Highly Diastereoselective Synthesis of C-Glycosides from Glycal Anomers.

This Letter presents a highly diastereoselective synthesis of C-hydroxymethine glycosides from glycal anomers using a chiral N-heterocyclic carbene-copper catalyst. The high diastereoselectivity was synergistically controlled by the stereocenter of the substrate and chirality of the N-heterocyclic carbene-copper complex without being interrupted by the stereochemistry of C5 and the anomeric position. This approach enables the production of a diverse array of C-hydroxymethine glycosides using synthetically versatile glycals and various functionalized aldehydes.

Dedifferentiated endometrial carcinoma arising from serous carcinoma: Diagnostic challenges and recommendations.

•Dedifferentiated endometrial carcinoma arising from serous carcinoma (null-type P53).•Differential diagnosis including carcinosarcoma, FIGO grade 3 endometrioid carcinoma.•Also need to rule out SMARCA4-deficient uterine sarcoma and other sarcomas.

Gastric glomus tumor on EUS-FNA-based cytology: clinicopathologic and immunohistochemical features of 4 cases, including 1 case with associated MIR143HG-NOTCH2 fusion gene.

INTRODUCTION: Gastric glomus tumor (GT) is a rare submucosal tumor for which the preoperative diagnosis can be challenging. We report the cytomorphologic and immunohistochemical features of 4 gastric GTs diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology. MATERIALS AND METHODS: Files were searched to identify gastric GTs diagnosed by EUS-FNA between 2018 and 2021. A total of 4 cases of gastric GTs (3 men and 1 women; mean age, 60 years) were included. RESULTS: Three GTs were located in the gastric antrum and one in the gastric body. Their size ranged from 2 to 2.5 cm. Three patients presented with epigastric discomfort and one with chest wall discomfort. Rapid on-site evaluation was performed for 3 cases; the findings for all 3 were indeterminate. The smears were moderate to highly cellular and showed loose clusters of evenly distributed small- to medium-size bland tumor cells. The tumor cells had centrally located round to oval nuclei with inconspicuous nucleoli and scant to moderate amount of eosinophilic to clear cytoplasm. Examination of the cell blocks revealed branching small vessels surrounded by small- to medium-size cells. The neoplastic cells were positive for smooth muscle actin and synaptophysin and negative for AE1/AE3 and S-100. C-KIT and CD34 were variably positive. Ki-67 was <2% positive. In 1 case, the fusion panel-solid tumor (50 genes) revealed the MIR143HG-NOTCH2 fusion gene. CONCLUSIONS: Smears and cell block preparation revealed angiocentric sheets of uniform, small round to oval tumor cells with pale to eosinophilic cytoplasm, intermingled with endothelial cells. The differential diagnosis of gastric GTs on rapid on-site evaluation includes neuroendocrine tumors and epithelioid or spindled cell neoplasms. Immunohistochemical and molecular studies can be helpful in the preoperative diagnosis of gastric GT.

Revisiting the cytologic features of autoimmune pancreatitis: An institutional experience.

BACKGROUND: Autoimmune pancreatitis (AIP) is a known mimicker of pancreatic ductal adenocarcinoma both clinically and radiologically. In this study, the authors present their institutional experience in diagnosing AIP on cytology and correlate results with the histologic findings. METHODS: A 14-year computerized search for patients who had histologically confirmed AIP with concurrent or prior cytology was performed. Clinical data, cytology findings, and surgical pathology results were reviewed for analysis. RESULTS: Eighteen patients were identified. The patients showed a male predominance, with a mean age of 59 years. Jaundice, weight loss, and abdominal pain were the most common clinical presentation. Five of 12 patients who were tested for serum immunoglobulin G4 had elevated levels. Cytologic findings of 16 cases that were available for review showed markedly inflamed fibrous stroma (54%) and cytologic atypia (50%). The final cytologic diagnoses were suspicious for adenocarcinoma (n = 1), atypical (n = 8), and benign/negative (n = 9). The corresponding surgical pathology diagnoses were classified as type 1 (n = 10), type 2 (n = 6), and AIP, not otherwise specified (n = 2). All type 2 AIP cases had at least atypical cytologic diagnoses, with one called suspicious for adenocarcinoma and another called adenocarcinoma at the time of rapid on-site evaluation. In contrast, eight of 10 type 1 AIP cases were negative/benign, and two of 10 were atypical. In these two atypical cases, the possibility of AIP was raised because of the presence of inflamed stroma. CONCLUSION: AIP is a pitfall in cytology because moderate-to-marked atypia can be present, especially in type 2 AIP. Because atypia can be severe, the presence of cellular fibrous stroma with lymphocytic stromal infiltrates and the integration of serum immunoglobulin G4 levels could be helpful in avoiding diagnostic overcall in AIP.

Cyto-histo correlation and false-negative urine: Before and after the Paris system for reporting urinary cytology.

BACKGROUND: The impact of implementing the Paris system (TPS) on the rate of discrepant cases in the negative for high-grade urothelial carcinoma (NHGUC) category that had a subsequent diagnosis of high-grade urothelial carcinoma (HGUC) on histology is not well studied. METHODS: We adopted TPS in May 2019. We searched discrepant cases with negative urine cytology 2017-2019 in our cyto-histo correlation database. The urine cytology and follow-up biopsy/resection were reviewed by a cytopathologist who also did Genitourinary (GU) Pathology subspecialty sign-out. Voided urine and instrumented urine were included in this study. RESULTS: There were total of 70 discrepant cases with negative cytology interpretation but HGUC on the subsequent biopsy or resected specimen. Following the TPS criteria, the rate of discrepant negative cytology cases increased from 6 cases between January 2017 and May 2019 to 64 cases after May 2019 when we adopted TPS. There were 2 discrepant negative cases in 2017, 3 cases in 2018, and 65 cases in 2019. Out of 65 cases in 2019, 64 cases were identified after May 2019. Additional 55 urine cytology slides were reviewed according to the TPS criteria, of which, the diagnoses remained unchanged in 45 (82%) cases and 10 (19%) cases were reassigned to either atypical or suspicious categories. The discrepancy was noted more on the instrumented urine and the upper tract urine. However, the false-negative rate rose faster in voided urine and lower tract urine. The risk of HGUC with the category of NHGUC was 0.03% in 2017, 0.05% in 2018, and 1.06% in 2019 at our institution. The increase in false-negative rate could not be attributed to a single cytopathologist. CONCLUSION: After adopting TPS for reporting urine cytology, there was an increase in HGUC from negative urine cytology which was subsequently confirmed on histology as cases of HGUC. The quality control of negative urines could be important monitoring the process when implementing TPS.

Hürthle cell-predominant thyroid fine needle aspiration cytology: A four risk-factor model highly accurate in excluding malignancy and predicting neoplasm.

BACKGROUND: Interpretation of Hürthle cell-predominant cytologies (HCP) is very challenging as a majority is diagnosed as indeterminate. Prior studies have reported various cytologic features to help distinguish non-neoplastic (NN) from neoplastic and malignant lesions but had contradicting results. Our aim was to identify risk factors predictive of neoplasm and/or malignancy by correlating cytologic features with clinical and ultrasound findings. METHODS: Sixty-nine HCP cases with surgical follow-up were identified, including 35 NN, 20 adenomas, and 14 carcinomas. Ultrasound data were recorded utilizing Thyroid Imaging Reporting and Data System (TI-RADS) and American Thyroid Association (ATA) scoring systems. Sixteen cytologic criteria were evaluated and semi-quantitatively scored. Data were assessed by univariable, multivariable and stepwise logistic regression analysis; and statistical significance achieved at P-value <0.05. RESULTS: On univariable analysis, significant predictors of neoplasm were high cellularity, isolated single cells, absent colloid, non-uniform HC population (anisonucleosis), larger nodule size, and higher ATA score. Large-cell dysplasia and transgressing blood vessels were not found to be significant factors. Multivariable analysis identified a combination of four risk factors (high cellularity, anisonucleosis, absent colloid, and size ≥2.9 cm) that was associated with neoplasm in 10/11 patients. None of 15 patients with zero or 1 out of 4 risk factors had malignancy or neoplasm on follow-up. This model also significantly outperformed ATA and TI-RADS scoring systems. CONCLUSION: In the absence of four or three risk factors, the model excluded malignancy and neoplasm in all patients. The presence of all four factors predicted neoplasm and malignancy in 91% and 46% of cases, respectively.

BRD3-NUTM1-expressing NUT carcinoma of lung on endobronchial ultrasound-guided transbronchial needle aspiration cytology, a diagnostic pitfall.

BACKGROUND: Nuclear protein in testis (NUT) carcinoma (NC) is an aggressive type of poorly differentiated carcinoma with a variable degree of squamous differentiation. NC is defined by the presence of BRD-NUT fusion oncogenes, the most common fusion form being the BRD4-NUTM1 gene. Variant rearrangements involving the BRD3 and NSD3 genes. Variant rearrangements involving the BRD3 and NSD3 genes occur in approximately one-third of the cases. AIMS: This is the first case regarding the study of cytological features of NC of the lung with BRD3-NUTM1 fusion. MATERIALS AND METHODS: A 36-year-old female with chest heaviness and shortness of breath was found to have a right-sided pleural effusion; she was non-smoker and denied any significant past medical illness. CT-chest revealed an 8.5 cm heterogeneous mass in the right and mid-upper lung. She underwent endobronchial ultrasound-guided (EBUS) transbronchial fine-needle aspiration (FNA) of the lung mass. Thoracocentesis was performed, and pleural fluid was sent to the laboratory for cytological evaluation RESULTS: The cytopathological findings showed atypical squamoid cells with variably prominent single or multiple nucleoli. Monotonous-looking cells with high nuclear to cytoplasmic ratio and hyperchromasia were also present. The atypical squamoid cells showed abundant clear to eosinophilic cytoplasm with rare individual cell keratinization and focal keratin pearl formation. The atypical cells were positive for CK7, p40, p63, mCEA and equivocal for NUT-specific antibody. The cytopathological findings were consistent with squamous cell carcinoma with focal keratinization. The Fusion Panel-Solid Tumor (50 genes) revealed BRD3-NUTM1 fusion gene. Diagnosis was amended to pulmonary NC. DISCUSSION: NC is a diagnostic challenge for pathologists as it can morphologically mimic undifferentiated carcinoma, squamous cell carcinoma, or neuroendocrine carcinoma. The challenge is not how to diagnose NC but rather determining when to include it in the differential diagnosis and perform the diagnostic molecular tests (FISH or NGS) or IHC study for NUT-specific antibody. CONCLUSION: When a specimen demonstrates a dual cell population of squamoid cells and primitive-looking tumor cells in the wrong clinical context (i.e., young patient with no smoking history), further molecular profiling is warranted to include the differential of a primary NC of the lung. The cytological features of NC itself have rarely been documented and moreover, that of a primary NC of the lung with BRD3-NUTM1 fusion has never been reported. We herein report cytological findings of a primary NC of the lung with BRD3-NUTM1 fusion gene.

Palladium catalyzed reductive Heck coupling and its application in total synthesis of (-)-17-nor-excelsinidine.

Monoterpene indole alkaloids, bearing a highly substituted piperidine ring, are a structurally diverse class of bioactive natural products, found in various parts of the world. Herein, we reported the construction of the key piperidine ring via palladium catalyzed reductive Heck coupling with a good syn selective manner, avoiding the usage of stoichiometric, highly toxic, air sensitive and moisture sensitive Ni(COD)2. To further showcase the value of this methodology, we realized the total synthesis of the structurally unique zwitterionic monoterpene indole alkaloid (-)-17-nor-excelsinidine in 9 steps, in which the key ammonium-acetate connection (N4-C16) of (-)-17-nor-excelsinidine was constructed via oxidative coupling in excellent yield and high regioselectivity under NBS/pyridine from the enolate of geissoschizine.

The Role of Ultrasound-Guided Fine-Needle Aspiration of Thyroid Bed Lesions and Clinical Predictors of Recurrent Papillary Thyroid Carcinoma.

OBJECTIVES: Fine-needle aspiration (FNA) of thyroid bed lesions after thyroidectomy is challenging to evaluate. We determined the sensitivity, specificity, and positive and negative predicative value of thyroid bed FNA (TB-FNA) for detecting local recurrence of thyroid carcinoma. METHODS: A retrospective search was conducted for TB-FNAs from patients with a prior thyroid resection and subsequent ipsilateral FNA from the thyroid bed. Clinical and pathologic data were retrieved from the medical record. Patients were ultimately classified as "malignant" or "benign" based on the worst pathology identified and follow-up available. RESULTS: Forty-two cases were included, and the prior thyroidectomy pathology included 36 papillary thyroid carcinomas, two follicular carcinomas, one medullary carcinoma, and three benign cases. TB-FNA was adequate in 38 (90.5%) cases and interpreted as positive for malignancy (n = 22; 52.4%), suspicious for follicular neoplasm (n = 3; 7.1%), atypia of unknown significance (n = 2; 4.8%), and benign (n = 10; 23.8%). Twenty-seven patients had histologic follow-up, and 24 (87.5%) showed recurrent malignancy. The cytology sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 96%, 100%, 100%, 92.3%, and 97.4%, respectively, for identification of recurrent malignancy. CONCLUSIONS: Most TB-FNA cases ultimately were diagnosed with malignancy on follow-up, although there may be sampling bias, as not all clinically benign cases had surgical follow-up.

Significance of atypical endometrial cells in women younger than 40 years of age.

INTRODUCTION: The presence of atypical endometrial cells in the Papanicolaou (Pap) test has been associated with an increased rate of endometrial malignancy, with reported rates ranging from 14% to 47%. However, most reported studies have focused on patients who were aged >40 years. The purpose of the present study was to investigate the clinical significance of identifying atypical endometrial cells in Pap test samples in women aged <40 years of age. MATERIALS AND METHODS: A search of the cytology Pap test database was performed from 2000 to 2014 using the keywords "atypical endometrial cells" or "atypical glandular cells favor endometrial origin" in women aged <40 years. The available ThinPrep slides were reviewed. The patients' clinical presentation, follow-up endometrial biopsy findings, treatment, and clinical follow-up data were recorded. Endometrial carcinoma tissue sections were screened for Lynch syndrome. RESULTS: The database search yielded 63 study cases. Of these 63 patients, 52 had subsequently undergone endometrial biopsy. Of the 52 patients with follow-up biopsy findings available, 9 (17.3%) had premalignant (5 with atypical hyperplasia) or malignant (4 with endometrioid adenocarcinoma) lesions. In addition, 16 patients (30.8%) had other endometrial pathologic features. The 9 patients with premalignant or malignant endometrial lesions (8 white, 1 black) were overweight or obese; 3 of the patients did not have any clinical symptoms. All 4 patients with endometrioid adenocarcinoma had negative Lynch syndrome screening findings. CONCLUSIONS: Our results suggest that it is important to recognize the presence of atypical endometrial cells in the Pap tests from young patients, given its association with the finding of premalignant and malignant pathologic features in subsequent endometrial biopsies.

Pulmonary Myoepithelial Tumors With Exuberant Reactive Pneumocytes: Proposed Reclassification of So-called Pneumocytic Adenomyoepithelioma.

Pneumocytic adenomyoepithelioma (PAM) was first described in 2007 and was included in the 2015 World Health Organization Classification of lung tumors as a variant of epithelial-myoepithelial tumor. This rare pulmonary neoplasm was reported to show both myoepithelial and duct-like components, with the latter exhibiting pneumocytic differentiation with TTF-1 expression. We present an index case and 6 additional retrospectively identified cases of pulmonary tumors with prototypical features of PAM. However, with additional clinicoradiologic, histologic, immunohistochemical and cytogenetic data, we were able to reclassify them as myoepithelial neoplasms-both primary and metastatic-with entrapped exuberantly hyperplastic alveolar structures lined by TTF-1 pneumocytes. We reviewed the available literature related to PAM and myoepithelial tumors. Our cases suggest that the entity referred to as PAM represents interstitial growth of myoepithelial neoplasms enticing marked proliferation of entrapped pneumocytes rather than a distinct biphasic neoplasm with pneumocytic differentiation.

Primary effusion lymphoma in human immune deficiency (HIV)-negative non-organ transplant immunocompetent patients.

Primary effusion lymphoma (PEL) is a rare non-Hodgkin's lymphoma most commonly occurring in the context of human immune deficiency (HIV) infection. Herpes virus 8 (HHV-8) has been associated with PEL and considered to be the etiologic agent. In addition, most cases (60%-90%) also show evidence of Epstein-Barr virus (EBV) infection. We describe here an elderly man who was HIV seronegative and immunocompetent, and presented with worsening weakness and ascites. The diagnosis of PEL was rendered cytologically and supported by the results of flow cytometry. The presence of HHV-8 was demonstrated by immunohistochemistry, whereas EBV-associated genetic material was absent by EBER ISH. No lymphadenopathy or organ involvement with lymphoma was found. Systemic chemotherapy with lenalidomide was started given the poor prognosis and commodities of severe coronary artery disease; however, the patient did not respond and succumbed to his disease in 4 months. We present detailed cytologic and clinical findings of this very rare occurrence, and review literature of all reported PEL cases of HIV-negative, nontransplant, immunocompetent patients.

pheS* as a counter-selectable marker for marker-free genetic manipulations in Bacillus anthracis.

Several genetic tools have been developed for use in Bacillus anthracis, but there is still a need for a more marker-free gene inactivation protocols. Thus, we report a method to generate unmarked mutations in B. anthracis. This approach was based on the counter-selectable pheS* gene with assistance by the I-SceI homing endonuclease. Using this strategy, the NprR gene, a transcriptional activator of B. anthracis, was deleted at an extremely high efficiency. Our study indicates that mutated pheS is a useful counter-selective marker to design a valuable genetic tool for in-frame and unmarked gene deletions of B. anthracis.

Association of granulomas in mesenteric lymph nodes in Crohn's disease with younger age and transmural inflammation.

BACKGROUND AND AIMS: Mesenteric lymph nodes were usually removed during bowel resection surgery for Crohn's disease (CD). Mesenteric lymph node (MLN) granuloma predicted postoperative disease recurrence in patients with CD after ileocolic resection (ICR). This study was aimed to identify factors associated with MLN granulomas in a cohort of CD patients who underwent ICR. METHODS: The study group consisted of 18 patients with CD who underwent the index ICR between 2004 and 2012 and had MLN granulomas. The control group included 32 cases negative for MLN granulomas, which were randomly selected from the same period. Clinicodemographic and histological features were compared in these two groups. RESULTS: The presence of MLN granuloma was associated with younger age, perianal disease, and ileocolic disease. Gender, body mass index, smoking status, disease duration, extraintestinal manifestation, length of bowel resected, total number of nodes examined, medical treatment, and indications for surgery were not significantly different between the groups. The presence of MLN granuloma was associated with mural granuloma, transmural inflammation, mural abscess, hypertrophy of the muscularis propria, fibrosis of the muscularis propria, and serosal fibrosis in the small bowel. The multivariable analysis confirms that MLN granuloma was associated with age and transmural inflammation. CONCLUSIONS: In CD patients who underwent the index ICR, the presence of MLN granuloma was associated with younger age and transmural inflammation. Our current results suggest that the detection of MLN granulomas may be enhanced in patients at higher risk, that is, younger patients or those with transmural inflammation on imaging or histopathology.

Comparison of clinical features, treatment, and outcomes of collagenous sprue, celiac disease, and collagenous colitis.

BACKGROUND: Collagenous sprue (CS) is a rare form of enteropathy that had been reported to be associated with celiac disease (CD) and collagenous colitis (CC). The aim of our study was to compare the clinical features, treatments, and outcomes of CS, CD, and CC. METHODS: All patients with histologic diagnosis of CS, CD, or CC with complete clinical data were extracted from our pathology database between 1990 and 2015. Demographic and clinical features were recorded along with treatments and outcomes. RESULTS: A total of 21 patients with CS were included. Overall CS patients were more symptomatic with 17 (81.0%) patients with diarrhea and 15 (71.4%) with unintentional weight loss. Positive celiac serology was noted in 5 (23.8%) CS patients. CS patients had higher rates for disease-related temporary total parenteral nutrition (TPN) use (38.1% vs. 1.1% vs. 1.0%, P < 0.0001) and disease-related hospitalization (52.4% vs. 3.3% vs. 8.2%, P < 0.0001) than that in CD and CC patients. Twenty CS patients received treatments, including the combination of gluten-free diet (GFD) and corticosteroids (n = 12), GFD only (n = 2), and corticosteroids only (n = 6). All CS patients showed symptomatic reliefs with treatment. Although CS patients had a higher rate for hospitalization and TPN use, disease-related death was not observed in all three groups. CONCLUSIONS: Collagenous sprue patients had more severe clinical presentation than patients with CD and CC and therefore had higher demand for temporary TPN and hospitalization. Nevertheless, a prompt use of steroids and/or GFD upon histologic diagnosis of CS may have contributed to an overall excellent prognosis.

17ß-Estradiol alters oxidative damage and oxidative stress response protein expression in the mouse mammary gland.

Although substantial evidence has demonstrated that parity and 17ß-estradiol (E2) reduce mammary carcinogenesis, it is not clear how this protection is conferred. Thus, we examined the effects of parity and E2 treatment in the mammary glands of ovariectomized 15 week-old virgin mice, 15 week-old primiparous mice, and 9 month-old retired breeders. E2 treatment significantly increased lipid peroxidation, protein carbonylation, and protein nitrosylation in the virgin mice, but not in the age-matched primiparous mice or retired breeders. Mammary gland expression of the oxidative stress response protein Cu/Zn superoxide dismutase was consistently reduced in all of the E2-treated mice regardless of parity. Expression of the oxidative stress and DNA repair protein apurinic endonuclease (Ape1) was significantly increased only in the mammary glands of the E2-treated retired breeders. These findings suggest that E2 and parity help to reduce mammary oncogenesis by maintaining the structure and function of proteins, lipids, and DNA.

Syndromic and sporadic inflammatory/hyperplastic small-bowel polyps: a comparative study.

BACKGROUND: Inflammatory/hyperplastic small-bowel polyps (SBPs) occur either sporadically or in patients with a polyposis syndrome; however, comparison between these two settings of the histological features of SBPs has not been reported and the etiology of sporadic inflammatory/hyperplastic SBPs remains unclear. METHOD: Twenty-eight cases of sporadic inflammatory/hyperplastic SBPs and nine cases of syndromic SBPs were retrieved from the Department of Anatomic Pathology at the Cleveland Clinic. Clinico-demographics and histological features were compared between the two groups. RESULTS: Patients with syndromic inflammatory/hyperplastic SBPs were younger (48 vs. 63 years; P = 0.007) and had higher rates of hemorrhagic telangiectasia (55.6% vs. 0%; P = 0.000), gastric polyps (87.5% vs. 21.4%; P = 0.001), and family history of colon cancer (62.5% vs. 11.1%; P = 0.014). Sporadic cases were more frequently associated with gastro-esophageal reflux (35.7% vs. 0%; P = 0.079) and anti-reflux medication use (55.6% vs. 11.1%; P = 0.026). Histologically, the syndromic SBPs were more often of pure intestinal type (45.4% vs. 3.8%; P = 0.005) and had prominent vessels (81.8% vs. 42.3%; P = 0.036). CONCLUSIONS: Patients with syndromic SBPs are younger and have higher rates of hemorrhagic telangiectasia, gastric polyps, and family history of colon cancer. Histologically, syndromic inflammatory/hyperplastic SBPs are more likely to be of pure intestinal type and to have prominent vessels.

Optic nerve aspergillosis.

We report a 55-year-old woman with optic nerve Aspergillosis. Aspergillus is an ubiquitous airborne saprophytic fungus. Inhaled Aspergillus conidia are normally eliminated in the immunocompetent host by innate immune mechanisms; however, in immunosuppressed patients, they can cause disease. The woman had a past medical history of hypertension and migraines. She presented 1 year prior to death with a new onset headache behind the left eye and later developed blurred vision and scotoma. A left temporal artery biopsy was negative for giant cell arteritis. One month prior to the current admission, she had an MRI showing optic nerve thickening with no other findings. Because of the visual loss and a positive antinuclear antibody test, she was given a trial of high dose steroids and while it significantly improved her headache, her vision did not improve. At autopsy, the left optic nerve at the level of the cavernous sinus and extending into the optic chiasm was enlarged in diameter and there was a 1.3 cm firm nodule surrounding the left optic nerve. Histologically, an abscess surrounded and involved the left optic nerve. Acute angle branching, angioinvasive fungal hyphae were identified on Grocott's methenamine silver stained sections, consistent with Aspergillus spp. No gross or microscopic evidence of systemic vasculitis or infection was identified in the body. The literature on optic nerve Aspergillosis is reviewed.

17ß-Estradiol alters oxidative stress response protein expression and oxidative damage in the uterus.

The steroid hormone 17ß-estradiol (E2) has profound effects on the uterus. However, with the E2-induced increase in uterine cell proliferation and metabolism comes increased production of reactive oxygen species (ROS). We examined the expression of an interactive network of oxidative stress response proteins including thioredoxin (Trx), Cu/Zn superoxide dismutase (SOD1), apurinic endonuclease (Ape1), and protein disulfide isomerase (PDI). We demonstrated that treatment of ovariectomized C57BL/6J female mice with E2 increased the mRNA and protein levels of Trx, but decreased SOD1 and Ape1 mRNA and protein expression. In contrast, E2 treatment increased PDI protein levels but had no effect on PDI transcript levels. Interestingly, E2 treatment also increased two markers of cellular damage, lipid peroxidation and protein carbonylation. Our studies suggest that the decreased expression of SOD1 and Ape1 caused by E2 treatment may in the long term result in disruption of ROS regulation and play a role in endometrial carcinogenesis.