Immunophenotypic Evaluation of DNA Mismatch Repair Markers in 2 Cases of Synchronous Histomorphologically Distinct Gastric Adenocarcinomas With Gastrointestinal Stromal Tumors of the Proximal Small Bowel

Objectives: To assess the prognostic value of combined mismatch DNA repair (MMR) phenotyping in 2 synchronous histomorphologically distinct gastric adenocarcinomas (GADCs), each accompanied by gastrointestinal stromal tumors (GISTs) of the proximal small bowel. Summary Background Data: A 72-year-old female and a 55-year-old male patient were submitted to partial and total gastrectomy, respectively, with synchronous resection of a GIST in the proximal small bowel. The 2 patients attained contrasting survival outcomes. The female survives disease-free 20 months after surgery having received no chemotherapy. The male who received adjuvant chemotherapy developed metastases in liver and lung, and died 18 months after surgery. Methods: We phenotype MSH2 and MLH1 protein expression in tumor relative to matched normal tissue by immunohistochemistry. Results: Immunohistochemistry analysis revealed different combined MMR phenotypes for the 2 histomorhologically distinct GADCs and similar for both GISTs studied. Conclusions: Good and bad prognosis for disease-free survival of patients based on reduced and elevated combined MMR phenotypic expression of the 2 histomorphologically distinct GADCs, could be explained by disease-associated emergence of genomic MMR alterations in the tumor. The impact of synchronous GISTs with common intermediate MMR phenotypes on patient survival is rather incidental and secondary to predominating GADCs

Maternal serum pregnancy-associated plasma protein-A concentration at 11–14 weeks of gestation and preeclampsia risk of women with common congenital anatomic uterine abnormalities

To evaluate maternal serum pregnancy-associated plasma protein-A (PAPP-A) levels at 11–14 weeks of gestation and preeclampsia risk in women with common congenital anatomic uterine abnormalities (AUAs). First trimester screening markers were compared between 12 AUA pregnancies, 60 age matched controls and 12 cases of early preeclampsia. PAPP-A level and birth weight were significantly lower in AUA compared to control and early preeclampsia group (p<.001). Preeclampsia was absent in the AUAs pregnancies group. Birth weight were similar in AUA group when we compared AUA and control group regarding weeks of gestation at delivery and lower but not significantly, when we compared AUA and early preeclampsia group. Our findings suggest that AUA pregnancies are associated with low first trimester maternal serum PAPP-A concentrations not predictive of susceptibility to preeclampsia.Impact statementWhat is already known on this subject? During first trimester screening for preeclampsia based on maternal pregnancy-associated plasma protein A (PAPP-A) levels, various parameters are used, such as the somatometric characteristics of pregnant woman, single or multiple pregnancy, smoking status, family history, diabetes, hypertension and measurement of blood pressure and uterine artery Dopplers. What do the results of this study add? Our pioneer study revealed that there is drastic difference in PAPP-A concentration in women with common anatomic uterine abnormalities (AUAs), in comparison with their age matched control women with normal uterus. What are the implications of these findings for clinical practice and further research? Based on our results, uterine anatomical deviations, is another factor which must be taken in account for preeclampsia risk calculation and further clinical consultation and follow up in those pregnancies. Lower PAPP-A levels in AUA cases is a weak predictor of susceptibility to preeclampsia and could be associated to smaller placental size rather than poor placentation and in future research the calculation of the uterine cavity functional dimension may lead to a more accurate clinical assessment. © 2022 Informa UK Limited, trading as Taylor & Francis Group

Sequence-based genotyping HPV L1 DNA and RNA transcripts in clinical specimens

We developed a direct sequence-based genotyping method to detect single and multiple HPV L1 DNA and RNA types in genital and dermatological specimens. Our method couples PCR amplification of a highly conserved HPV L1 segment using a broad spectrum-generic primer cocktail mix with automated sequencing of amplified PCR products, followed by GenBank sorting of sequencing data. We genotyped 5 skin and 30 cervical HPV DNA-positive specimens using this method and established its first experimentally derived working cutoff value with the aid of commercial hybridization-based techniques. We suggest that sequence-based genotyping of appropriately amplified DNA and RNA products may serve as a primary HPV detection method in dermatological specimens. It can be applied as an all-purpose genotyping method for rare HPV types not detectable by commercial hybridization-based techniques and for sorting multiple HPV infections by order of prevalence. (C) 2009 Elsevier GmbH. All rights reserved

Susceptibility of β-thalassemia heterozygotes to COVID-19

Background: β-Thalassemia is the most prevalent single gene blood disorder, while the assessment of its susceptibility to coronavirus disease 2019 (COVID-19) warrants it a pressing biomed-ical priority. Methods: We studied 255 positive COVID-19 participants unvaccinated against severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), consecutively recruited during the last trimester of 2020. Patient characteristics including age, sex, current smoking status, atrial fibrillation, chronic respiratory disease, coronary disease, diabetes, neoplasia, hyperlipidemia, hypertension, and β-thalassemia heterozygosity were assessed for COVID-19 severity, length of hospitalization, intensive care unit (ICU) admission and mortality from COVID-19. Results: We assessed patient characteristics associated with clinical symptoms, ICU admission, and mortality from COVID-19. In multivariate analysis, severe-critical COVID-19 was strongly associated with male sex (p = 0.023), increased age (p <0.001), and β-thalassemia heterozygosity (p = 0.002, OR = 2.89). Regarding the requirement for ICU care, in multivariate analysis there was a statistically significant association with hypertension (p = 0.001, OR = 5.12), while β-thalassemia heterozygosity had no effect (p = 0.508, OR = 1.33). Mortality was linked to male sex (p = 0.036, OR = 2.09), increased age (p < 0.001) and β-thalassemia heterozygosity (p = 0.010, OR = 2.79) in multivariate analysis. It is worth noting that hyperlipidemia reduced mortality from COVID-19 (p = 0.008, OR = 0.38). No statistically significant association of current smoking status with patient characteristics studied was observed. Conclusions: Our pilot observations indicate enhanced mortality of β-thalassemia heterozygotes from COVID-19. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Phenotypic mismatch repair hMSH2 and hMLH1 gene expression profiles in primary non-small cell lung carcinomas

Background: Defects in the human DNA mismatch repair genes (MMR) hMSH2 and hMLH1 arc responsible for the development of sporadic and hereditary colorectal cancers. The role of MMR genes in the pathogenesis of lung cancer has not been elucidated. The aim of this study was to address the phenotypic mRNA expression profiles of mismatch DNA repair system in lung cancer. Materials and methods: We evaluated the mRNA levels of the hMSH2 and hMLH1 components of the mismatch DNA repair (MMR) system in 29 unselected frozen pairs of primary non-small cell lung carcinomas (NSCLCs) and their adjacent normal tissue (ANTs) specimens by quantitative real-time PCR analysis relative to housekeeping Porphobilinogen deaminase (hPBGD) mRNA. To simplify and potentially improve the analysis of data, we defined for each individual MMR mRNA two possible phenotypes: a regular (R(2): hMSH2/hPBGD mRNAs >= 1 and R(1): hMLH1/hPBGD mRNAs >= 1) and a reduced (r(2): hMSH2/hPBGD mRNAs < 1 and r(1): hMLH1/hPBGD mRNAs < 1). The presence of MMR gene expression was evaluated after conversion of the molecular mRNA levels into clinically distinct phenotypic entities by these working criteria, based on the hypothesis that reduced mRNA and protein levels result in lower or non-functional MMR. Results: Phenotyping defined four distinct MMR system expression profiles, R(2)R(1), r(2)R(1), R(2)r(1) and r(2)r(1) by ascending tumor progression rate and identified a previously unrecognized disease-associated phenotypic entity (r(2)r(1)). The phenotype-based biological aspects of the MMR system suggested that its two components: (1) function independently and (2) are not directly involved in the onset of the transformation process, since healthy lung tissue was devoid of r(2)r(1) phenotypes. Conclusion: These findings link MMR mRNA levels of paired lung tissue specimens to patients' clinical condition and suggest that phenotypic translation of molecular MMR data refines the biology of the MMR system with consequent diagnostic implications in the clinical assessment of lung cancer patients. (C) 2008 Elsevier Ireland Ltd. All rights reserved

Vulnerability of β-Thalassemia Heterozygotes to COVID-19: Results from a Cohort Study

Background: The assignment of mortality risk from SARS-CoV-2 virus (COVID-19) to vulnerable patient groups is an important step toward containment of the pandemic. Methods: A total of 760 patients with a positive molecular test for SARS-CoV-2 who were unvaccinated against COVID-19 were recruited between 1 January and 30 June 2021. Patients were grouped by age; sex; and common morbidities, such as atrial fibrillation, chronic respiratory disease, coronary disease, diabetes type II, neoplasia, hypertension and β-Thalassemia heterozygosity. As a primary endpoint, we assessed mortality risk from COVID-19, and as secondary endpoints, we considered clinical severity and need for Intense Care Unit (ICU) admission. Results: In multivariate analysis, male sex (p < 0.001, OR = 2.59), increasing age (p < 0.001, OR = 1.049), β-Thalassemia heterozygosity (p = 0.001, OR = 2.41) and chronic respiratory disease (p = 0.018, OR = 1.84) were identified as risk factors associated with mortality due to COVID-19. Moreover, male sex (p < 0.001, OR = 1.98), increasing age (p < 0.001, OR = 1.052) and β-Thalassemia heterozygosity (p = 0.001, OR = 2.59) were associated with clinical severity in logistic regression. Regarding ICU admission, the risk factors were identified as male sex (p = 0.002, OR = 1.99), chronic respiratory disease (p = 0.007, OR = 2.06) and hypertension (p < 0.001, OR = 5.81). Conclusions: An increased mortality risk from COVID-19 was observed for older age, male sex, β-Thalassemia heterozygosity and respiratory disease. Carriers of β-Thalasse-mia were identified as more vulnerable for severe clinical symptomatology, but there was no increased possibility for ICU admission. Readjustment of these findings to consider impacts of variant strains prevailing during the latest viral outbreak among vulnerable patient groups may offer timely relief from the pandemic. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Association of maternal angiotensin II type 1 and type 2 receptor combination genotypes with susceptibility to early-onset preeclampsia

Allelic variations affecting the activity of the maternal renin-angiotensin system may play a role in the development of hypertensive disorders of pregnancy like preeclampsia, its more severe early-onset form, and intrauterine growth restriction. We examined the association of common allelic variants of angiotensin II type 1 and type 2 receptor genes (AT1R and AT2R) sorted in five AT1R/AT2R receptor combination genotype groups with susceptibility to early-onset preeclampsia (EOP). The occurrence of AT1R (A1166C) and A2TR (C3123A) alleles in wild type (AA, CC), heterozygous (A/C, C/A), and homozygous (C/C, A/A) states was recorded in 84 women with a history of EOP and 84 age-matched controls sorted in five AT1R/AT2R receptor combination genotype (wild type: AA/CC, one mutant: AA/CA, AC/CC, two mutant: AC/CA, AA/AA, CC/CC, three mutants: AC/AA, CC/CA and four mutant: CC/AA) groups, by polymerase chain reaction-RFLP analysis. Three mutant receptor combination genotype carriers were more common in women with a history of EOP than in controls (26.18% vs. 4.76%, p = 0.003, OR = 8.25). Receptor combination genotyping may be of clinical value in: (a) maternal prediction of susceptibility to EOP, (b) disease subtyping for directed studies with receptor signaling antagonists, (c) the broader study of hypertension. © 2021, The Author(s), under exclusive licence to Springer Nature Limited

Expression of 6 Common Antigenic Markers in Invasive Ductal Breast Carcinoma: Potential Clinical Implications

Expression of estrogen (ER) and progesterone receptors, c-erbB-2 oncogene, mutant p53 antioncogene (mp53), e-cadherin adhesion, and apoptotic caspase-8 antigens in tumor relative to matched normal tissue specimens from 102 unselected patients with primary ductal breast carcinoma of various tumor grades was assessed by immunohistochemistry and correlated with patient's biologic and clinical features, such as age, menstrual status, age of menarche, tumor grade and diameter, the presence or absence of metastases, and number of infiltrated lymph nodes. We observed association of e-cadherin adhesion, ER and progesterone antigen marker expression with low histologic grade tumors and limited number of lymph node metastases and of c-erbB-2, mp53, and casp-8 antigen marker expression with high histologic grade tumors and increased number of lymph node metastases. We also observed strong correlation (P < 0.05) between 4 of the 6 biomarkers and 4 of the 7 patient/tumor parameters examined. Our findings support the hypothesis of independent expression of these 4 strong biomarkers and reveal that nearly 40% of all breast tumor cases studied express similar proportions of 2 major phenotypic combinations [ER/c-erbB-2/mp53/casp-8: +/+/-/+ (19.6%) & +/-/-/+ (17.8%)]. We conclude that, in agreement with earlier reports, our findings support the diagnostic and potential prognostic value of these markers in the clinical assessment of breast cancer