Research should compare patient education focusing on HPV vaccine only versus all adolescent vaccines.

Trial Registration: Retrospectively registered with ClinicalTrials.gov NCT02808832 , 9/12/16.
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http://dx.doi.org/10.1186/s12889-017-4094-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290601PMC
February 2017

An asymptomatic mutation complicating severe chemotherapy-induced peripheral neuropathy (CIPN): a case for personalised medicine and a zebrafish model of CIPN.

NPJ Genom Med 2016 8;1:16016. Epub 2016 Jun 8.

Department of Pediatrics, Division of Pediatric Hematology-Oncology, Hasbro Children's Hospital and The Warren Alpert Medical School at Brown University, Providence, RI, USA.

Targeted next-generation sequencing (NGS) identified a novel loss of function mutation in , a gene linked to Charcot-Marie-Tooth disease (CMT), in a paediatric acute lymphoblastic leukaemia patient with severe chemotherapy-induced peripheral neuropathy (CIPN) due to vincristine. The patient was clinically asymptomatic, and lacked a family history of neuropathy. The effect of the mutation was modelled in a zebrafish knockdown system that recapitulated the symptoms of the patient both prior to and after treatment with vincristine. Confocal microscopy of pre- and post-synaptic markers revealed that the GARS knockdown results in changes to peripheral motor neurons, acetylcholine receptors and their co-localisation in neuromuscular junctions (NMJs), whereas a sensitive and reproducible stimulus-response assay demonstrated that the changes correlating with the GARS mutation in themselves fail to produce peripheral neuropathy symptoms. However, with vincristine treatment the GARS knockdown exacerbates decreased stimulus response and NMJ lesions. We propose that there is substantial benefit in the use of a targeted NGS screen of cancer patients who are to be treated with microtubule targeting agents for deleterious mutations in CMT linked genes, and for the screening in zebrafish of reagents that might inhibit CIPN.
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http://dx.doi.org/10.1038/npjgenmed.2016.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685301PMC
June 2016

The clinical significance of K-ras mutation in endometrial "surface epithelial changes" and their associated endometrial adenocarcinoma.

Gynecol Oncol 2016 07 13;142(1):163-168. Epub 2016 May 13.

Department of Pathology, Women and Infants Hospital of Rhode Island, United States.

Objectives: The entity of 'surface epithelial changes' (SECs) was first described in 1995 [1]. Morphologically, SECs usually arise from malignant glands at the superficial aspect of well differentiated (WD) endometrioid carcinomas (ECs) and impart the appearance of a 'maturational' phenomenon at the surface of the cancer. Exhibiting a paradoxically bland histologic appearance, SECs typically show morphologic features that mimic benign entities, particularly endocervical microglandular hyperplasia (MGH). SECs have been associated with approximately half of WD endometrioid carcinomas many of which showed focal mucinous differentiation. Despite their morphologically benign histology, some have questioned whether the presence of SECs represents a 'marker' for an underlying malignancy, especially in postmenopausal women with endocervical or MGH-type SECs in their endometrial sampling. Since the biologic nature of SECs is unknown, we aimed to study the prevalence of KRAS gene mutations in SECs and the underlying WD endometrioid adenocarcinomas (EC) from which they directly arise.

Methods: 24 cases with biopsy proven SECs and ECs in their subsequent hysterectomy were retrieved. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue. PCR amplification for KRAS codons 12 and 13 was performed, followed by sequencing using capillary electrophoresis.

Results: KRAS codons 12 and 13 mutations were detected in 19 of 24 (79%) SECs, and 19 of 24 (79%) ECs. All SECs had the same KRAS mutation as the underlying EC.

Conclusions: Our results suggest that SECs are of neoplastic origin and that KRAS mutations play an important role in the tumorigenesis of ECs and SECs.
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http://dx.doi.org/10.1016/j.ygyno.2016.05.001DOI Listing
July 2016

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target.

Clin Cancer Res 2016 08 1;22(15):3831-40. Epub 2016 Mar 1.

Oncology Division, Department of Internal Medicine, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, Rhode Island.

Purpose: Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN-ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort.

Experimental Design: Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed.

Results: Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib.

Conclusions: Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831-40. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-3000DOI Listing
August 2016

Application of BRAF V600E mutation analysis for the diagnosis of metanephric adenofibroma.

Am J Surg Pathol 2015 Sep;39(9):1301-4

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI.

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http://dx.doi.org/10.1097/PAS.0000000000000501DOI Listing
September 2015

KRAS Mutations in Mucinous Lesions of the Uterus.

Am J Clin Pathol 2015 Jun;143(6):778-84

From the Department of Pathology and Laboratory Medicine, Women and Infants Hospital of Rhode Island, Providence; Warren Alpert Medical School of Brown University, Providence, RI; and.

Objectives: The current study examined the KRAS mutation status in a spectrum of mucinous lesions of the uterus, including mucinous metaplasia (MM), atypical mucinous proliferation (AMP), endocervical mucosa, and microglandular hyperplasia (MGH).

Methods: Thirty-nine cases, including 15 AMPs, nine MMs, nine MGHs, and six normal endocervical mucosas, were selected from the departmental archive. All AMP cases with follow-up biopsies or hysterectomies were reviewed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue and KRAS codons 12 and 13 sequence analyzed.

Results: KRAS codon 12 and 13 mutations were detected in 10 (67%) of the 15 AMP cases. No KRAS mutations were identified in MMs, MGHs, and endocervical mucosas (P = .002, AMP vs MM or MGH, Fisher exact test). Most women with AMP were postmenopausal (13/15 [86.7%]) and presented with dysfunctional uterine bleeding. Among the 10 cases of AMP harboring KRAS mutations, six (60%) cases were subsequently diagnosed with carcinoma, one with atypical complex hyperplasia, and two with AMP within endometrial polyps.

Conclusions: The results suggest a possible association between KRAS mutations and mucinous differentiation in endometrial carcinogenesis. KRAS status can help in assessing benign from precursor or malignant mucinous lesions as well as differentiate endometrial lesions from those of cervical origin.
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http://dx.doi.org/10.1309/AJCP69RBNUHHOJRIDOI Listing
June 2015

Sponsors meet scientists to speed pediatric medicines development.

Sci Transl Med 2015 Mar;7(279):279fs11

National Institute for Child Health and Human Development, Bethesda, MD 20892, USA.

The Point-Person Project, a child-health research initiative, enables rapid response to opportunities for participation in multicenter pediatric clinical trials.
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http://dx.doi.org/10.1126/scitranslmed.aaa2045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459888PMC
March 2015

Comparison of tyrosine kinase receptors HER2, EGFR, and VEGFR expression in micropapillary urothelial carcinoma with invasive urothelial carcinoma.

Target Oncol 2015 Sep 8;10(3):355-63. Epub 2014 Oct 8.

Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA,

Invasive micropapillary urothelial carcinomas (MPUC) emerge at higher stages and follow a more aggressive course than conventional invasive urothelial carcinomas (UC). Little is known about the target therapies using tyrosine kinase inhibitors in MPUC. This study is to investigate potential effectiveness of tyrosine kinase receptor inhibitors by determining expression of epidermal growth factor receptor (EGFR), human epidermal receptor 2 (HER2), and vascular endothelial growth factor receptor 2 (VEGFR) proteins in MPUC and UC. 16 cases of MPUC and 16 stage-matched UC were identified. Immunohistochemistry for EGFR, HER2, and VEGFR2 and HER2 gene amplification by fluorescence in situ hybridization (FISH) were performed. HER2 and EGFR proteins were expressed in MPUC and UC, with significantly higher HER2 expression in MPUC (ratio 1.82, p < 0.01). HER2 gene amplification was identified in 4 of 16 MPUC (25 %). Amplification was limited to cases with 3+ HER2 expression (100% concordance). EGFR expression in MPUC was slightly higher than UC but not statistically significant (ratio 1.57, p = 0.19). EGFR and HER2 coexpression was noted in 75% of MPUC and 37.5% of UC. No VEGFR expression was identified in the urothelium. Strong VEGFR expression was noted in stromal vessels in both MPUC and UC. In conclusion, EGFR and HER2 are potential targets for neoadjuvant chemotherapy in MPUC and UC. There is no direct anti-tumor effect expected for VEGFR inhibitors.
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http://dx.doi.org/10.1007/s11523-014-0341-xDOI Listing
September 2015

Endometrial carcinomas with significant mucinous differentiation associated with higher frequency of k-ras mutations: a morphologic and molecular correlation study.

Int J Gynecol Cancer 2013 Sep;23(7):1231-6

Department of Pathology, Women & Infants Hospital of Rhode Island, Brown University, Providence, RI 02905, USA.

Objectives: K-ras gene product in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway is critical in the development of certain types of malignancies. K-ras mutation-associated pancreatic and ovarian carcinomas often display mucinous differentiation. Previous studies have shown that k-ras mutation is found in 10% to 30% of endometrial carcinomas. We investigated k-ras mutations in several morphologic subtypes of endometrial carcinomas with particular emphasis on various degrees of mucinous differentiation.

Methods: Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue sections. Polymerase chain reaction amplification for k-ras codons 12 and 13 were performed, followed by sequencing using capillary electrophoresis. The Fisher exact test is used to compare the prevalent difference of k-ras mutation among the groups. P < 0.05 was considered significant.

Results: K-ras mutations were detected in 8 (80%) of 10 mucinous carcinomas, 12 (67%) of 18 endometrioid carcinomas (ECs) with significant mucinous differentiation (ECMD), 4 (25%) of 16 ECs, and 1 (9%) of 11 serous carcinomas. The differences were statistically significant between mucinous carcinomas versus EC (P < 0.01) and ECMD versus EC (P < 0.05).

Conclusion: The findings suggest that mucinous carcinoma and endometrioid carcinoma with significant mucinous component are more likely to be associated with k-ras mutation. Potential clinical implications of k-ras mutation lies in the management of recurrent or higher-stage endometrial mucinous tumors, which would not be responsive to treatment protocols containing epidermal growth factor receptor inhibitors.
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http://dx.doi.org/10.1097/IGC.0b013e31829ea82fDOI Listing
September 2013

BRAF V600E Mutations in Endometrial Adenocarcinoma.

Diagn Mol Pathol 2013 Mar;22(1):35-40

Department of Pathology & Laboratory Medicine, Women & Infants Hospital of Rhode Island, Providence, RI 02905, USA.

The BRAF V600E somatic mutation is recognized as an oncogenic driver of many human cancers involving the MAPK/ERK pathway. Colorectal and lung cancers associated with the BRAF V600E mutation often demonstrated mucinous morphology. This study hypothesized that the BRAF V600E mutation may be associated with mucinous morphology in endometrial cancer and aimed to investigate its prevalence in mucinous (endometrial) carcinoma (MC) and endometrioid adenocarcinoma with significant mucinous differentiations (ECMD) (>10% neoplastic cells). Twenty-eight cases of endometrial cancer were selected, including 17 (60.7%) cases of MC or ECMD. All patients were Caucasian with age ranging from 50 to 87 years old (median 65). Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue and subjected to both real-time mutant allele-specific amplification polymerase chain reaction (PCR) and PCR amplification, followed by direct sequencing. Three (3/28, 10.7%) BRAF V600E mutations were detected by real-time mutant allele-specific amplification PCR and confirmed by direct sequencing. Two of 3 cases positive for BRAF V600E mutation were ECMDs with "surface epithelial changes." KRAS mutations were found in 9 cases (32.1%), none with BRAF mutation. This is the first report of BRAF V600E mutation in endometrial cancer, indicating that it may contribute to tumorigenesis of endometrial cancer, although at a low frequency compared with KRAS mutations.
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http://dx.doi.org/10.1097/PDM.0b013e31826c7fe0DOI Listing
March 2013

Collaboration: The Paradigm of Practice Approach between the Forensic Psychiatrist and the Forensic Psychologist.

Front Psychiatry 2012 15;3:89. Epub 2012 Nov 15.

Department of Psychiatry and Behavioral Sciences, Meharry Medical College Nashville, TN, USA.

The importance and relevance of forensic practice to societal evolution has increased exponentially in recent years. As society evolves in its understanding of the complex relationships between mankind and society, we rely more and more on the services of forensic experts. This article elucidates the professions of forensic psychiatry and forensic psychology. We examine the two distinct professions from the spectrum of collaboration, integration of services, differences, and similarities. We also compare and contrast the educational background and training requirements for these two professions; and present illustrative scenarios and real life examples of the daily functions of both professionals. Lastly, we present demographic data for the areas of employment, numbers, and geographic distribution of the two professions. Forensic psychiatry is the interface between medicine and law, while forensic psychology is the interface between psychology and law. As such, these professions are mired with complexities and challenged by vulnerabilities. Professionals from both fields can serve as expert witnesses in court and therefore face similar challenges in their course of professional practice. Collaboration between these two professions has the potential to increase both the credibility and utility of forensic services to the courts, the individuals served, and the general public.
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http://dx.doi.org/10.3389/fpsyt.2012.00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498621PMC
November 2012

Acute Myeloid Leukemia Evolving from JAK 2-Positive Primary Myelofibrosis and Concomitant CD5-Negative Mantle Cell Lymphoma: A Case Report and Review of the Literature.

Case Rep Hematol 2012 2;2012:875039. Epub 2012 Aug 2.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.

Primary myelofibrosis (formerly known as chronic idiopathic myelofibrosis), has the lowest incidence amongst the chronic myeloproliferative neoplasms and is characterized by a rather short median survival and a risk of progression to acute myeloid leukemia (AML) noted in a small subset of the cases, usually as a terminal event. As observed with other chronic myeloproliferative neoplasms, the bone marrow biopsy may harbor small lymphoid aggregates, often assumed reactive in nature. In our paper, we present a 70-year-old Caucasian male who was diagnosed with primary myelofibrosis, and after 8 years of followup and therapy developed an AML. The small lymphoid aggregates noted in his bone marrow were neoplastic in nature and represented bone marrow involvement by a CD5-negative mantle cell lymphoma (MCL) that presented without any associated lymphadenopathy. We reviewed the English medical literature to identify a single case report of simultaneous association of AML and a MCL in the bone marrow. The unusual association presented here suggests an increase in observer awareness to apparently benign lymphoid aggregates in chronic myeloproliferative neoplasms.
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http://dx.doi.org/10.1155/2012/875039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420541PMC
September 2012

Reflections on caring. Fighting words.

RN 2008 Feb;71(2):56

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February 2008

Analysis of T-cell clonality using laser capture microdissection and high-resolution microcapillary electrophoresis.

J Mol Diagn 2007 Sep 9;9(4):490-7. Epub 2007 Jul 9.

Department of Pathology, Rhode Island Hospital, APC-12, 593 Eddy St., Providence, RI 02903, USA.

Identification of clonal lymphocytic populations by polymerase chain reaction may be difficult in cases with scant cellular infiltrates or those with a heterogeneous population of cells. Here, we assessed the diagnostic utility of laser capture microdissection (LCM) and high-resolution microcapillary electrophoresis in the analysis of clonality of small biopsy specimens. Clonality was determined in 24 cases: five reactive tonsils, five reactive lymph nodes, six inflammatory skin lesions, and eight T-cell lymphomas. CD3-positive T lymphocytes were captured by LCM from paraffinized immunohistochemically stained sections. Genomic DNA was analyzed for T-cell receptor-gamma gene rearrangement by polymerase chain reaction followed by high-resolution microcapillary electrophoresis with the DNA 500 LabChip and the Agilent Bioanalyzer. In the reactive specimens, T-cell receptor-gamma polymerase chain reaction revealed monoclonal bands when 10 to 1000 cells were captured. This pattern changed to polyclonal when higher numbers of cells were microdissected (2000 to 10,000 cells). In contrast, lymphoma cells were consistently monoclonal whether low or high numbers were microdissected. Microcapillary electrophoresis coupled with LCM facilitated clonality analysis in equivocal cases. In two of eight lymphoma cases, LCM revealed diagnostic monoclonal bands, whereas routine T-cell receptor-gamma assessment of whole tissue sections with 10% polyacrylamide gel electrophoresis demonstrated only minor clonal bands. We conclude that clonality determined by LCM is cell number-dependent. Biopsy specimens containing low numbers of reactive polyclonal T cells may produce pseudomonoclonal bands and therefore should be interpreted with great caution.
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http://dx.doi.org/10.2353/jmoldx.2007.070006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1975101PMC
September 2007

Introduction. Pathology.

Med Health R I 2005 Jul;88(7):210-1

Department of Pathology, Rhode Island Hospital, Providence 02903, USA.

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July 2005

Characterization of a rabbit kidney prostaglandin F(2{alpha}) receptor exhibiting G(i)-restricted signaling that inhibits water absorption in the collecting duct.

J Biol Chem 2005 Oct 10;280(41):35028-37. Epub 2005 Aug 10.

Departments of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.

PGF(2alpha) is the most abundant prostaglandin detected in urine; however, its renal effects are poorly characterized. The present study cloned a PGF-prostanoid receptor (FP) from the rabbit kidney and determined the functional consequences of its activation. Nuclease protection assay showed that FP mRNA expression predominates in rabbit ovary and kidney. In situ hybridization revealed that renal FP expression predominates in the cortical collecting duct (CCD). Although FP receptor activation failed to increase intracellular Ca(2+), it potently inhibited vasopressin-stimulated osmotic water permeability (L(p), 10(-7) cm/(atm.s)) in in vitro microperfused rabbit CCDs. Inhibition of L(p) by the FP selective agonist latanoprost was additive to inhibition of vasopressin action by the EP selective agonist sulprostone. Inhibition of L(p) by latanoprost was completely blocked by pertussis toxin, consistent with a G(i)-coupled mechanism. Heterologous transfection of the rabbit FPr into HEK293 cells also showed that latanoprost inhibited cAMP generation via a pertussis toxin-sensitive mechanism but did not increase cell Ca(2+). These studies demonstrate a functional FP receptor on the basolateral membrane of rabbit CCDs. In contrast to the Ca(2+) signal transduced by other FP receptors, this renal FP receptor signals via a PT-sensitive mechanism that is not coupled to cell Ca(2+).
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http://dx.doi.org/10.1074/jbc.M505852200DOI Listing
October 2005

Postmortem RNA and protein stability in perinatal human lungs.

Diagn Mol Pathol 2002 Sep;11(3):170-6

Department of Pathology, Women and Infants' Hospital, Providence, RI 02905, USA.

The availability of fetal and neonatal lung tissue is an invaluable resource to elucidate the molecular regulation of human lung development. In this study, we have investigated the mRNA and protein stability of perinatal lung tissues treated with RNA (Ambion Inc., Austin, TX) or snap frozen in liquid nitrogen (LN ). Lung samples were obtained from 25 consecutive perinatal autopsies of live-born and stillborn infants (median gestational age, 23 weeks) with various clinical presentations. Treatment of lung tissue with RNA yielded more total RNA and protein than LN freezing. The integrity of RNA, assessed by spectrophotometry and gel electrophoresis, was equivalent between both tissue preservation methods, and both methods produced RNA suitable for reverse transcriptase-polymerase chain reaction analysis of representative genes (beta-actin and surfactant protein-B [SP-B]). Similarly, the protein integrity of RNA -treated tissues was equivalent to that of LN -frozen tissues, as judged by Western blot analysis of SP-B/actin protein expression. Although the total yield was similar in live-born, nonmacerated stillborn and macerated stillborn infants, only RNA and protein from live-born or nonmacerated stillborn infants was suitable for subsequent molecular analyses. Within the 41-hour range studied, the duration of the postmortem interval did not affect the yield or integrity of RNA and protein with either tissue preservation method. In summary, high-quality RNA and protein, suitable for routine molecular analyses, can be obtained from postmortem lung tissue from live-born and nonmacerated stillborn infants, even with prolonged postmortem intervals. RNA is equivalent, if not superior, to LN for preservation of postmortem RNA and protein in developing human lungs.
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http://dx.doi.org/10.1097/00019606-200209000-00008DOI Listing
September 2002

Clinical experience with pneumococcal conjugate vaccines in infants and children.

J Am Osteopath Assoc 2002 Aug;102(8):431-6

Department of Medical and Scientific Services, Quintiles Transnational Corporation, Research Triangle Park, NC, USA.

Streptococcus pneumoniae is a leading cause of morbidity and mortality in pediatric patients, particularly in infants and children younger than 2 years. Each year, S pneumoniae is responsible for significant morbidity and mortality in the United States. During the past several decades, the emergence of penicillin-nonsusceptible and multidrug-resistant pneumococcal isolates has become a major cause for concern, with the overuse or inappropriate use of antibiotics playing a significant role in the increase of resistance. Because the resistance of S pneumoniae to antibiotics has complicated the treatment of pneumococcal infections, attention has focused on the need to prevent disease through vaccination. The objective of this article is to describe the rationale for the development of pneumococcal conjugate vaccines and to summarize the clinical experience to date with these vaccines in infants and children.
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August 2002

A conjugate vaccine for the prevention of pediatric pneumococcal disease.

Mil Med 2002 Aug;167(8):671-7

Department of Pediatrics, Medical College of Georgia, Augusta 30912-3735, USA.

The use of the pneumococcal 7-valent conjugate vaccine (PCV7 [Prevnar], Wyeth Lederle Vaccines), and the impact it is likely to have on pneumococcal disease are reviewed. Pneumococcal disease in infants and young children is a major health care burden, and the increase in antibiotic resistance among pneumococci has complicated disease management. The 23-valent polysaccharide pneumococcal vaccines do not protect infants and children younger than 2 years of age. PCV7 is effective in this population and should dramatically reduce the incidence of invasive pneumococcal disease and have an impact on the incidence of infections caused by Streptococcus pneumoniae serotypes present in the vaccine. Research has shown that pneumococcal conjugate vaccines reduce nasopharyngeal carriage of vaccine serotype S. pneumoniae, including antibiotic-resistant strains. Routine immunization is expected to substantially reduce the morbidity and mortality associated with invasive pneumococcal disease in children, and coupled with expected herd immunity and decreased antibiotic selective pressure, it should have a positive impact beyond the immunized population.
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August 2002

Beta-carotene alters the morphology of NCI-H69 small cell lung cancer cells.

J Nutr 2002 Jan;132(1):121-4

Department of Food Science and Nutrition, University of Rhode Island, Kingston, RI 02881, USA.

The effect of beta-carotene on the morphology of NCI-H69 small cell lung cancer cells that had undergone beta-carotene-induced growth reduction (P < 0.05) was examined. The cells were grown at 1 x 10(8) cells/L and were cultured with or without 20 micromol/L beta-carotene. The qualitative electron microscopic observations revealed that beta-carotene-treated cells contained more vacuoles than control cells not treated with beta-carotene. The quantitative image analysis showed a significantly smaller (P < 0.05) value of the nuclear roundness factor for treated cells compared with control cells, indicating an irregular nuclear morphology of beta-carotene-treated cells. The major diameter of the cells and the minor diameter of the nuclei were significantly smaller (P < 0.05), and the nuclear perimeter was significantly larger (P < 0.05) in beta-carotene-treated cells. The ratio of nucleus to cytoplasm was significantly less (P < 0.05) in beta-carotene-treated cells compared with control cells, indicating a less malignant growth of the cells. These results demonstrate that the treatment of small cell lung cancer cells with beta-carotene induces morphological changes in the cells concomitant with a reduction in their proliferation. Further investigation is required to show a direct effect of beta-carotene or its intracellular polar metabolites on the morphology of these cells.
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http://dx.doi.org/10.1093/jn/132.1.121DOI Listing
January 2002