Type XIII collagen: regulation of cardiovascular development and malignant transformation in transgenic mice

AbstractType XIII collagen is a type II oriented transmembrane protein with a short intracellular domain, a single transmembrane domain and a large, mostly collagenous extracellular domain. Tissue localization and cell culture studies have implicated that it is involved in cell adhesion.The spatio-temporal expression of type XIII collagen mRNA and protein during murine development is studied here. Type XIII collagen mRNAs were expressed at a constant rate during development, with an increase of expression towards birth. The strongest expression was detected in the central and peripheral nervous systems of the developing mouse fetus. Cultured primary neurons expressed this collagen, and recombinant type XIII collagen was found to enhance neurite outgrowth. Strong expression was also detected in the heart, with localization to cell-cell contacts and perinatal accentuation in the intercalated discs. Other sites of type XIII collagen expression included cartilage, bone, skeletal muscle, lung, intestine and skin. Clear developmental shifts in expression suggest a role in endochondral ossification of bone and the branching morphogenesis in the lung.To elucidate the function of type XIII collagen transgenic mice were generated by microinjection of a cDNA construct that directs the synthesis of truncated α1(XIII) chains with an in-frame deletion of the central collagenous COL2 domain. This construct was thought to disrupt the assembly of normal type XIII collagen trimers. Expression of shortened α1(XIII) chains by fibroblasts derived from mutant mice was demonstrated, and the lack of intracellular accumulation in immunohistochemical analysis of tissues suggested that the mutant molecules were expressed on the cell surface. Transgene expression led to developmental arrest and fetal mortality in offspring from heterozygous mating with two distinct phenotypes. The early phenotype fetuses were aborted by day 10.5 of development due to a failure in the fusion of the chorion and allantois membranes and subsequent disruption in placentation, while the late phenotype fetuses were aborted by day 13.5 of development due to cardiovascular and placental defects. Furthermore, it was shown that the heterozygous mice that were initially of normal appearance and bred normally had an increased susceptibility to develop T-cell lymphomas and angiosarcomas later in life.The results presented here increase the evidence that type XIII collagen is involved in cell adhesion, with several important tasks during development. A role of type XIII collagen in malignant transformation of certain mesenchymal cell populations is also implicated.Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium of the Department of Medical Biochemistry, on December 5th, 2001, at 10 a.m.Abstract Type XIII collagen is a type II oriented transmembrane protein with a short intracellular domain, a single transmembrane domain and a large, mostly collagenous extracellular domain. Tissue localization and cell culture studies have implicated that it is involved in cell adhesion. The spatio-temporal expression of type XIII collagen mRNA and protein during murine development is studied here. Type XIII collagen mRNAs were expressed at a constant rate during development, with an increase of expression towards birth. The strongest expression was detected in the central and peripheral nervous systems of the developing mouse fetus. Cultured primary neurons expressed this collagen, and recombinant type XIII collagen was found to enhance neurite outgrowth. Strong expression was also detected in the heart, with localization to cell-cell contacts and perinatal accentuation in the intercalated discs. Other sites of type XIII collagen expression included cartilage, bone, skeletal muscle, lung, intestine and skin. Clear developmental shifts in expression suggest a role in endochondral ossification of bone and the branching morphogenesis in the lung. To elucidate the function of type XIII collagen transgenic mice were generated by microinjection of a cDNA construct that directs the synthesis of truncated α1(XIII) chains with an in-frame deletion of the central collagenous COL2 domain. This construct was thought to disrupt the assembly of normal type XIII collagen trimers. Expression of shortened α1(XIII) chains by fibroblasts derived from mutant mice was demonstrated, and the lack of intracellular accumulation in immunohistochemical analysis of tissues suggested that the mutant molecules were expressed on the cell surface. Transgene expression led to developmental arrest and fetal mortality in offspring from heterozygous mating with two distinct phenotypes. The early phenotype fetuses were aborted by day 10.5 of development due to a failure in the fusion of the chorion and allantois membranes and subsequent disruption in placentation, while the late phenotype fetuses were aborted by day 13.5 of development due to cardiovascular and placental defects. Furthermore, it was shown that the heterozygous mice that were initially of normal appearance and bred normally had an increased susceptibility to develop T-cell lymphomas and angiosarcomas later in life. The results presented here increase the evidence that type XIII collagen is involved in cell adhesion, with several important tasks during development. A role of type XIII collagen in malignant transformation of certain mesenchymal cell populations is also implicated

Head and neck cancer surgery during the COVID-19 pandemic : An international, multicenter, observational cohort study

Background The aims of this study were to provide data on the safety of head and neck cancer surgery currently being undertaken during the coronavirus disease 2019 (COVID-19) pandemic. Methods This international, observational cohort study comprised 1137 consecutive patients with head and neck cancer undergoing primary surgery with curative intent in 26 countries. Factors associated with severe pulmonary complications in COVID-19-positive patients and infections in the surgical team were determined by univariate analysis. Results Among the 1137 patients, the commonest sites were the oral cavity (38%) and the thyroid (21%). For oropharynx and larynx tumors, nonsurgical therapy was favored in most cases. There was evidence of surgical de-escalation of neck management and reconstruction. Overall 30-day mortality was 1.2%. Twenty-nine patients (3%) tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 30 days of surgery; 13 of these patients (44.8%) developed severe respiratory complications, and 3.51 (10.3%) died. There were significant correlations with an advanced tumor stage and admission to critical care. Members of the surgical team tested positive within 30 days of surgery in 40 cases (3%). There were significant associations with operations in which the patients also tested positive for SARS-CoV-2 within 30 days, with a high community incidence of SARS-CoV-2, with screened patients, with oral tumor sites, and with tracheostomy. Conclusions Head and neck cancer surgery in the COVID-19 era appears safe even when surgery is prolonged and complex. The overlap in COVID-19 between patients and members of the surgical team raises the suspicion of failures in cross-infection measures or the use of personal protective equipment. Lay Summary Head and neck surgery is safe for patients during the coronavirus disease 2019 pandemic even when it is lengthy and complex. This is significant because concerns over patient safety raised in many guidelines appear not to be reflected by outcomes, even for those who have other serious illnesses or require complex reconstructions. Patients subjected to suboptimal or nonstandard treatments should be carefully followed up to optimize their cancer outcomes. The overlap between patients and surgeons testing positive for severe acute respiratory syndrome coronavirus 2 is notable and emphasizes the need for fastidious cross-infection controls and effective personal protective equipment.Peer reviewe

Death following pulmonary complications of surgery before and during the SARS-CoV-2 pandemic

Peer reviewe

Kirurgisia leikkauksia, joita ei tulisi tehdä

Lääketiede on kehittynyt valtavasti viime vuosikymmeninä. Monia leikkauksia on lakattu tekemästä. Lobotomia on ilmeisin esimerkki, mutta myös muun muassa syöpähoidoissa kajotaan entistä vähemmän potilaiden kehoon

Productivity in relation to organization of a surgical department : a retrospective observational study

Background Responsible and efficient resource utilization are important factors in healthcare. The aim of this study was to investigate how total case time differs between two differently organized surgical departments. Methods This is a retrospective observational study of a cohort of patients undergoing elective surgery for breast cancer or malignant melanoma in a university hospital setting in Sweden. All patients were operated on by the same set of surgeons but in two different surgical departments: a general surgery (GS) and a cardiothoracic (CT) surgery department. Patients were selected to the two departments from a waiting list in the order of referral for surgery. The effect of being operated on at the CT department compared to the GS department was estimated by linear regression. Results The final study cohort comprised 349 patients in the GS department and 177 patients in the CT department. Both groups were similar regarding surgical procedures, American Society of Anesthesiologists' score, body mass index, age, sex, and the skill level of the operating surgeon. These covariates were included in the linear regression model. The total case time, defined by the Procedural Time Glossary as room set-up start to room clean-up finish, was significantly shorter for the patients who underwent a surgical procedure at the CT department compared to the GS department, even after adjusting for the background characteristics of the patients and surgeon. After adjusting for the selected covariates, the average difference in total case time between the two departments was - 30.67 min (p = 0.001). Conclusions A significantly shorter total case time was measured for operations in the CT department. Plausible explanations may be more beneficial organizational factors, such as staffing ratio, skill mix in the operating room team, and working behavioral aspects regarding resource utilization.Peer reviewe

Correlation of tumour subtype with long-term outcome in small breast carcinomas : a Swedish population-based retrospective cohort study

Purpose To investigate if molecular subtype is associated with outcome in stage 1 breast cancer (BC). Methods Tissue samples from 445 women with node-negative BCPeer reviewe

Prognostic Value of Stromal Type IV Collagen Expression in Small Invasive Breast Cancers

Breast cancer is the most common cause of cancer death among women worldwide. Localized breast cancer can be cured by surgery and adjuvant therapy, but mortality remains high for tumors that metastasize early. Type IV collagen is a basement membrane protein, and breach of this extracellular matrix structure is the first step of cancer invasion. Type IV collagen is found in the stroma of many cancers, but its role in tumor biology is unclear. Here, expression of type IV collagen in the stroma of small breast cancers was analyzed, correlated to clinically used prognostic biomarkers and patient survival. The findings were further validated in an independent gene expression data cohort. Tissue samples from 1,379 women with in situ and small invasive breast cancers (Peer reviewe

Ex vivo detection of lipopolysaccharide immunopositivity in Rushton bodies

Aim. Our aim was to investigate how bacterial lipopolysaccharide (LPS) is immunoexpressed in periapical lesions. By surprise we detected Rushton bodies (RBs) whose origin has been debatable to be positive for LPS. Methodology. Samples of radicular cysts (N=70) were stained in order to identify variations in LPS immunoexpression indicating bacterial background. For immunostaining, we used an anti-LPS antibody from Escherichia coli, and for visualization Horse Radish Peroxidase labeled polymer as the secondary antibody. Results. RBs showed positivity for LPS in radicular cysts. After collection of radicular cyst samples (70 in total), we noted that all RBs (N=25) histologically detected in tissue samples were positive for LPS. Furthermore, calcification in the cyst capsule showed immunopositivity. Conclusion. We demonstrate for the first time that LPS is present in RBs, indicating that host response to bacteria might be the initial cause of the formation of these hyaline bodies in the cyst epithelium and cyst capsule calcifications

Association between pharmaceutical modulation of oestrogen in postmenopausal women in Sweden and death due to COVID-19 : a cohort study

Objective Determine whether augmentation of oestrogen in postmenopausal women decreases the risk of death following COVID-19. Design Nationwide registry-based study in Sweden based on registries from the Swedish Public Health Agency (all individuals who tested positive for SARS-CoV-2); Statistics Sweden (socioeconomical variables) and the National Board of Health and Welfare (causes of death). Participants Postmenopausal women between 50 and 80 years of age with verified COVID-19. Interventions Pharmaceutical modulation of oestrogen as defined by (1) women with previously diagnosed breast cancer and receiving endocrine therapy (decreased systemic oestrogen levels); (2) women receiving hormone replacement therapy (increased systemic oestrogen levels) and (3) a control group not fulfilling requirements for group 1 or 2 (postmenopausal oestrogen levels). Adjustments were made for potential confounders such as age, annual disposable income (richest group as the reference category), highest level of education (primary, secondary and tertiary (reference)) and the weighted Charlson Comorbidity Index (wCCI). Primary outcome measure Death following COVID-19. Results From a nationwide cohort consisting of 49 853 women diagnosed with COVID-19 between 4 February and 14 September 2020 in Sweden, 16 693 were between 50 and 80 years of age. We included 14 685 women in the study with 11 923 (81%) in the control group, 227 (2%) women in group 1 and 2535 (17%) women in group 2. The unadjusted ORs for death following COVID-19 were 2.35 (95% CI 1.51 to 3.65) for group 1 and 0.45 (0.34 to 0.6) for group 2. Only the adjusted OR for death remained significant for group 2 with OR 0.47 (0.34 to 0.63). Absolute risk of death was 4.6% for the control group vs 10.1% and 2.1%, for the decreased and increased oestrogen groups, respectively. The risk of death due to COVID-19 was significantly associated with: age, OR 1.15 (1.14 to 1.17); annual income, poorest 2.79 (1.96 to 3.97), poor 2.43 (91.71 to 3.46) and middle 1.64 (1.11 to 2.41); and education (primary 1.4 (1.07 to 1.81)) and wCCI 1.13 (1.1 to 1.16). Conclusions Oestrogen supplementation in postmenopausal women is associated with a decreased risk of dying from COVID-19 in this nationwide cohort study. These findings are limited by the retrospective and non-randomised design. Further randomised intervention trials are warranted.Peer reviewe

Exposure to oestrogen and risk of anastomotic leakage after colorectal cancer surgery - A clue to the different leak rates in men and women

Background Colorectal anastomotic leakage is consistently more common in men, regardless of tumour location. This fact is largely unexplained but might be a consequence of biological differences including hormonal exposure and not only related to anatomy. Methods This was a retrospective, nationwide registry-based observational study of post-menopausal women operated for colorectal cancer with an anastomosis between 2007 and 2016. Hormonal exposure before surgery, as defined by prescribed drugs affecting oestrogen levels, was related to postoperative anastomotic leakage, using mixed-effects logistic regression models with adjustment for confounding. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were derived. In addition, separate estimates according to tumour location were computed, and a sensitivity analysis excluding topical oestrogen hormone exposure was conducted. Results Some 16,535 post-menopausal women were included, of which 16.2% were exposed to drugs increasing oestrogen levels before surgery. In this exposed group compared to the unexposed, leak rates were 3.1 and 3.8%, respectively. After adjustment, a reduction of anastomotic leakage in the exposed group was detected (OR: 0.77; 95% CI: 0.59-0.99). This finding was largely attributed to the rectal cancer subgroup (OR: 0.55; 95% CI: 0.36-0.85), while the exclusion of topical oestrogen drugs further reduced the estimates of the main analysis (OR: 0.63; 95% CI: 0.38-1.02). Conclusions Anastomotic leakage rates are lower in women exposed to hormone replacement therapy before surgery for colorectal cancer, which might explain some of the difference in leak rates between men and women, especially regarding rectal cancer.Peer reviewe