CRYßB2 enhances tumorigenesis through upregulation of nucleolin in triple negative breast cancer.

Expression of ß-crystallin B2 (CRYßB2) is elevated in African American (AA) breast tumors. The underlying mechanisms of CRYßB2-induced malignancy and the association of CRYßB2 protein expression with survival have not yet been described. Here, we report that the expression of CRYßB2 in breast cancer cells increases stemness, growth, and metastasis. Transcriptomics data revealed that CRYßB2 upregulates genes that are functionally associated with unfolded protein response, oxidative phosphorylation, and DNA repair, while down-regulating genes related to apoptosis. CRYßB2 in tumors promotes de-differentiation, an increase in mesenchymal markers and cancer-associated fibroblasts, and enlargement of nucleoli. Proteome microarrays identified a direct interaction between CRYßB2 and the nucleolar protein, nucleolin. CRYßB2 induces nucleolin, leading to the activation of AKT and EGFR signaling. CRISPR studies revealed a dependency on nucleolin for the pro-tumorigenic effects of CRYßB2. Triple-negative breast cancer (TNBC) xenografts with upregulated CRYßB2 are distinctively sensitive to the nucleolin aptamer, AS-1411. Lastly, in AA patients, higher levels of nucleolar CRYßB2 in primary TNBC correlates with decreased survival. In summary, CRYßB2 is upregulated in breast tumors of AA patients and induces oncogenic alterations consistent with an aggressive cancer phenotype. CRYßB2 increases sensitivity to nucleolin inhibitors and may promote breast cancer disparity.

A panel of miRNAs as prognostic markers for African-American patients with triple negative breast cancer.

BACKGROUND: To investigate the global expression profile of miRNAs, their impact on cellular signaling pathways, and their association with poor prognostic parameters in African-American (AA) patients with triple negative breast cancer (TNBC). METHODS: Twenty-five samples of AA TNBC patients were profiled for global miRNA expression and stratified considering three clinical-pathological parameters: tumor size, lymph node (LN), and recurrence (REC) status. Differential miRNA expression analysis was performed for each parameter, and their discriminatory power was determined by Receiver Operating Characteristic (ROC) curve analysis. KMplotter was assessed to determine the association of the miRNAs with survival, and functional enrichment analysis to determine the main affected pathways and miRNA/mRNA target interactions. RESULTS: A panel of eight, 23 and 27 miRNAs were associated with tumor size, LN, and REC status, respectively. Combined ROC analysis of two (miR-2117, and miR-378c), seven (let-7f-5p, miR-1255b-5p, miR-1268b, miR-200c-3p, miR-520d, miR-527, and miR-518a-5p), and three (miR-1200, miR-1249-3p, and miR-1271-3p) miRNAs showed a robust discriminatory power based on tumor size (AUC = 0.917), LN (AUC = 0.945) and REC (AUC = 0.981) status, respectively. Enrichment pathway analysis revealed their involvement in proteoglycans and glycan and cancer-associated pathways. Eight miRNAs with deregulated expressions in patients with large tumor size, positive LN metastasis, and recurrence were significantly associated with lower survival rates. Finally, the construction of miRNA/mRNA networks based in experimentally validated mRNA targets, revealed nodes of critical cancer genes, such as AKT1, BCL2, CDKN1A, EZR and PTEN. CONCLUSIONS: Altogether, our data indicate that miRNA deregulated expression is a relevant biological factor that can be associated with the poor prognosis in TNBC of AA patients, by conferring to their TNBC cells aggressive phenotypes that are reflected in the clinical characteristics evaluated in this study.

Analysis of ß-catenin association with obesity in African Americans with premalignant and malignant colorectal lesions.

BACKGROUND: African Americans (AA) are at high risk for Colorectal Cancer (CRC). Studies report a 30-60% increase in CRC risk with physical inactivity, obesity and metabolic syndrome. Activation of the WNT/ß-catenin (CTNNB1) signaling pathway plays a critical role in colorectal carcinogenesis. Accumulating evidence also indicates a role of WNT-CTNNB1 signaling in obesity and metabolic diseases. AIM: To examine the association between obesity, ß-Catenin expression and colonic lesions in African Americans. METHODS: We reviewed the pathology records of 152 colorectal specimens from 2010 to 2012 (46 CRCs, 74 advanced adenomas and 32 normal colon tissues). Tissue Microarrays (TMA) were constructed from these samples. Immunohistochemistry (IHC) for CTNNB1 (ß-Catenin; clone ß-Catenin-1) was performed on the constructed TMAs. The IHC results were evaluated by 2 pathologists and the nuclear intensity staining was scored from 0 to 4. BMI, sex, age, location of the lesion and other demographic data were obtained. RESULTS: Positive nuclear staining in normal, advanced adenoma and CRC was 0, 24 and 41%, respectively (P < 0.001). CRC was asso ciated with positive status for nuclear CTNNB1 intensity (adjusted OR: 3.40, 95%CI = 1.42-8.15, P = 0.006 for positive nuclear staining) compared to non-CRC samples (Normal or advanced adenoma). Nuclear staining percentage has a fair diagnostic ability for CRC with an AUC of 0.63 (95%CI = 0.55-0.71). Overweight/obese patients (BMI > 25) did not show a significant difference in (p = 0.3) nuclear CTNNB1 staining (17% positive in normal weight vs. 27% positive in overweight/obese). The association between nuclear intensity and CRC was not different between normal and overweight patients (P for interaction = 0.6). The positive nuclear CTNNB1status in CRC stage III and IV (35% of all CRC) was not different from stage I and II (50% vs. 36%, respectively, P = 0.4). CONCLUSION: In our study, advanced adenoma and CRC were associated with activation of ß-catenin in physically fit, overweight and obese patients. Thus, obesity and WNT/ß-Catenin pathway seem to be independent in African American patients. WNT/ß-Catenin signaling pathway has a potential to be used as an effector in colon carcinogenic transformation. Whether or not BMI is a modifier of this pathway needs to be investigated further.

Factors influencing treatment outcome in hepatitis C virus minority patients at an inner-city hospital: A STROBE-complaint article.

Chronic hepatitis C virus (HCV) infection disproportionately affects African-Americans (AAs) and is a major contributor to liver failure and mortality. Genetic factors may not be the only cause in outcome disparity. We retrospectively investigated whether genetic host factors, viral genotypes, and treatment compliance in AA patients impacted the efficacy and the sustained virological response (SVR) rate of the interferon (IFN)-based treatment regimen. The medical chart review included 76 African-American patients (age ranging from 26 to 76) with varying levels of hepatitis condition. Fifty-seven (75%) of them had a clinically verifiable HCV infection and were followed by a hepatologist for 2 years at Howard University Hospital in Washington, DC. Both comprehensive metabolic profile and complete blood count analyses were performed. Among the 57 patients whose viral and IL28B genotypes were determined, sixty-eight percent (68%) were infected with viral genotype 1 and 71% harbored the CT allele of the IL28B gene. Among the 12 patients who completed treatment with IFN-based dual or triple therapy, 58% had achieved SVR 12 weeks following completion of treatment; 33% had a partial response with under 6000 viral count after 16 weeks of treatment; and there was one patient with viral genotype 1a and CT allele who did not respond to the medications. The results of this study prove that the PEG IFN-based regimen was effective in treating HCV-infected AA patients despite the current availability of new direct-acting antivirals. The major obstacles contributing to a low reduction in HCV infection and outcome in the AA community were avoidance or lack of treatment or compliance; contraindications, medication side effects, non-adherence, and payer eligibility restrictions.

Can the rate and location of sessile serrated polyps be part of colorectal Cancer disparity in African Americans?

BACKGROUND: Up to 30% of colorectal cancers develop through the serrated pathway. African Americans (AAs) suffer a disproportionate burden of colorectal cancer. The aim of this study was to evaluate clinicopathological features of AA patients diagnosed with sessile serrated polyps (SSPs). METHODS: We conducted a retrospective study of all colonoscopies (n = 12,085) performed at Howard University Hospital, from January 1st, 2010 to December 31st, 2015, of which 83% were in AA patients, (n = 10,027). Among AAs, pathology reports confirmed 4070 patients with polyps including 252 with SSPs. Demographic and clinical variables (i.e. sex, age, BMI, anatomic location, clinical symptoms, polyp size, and clinical indications were collected at colonoscopy. RESULTS: In the AA population, the median age was 56 with interquartile range (IQR) of 51 to 62 years, 54% were female, and 48% had a BMI > 30. The most common reason for colonoscopy was screening (53%), whereas the prevalent reasons for diagnostic colonoscopies were changes in bowel habits (18%) and gastrointestinal bleeding (17%). The total number of SSPs among the 252 AA (diagnosed with SSPs) was 338. Of these, 9% (n = 29/338) had some degree of cytological dysplasia, primarily in the ascending colon (n = 6/42, 14%), Transverse colon (n = 2/16, 13%) and rectosigmoid (n = 19/233, 8%). About 24% of patients had more than 2 polyps. Most patients (76%) had distal SSPs (rectal and rectosigmoid), in comparison to 14% of proximal polyps and 10% of bilateral locations. Median SSA/P size for all locations was 0.6 cm. CONCLUSION: The prevalence of SSPs accounts for 6% of all polyps in AA patients and was diagnosed in 2.5% of all colonoscopies (n = 252/10,027), which is higher than Caucasians in the US. SSPs were predominantly located in the left side, as compared to published literature showing the predominance in the right side of the colon. Screening of CRC will have the chance to detect high risk SSA/P in this population.

Obesity and Pancreatic Cysts in African American Patients.

Objective Obesity is one of the risk factors for pancreatic cancer and a prognostic factor for acute-chronic pancreatitis. Aim To explore the relationship and association between obesity and pancreatic cysts over a 25-year period in African American patients. Methods We reviewed the medical records of 207 patients diagnosed with pancreatic cysts via radiology and pathology data from January 1988 to December 2012. A control group was selected from a separate group of healthy patients without a history of pancreatic disease. The patients were evaluated in five groups according to the last 20 years of diagnosis in five-year intervals. Results Most patients with pancreatic cyst (73%) were overweight (defined as a body mass index (BMI) ≥ 25), and 53% had a history of chronic pancreatitis compared to patients in the control group. There was a significant difference between the two groups; 79% of patients group were overweight (BMI ≥ 25) vs. 66% in control group (p = 0.02). The incidence of obese and overweight patients was significant (85%) during the 2008 to 2012 interval for the test group (p = 0.009). Conclusion Given the increasing proportion of obese pancreatic cyst patients in recent decades compared to the proportion noted in the 1990s, obesity plays a large role in the formation of pancreatic cysts.

Gastrointestinal Lesions in African American Patients With Iron Deficiency Anemia.

BACKGROUND: Iron deficiency anemia (IDA) is a frequent disorder that is associated with many serious diseases. However, the findings of an evaluation of IDA-associated gastrointestinal disorders are lacking among African American patients. AIM: To determine the most prevalent gastrointestinal lesions among African American patients with IDA especially in young men. METHODS: We reviewed medical records (n = 422) of patients referred for evaluation of IDA from 2008 to 2012. Iron deficiency anemia was diagnosed using clinical laboratory tests. The results of esophagogastroduodenoscopy, colonoscopy, and pathology specimens along with demographic data were abstracted and analyzed using Stata. RESULTS: The mean age was 61.9 years, and 50.5% were women. In total, 189 patients (45%) had gross gastrointestinal (GI) bleeding. The most frequent diagnoses were gastritis (40%), benign colonic lesions (13%), esophagitis (9%), gastric ulcer (6%), and duodenitis (6%). GI bleeding was significantly more frequent in men (P = 0.001). Benign and malignant colonic lesions were significantly more present among older patients: 16% vs 6% (P = .005) and 5% vs 0% (P = .008), respectively. Colitis was more prevalent in younger patients (⩽50): 11% vs 2% (P = .001). In patients with gross lower GI bleeding, the top diagnoses were gastritis (25%), benign colon tumors (10%), and duodenitis (6%). Colon cancer was diagnosed among 15 patients, and all these patients were older than 50 years of age. CONCLUSIONS: Gastritis and colonic lesions are most common associated lesions with IDA among African Americans. So bidirectional endoscopy is required for unrevealing of the cause of IDA in asymptomatic patients.

Clinical and Pathological Risk Factors Associated with Liver Fibrosis and Steatosis in African-Americans with Chronic Hepatitis C.

BACKGROUND AND AIM: Several factors involved in the development of liver fibrosis in African-American patients with chronic hepatitis C have not been well studied. We aimed to evaluate some of these risk factors. METHODS: We reviewed pathology and medical records of 603 African-Americans with chronic hepatitis C virus (HCV) infection at Howard University Hospital from January 2004 to December 2013. Among the clinical and pathological data collected were HIV (human immunodeficiency virus), HCV genotype, hepatitis B virus (HBV), diabetes mellitus (DM), hypertension (HTN), body mass index (BMI), and hepatic steatosis. RESULTS: The frequency of DM, HTN, HIV, and HBV was 22, 16, 11, and 4%, respectively. Median BMI was 27.3 kg/m2. The frequency of fibrosis stages 0, 1, 2, 3, and 4 was 2, 48, 28, 11, and 11%, respectively. In multivariate logistic regression, we found a significant association between liver fibrosis stage (3-4 vs. 0-2) and HIV infection (OR 2.4, P = 0.026), HTN (OR 3.0, P = 0.001), age (OR 2.6 for every 10 years, P < 0.001), weight (OR 1.1 for every 10 lb increase, P = 0.002), and steatosis grade (OR 1.6, P = 0.002). The frequency of liver steatosis was 73%. In an ordinal logistic regression, significant risk factors for steatosis were female gender (OR 1.5, P = 0.034) and inflammation grade (P = 0.001). CONCLUSION: This study shows that steatosis is independently associated with fibrosis in African-American patients with HCV infection. Female patients were at higher risk of steatosis.