A dinocephalian therapsid fauna on the Ecca–Beaufort contact in Eastern Cape Province, South Africa

Systematic exploration of outcrops of the lowermost Beaufort Group for fossils of the oldest terrestrial vertebrates of South Africa, known only from the Permian age Eodicynodon Assemblage Zone in Western Cape Province, has resulted in the discovery of a therapsid fauna in Eastern Cape Province that is dominated by advanced dinocephalians. The new discoveries include the skull and partial skeleton of a juvenile Anteosaurus, skull and skeletal elements of tapinocephalids, as well as the skull of a scylacosaurid therocephalian. The combined presence of advanced tapinocephalid dinocephalians, the anteosaur Anteosaurus, and scylacosaurid therocephalians suggests that the rocks of the lowermost Beaufort Group in the Eastern Cape Province can be assigned to the Tapinocephalus Assemblage Zone, rather than to the Eodicynodon Assemblage Zone, which appears to be restricted to the southwestern part of the Karoo Basin. This biozone identity permits the recognition of a younger age for the Ecca-Beaufort contact eastwards along the southern margin of the basin, thus demonstrating the diachronous nature of the Ecca-Beaufort contact in the southern Karoo

Disturbances of attitudes and behaviours related to eating in black and white females at high school and university in South Africa

This paper reports two studies, which contribute to the increasing evidence that the attitudes and behaviours associated with eating disorders, are encountered among both black and white females in South Africa. In Study One, the Eating Disorders Inventory EDI was administered to black (n=39) and white (n=41) female students in Natal. There were no significant differences between black and white on the sub-scales which measure disturbed eating behaviour directly (Drive for Thinness, Bulimia, Body Dissatisfaction). However black respondents scrored higher on Perfectionism, Interpersonal Distrust and Maturity Fears, variables believed to predispose individuals to eating disorders. In Study Two, the Bulimia Test (BULIT) was administered to black and white females at three educational levels. There was no significant effect of Ethnicity, but there was a significant effect of Age: Standard 6 respondents had significantly higher scores than University students. In both studies, Body mass index (BMI) was significantly higher among blacks than whites. In Study One there was no significant correlation between BMI and Drive for Thinness in either blacks or whites. However in Study Two, the correlation between BMI and BULIT full scale was significant in the case of both blacks (r = 0,39; p <,01) and whites (r = 0,38; p<,05). These findings are consistent with those of other recent studies, which find disturbances in eating-related attitudes and behaviour in all ethnic groups in South Africa

Association of computed tomography measures of muscle and adipose tissue and progressive changes throughout treatment with clinical endpoints in patients with advanced lung cancer treated with immune checkpoint inhibitors

To investigate the association between skeletal muscle mass and adiposity measures with disease-free progression (DFS) and overall survival (OS) in patients with advanced lung cancer receiving immunotherapy, we retrospectively analysed 97 patients (age: 67.5 ± 10.2 years) with lung cancer who were treated with immunotherapy between March 2014 and June 2019. From computed tomography scans, we assessed the radiological measures of skeletal muscle mass, and intramuscular, subcutaneous and visceral adipose tissue at the third lumbar vertebra. Patients were divided into two groups based on specific or median values at baseline and changes throughout treatment. A total number of 96 patients (99.0 %) had disease progression (median of 11.3 months) and died (median of 15.4 months) during follow-up. Increases of 10 % in intramuscular adipose tissue were significantly associated with DFS (HR: 0.60, 95 % CI: 0.38 to 0.95) and OS (HR: 0.60, 95 % CI: 0.37 to 0.95), while increases of 10 % in subcutaneous adipose tissue were associated with DFS (HR: 0.59, 95 % CI: 0.36 to 0.95). These results indicate that, although muscle mass and visceral adipose tissue were not associated with DFS or OS, changes in intramuscular and subcutaneous adipose tissue can predict immunotherapy clinical outcomes in patients with advanced lung cancer

Disturbances of attitudes and behaviours related to eating in black and white females at high school and university in South Africa

This paper reports two studies, which contribute to the increasing evidence that the attitudes and behaviours associated with eating disorders, are encountered among both black and white females in South Africa. In Study One, the Eating Disorders Inventory EDI was administered to black (n=39) and white (n=41) female students in Natal. There were no significant differences between black and white on the sub-scales which measure disturbed eating behaviour directly (Drive for Thinness, Bulimia, Body Dissatisfaction). However black respondents scrored higher on Perfectionism, Interpersonal Distrust and Maturity Fears, variables believed to predispose individuals to eating disorders. In Study Two, the Bulimia Test (BULIT) was administered to black and white females at three educational levels. There was no significant effect of Ethnicity, but there was a significant effect of Age: Standard 6 respondents had significantly higher scores than University students. In both studies, Body mass index (BMI) was significantly higher among blacks than whites. In Study One there was no significant correlation between BMI and Drive for Thinness in either blacks or whites. However in Study Two, the correlation between BMI and BULIT full scale was significant in the case of both blacks (r = 0,39; p <,01) and whites (r = 0,38; p<,05). These findings are consistent with those of other recent studies, which find disturbances in eating-related attitudes and behaviour in all ethnic groups in South Africa

Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity

Overexpression and/or activity of c-Src non-receptor tyrosine kinase is associated with progression of several human epithelial cancers including breast cancer. c-Src activity in ‘pure' ductal carcinoma in situ (DCIS) was measured to assess whether this predicts recurrence and/or correlates with HER2 expression and other clinical parameters. Activated c-Src levels were evaluated in DCIS biopsies from 129 women, with median follow-up at 60 months. High levels of activated c-Src correlated with HER2 positivity, high tumour grade, comedo necrosis and elevated epithelial proliferation. In univariate analysis, high activated c-Src level associated with lower recurrence-free survival at 5 years (P=0.011). Thus, high c-Src activity may identify a subset of DCIS with high risk of recurrence or progression to invasive cancer where therapeutics targeting c-Src may benefit this patient subset

Diversity of Matriptase Expression Level and Function in Breast Cancer

Overexpression of matriptase has been reported in a variety of human cancers and is sufficient to trigger tumor formation in mice, but the importance of matriptase in breast cancer remains unclear. We analysed matriptase expression in 16 human breast cancer cell lines and in 107 primary breast tumors. The data revealed considerable diversity in the expression level of this protein indicating that the significance of matriptase may vary from case to case. Matriptase protein expression was correlated with HER2 expression and highest expression was seen in HER2-positive cell lines, indicating a potential role in this subgroup. Stable overexpression of matriptase in two breast cancer cell lines had different consequences. In MDA-MB-231 human breast carcinoma cells the only noted consequence of matriptase overexpression was modestly impaired growth in vivo. In contrast, overexpression of matriptase in 4T1 mouse breast carcinoma cells resulted in visible changes in morphology, actin staining and cell to cell contacts. This correlated with downregulation of the cell-cell adhesion molecule E-cadherin. These results suggest that the functions of matriptase in breast cancer are likely to be variable and cell context dependent

Absent in Melanoma 2 (AIM2) is an important mediator of interferon-dependent and -independent HLA-DRA and HLA-DRB gene expression in colorectal cancers

Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible, nuclear proteins, associated with both, infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, we and others have previously demonstrated a high frequency of AIM2-alterations in microsatellite unstable (MSI-H) tumors. To further elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive target genes by microarray based gene expression profiling of 22 244 human genes. A total of 111 transcripts were significantly upregulated, whereas 80 transcripts turned out to be significantly downregulated in HCT116 cells, constitutively expressing AIM2, compared with AIM2-negative cells. Among the upregulated genes that were validated by quantitative PCR and western blotting we recognized several interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA), as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in 10 different IFN-γ treated colorectal cancer cell lines. Moreover, small interfering RNA-mediated knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB and CIITA in IFN-γ-treated cells. IFN-γ independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon doxycyclin-regulated transient induction of AIM2. Luciferase reporter assays revealed induction of the HLA-DR promoter upon AIM2 transfection in different cell lines. STAT-signaling was not involved in IFN-γ independent induction of ISGs, arguing against participation of cytokines released in an autostimulating manner. Our data indicate that AIM2 mediates both IFN-γ dependent and independent induction of several ISGs, including genes encoding the major histocompatibility complex (MHC) class II antigens HLA-DR-α and -β. This suggests a novel role of the IFN/AIM2/ISG cascade likewise in cancer cells

Perturbation of adhesion molecule-mediated chondrocyte-matrix interactions by 4-hydroxynonenal binding: implication in osteoarthritis pathogenesis

ABSTRACT: INTRODUCTION: Objectives were to investigate whether interactions between human osteoarthritic chondrocytes and 4-hydroxynonenal (HNE)-modified type II collagen (Col II) affect cell phenotype and functions and to determine the protective role of carnosine (CAR) treatment in preventing these effects. METHODS: Human Col II was treated with HNE at different molar ratios (MR) (1:20 to 1:200; Col II:HNE). Articular chondrocytes were seeded in HNE/Col II adduct-coated plates and incubated for 48 hours. Cell morphology was studied by phase-contrast and confocal microscopy. Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and alpha1beta1 integrin at protein and mRNA levels were quantified by Western blotting, flow cytometry and real-time reverse transcription-polymerase chain reaction. Cell death, caspases activity, prostaglandin E2 (PGE2), metalloproteinase-13 (MMP-13), mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB) were assessed by commercial kits. Col II, cyclooxygenase-2 (COX-2), MAPK, NF-kappaB-p65 levels were analyzed by Western blotting. The formation of alpha1beta1 integrin-focal adhesion kinase (FAK) complex was revealed by immunoprecipitation. RESULTS: Col II modification by HNE at MR approximately 1:20, strongly induced ICAM-1, alpha1beta1 integrin and MMP-13 expression as well as extracellular signal-regulated kinases 1 and 2 (ERK1/2) and NF-kappaB-p65 phosphorylation without impacting cell adhesion and viability or Col II expression. However, Col II modification with HNE at MR approximately 1:200, altered chondrocyte adhesion by evoking cell death and caspase-3 activity. It inhibited alpha1beta1 integrin and Col II expression as well as ERK1/2 and NF-kappaB-p65 phosphorylation, but, in contrast, markedly elicited PGE2 release, COX-2 expression and p38 MAPK phosphorylation. Immunoprecipitation assay revealed the involvement of FAK in cell-matrix interactions through the formation of alpha1beta1 integrin-FAK complex. Moreover, the modification of Col II by HNE at a 1:20 or approximately 1:200 MR affects parameters of the cell shape. All these effects were prevented by CAR, an HNE-trapping drug. CONCLUSIONS: Our novel findings indicate that HNE-binding to Col II results in multiple abnormalities of chondrocyte phenotype and function, suggesting its contribution in osteoarthritis development. CAR was shown to be an efficient HNE-snaring agent capable of counteracting these outcomes

Complementation of diverse HIV-1 Env defects through cooperative subunit interactions: a general property of the functional trimer

<p>Abstract</p> <p>Background</p> <p>The HIV-1 Env glycoprotein mediates virus entry by catalyzing direct fusion between the virion membrane and the target cell plasma membrane. Env is composed of two subunits: gp120, which binds to CD4 and the coreceptor, and gp41, which is triggered upon coreceptor binding to promote the membrane fusion reaction. Env on the surface of infected cells is a trimer consisting of three gp120/gp41 homo-dimeric protomers. An emerging question concerns cooperative interactions between the protomers in the trimer, and possible implications for Env function.</p> <p>Results</p> <p>We extended studies on cooperative subunit interactions within the HIV-1 Env trimer, using analysis of functional complementation between coexpressed inactive variants harboring different functional deficiencies. In assays of Env-mediated cell fusion, complementation was observed between variants with a wide range of defects in both the gp120 and gp41 subunits. The former included gp120 subunits mutated in the CD4 binding site or incapable of coreceptor interaction due either to mismatched specificity or V3 loop mutation. Defective gp41 variants included point mutations at different residues within the fusion peptide or heptad repeat regions, as well as constructs with modifications or deletions of the membrane proximal tryptophan-rich region or the transmembrane domain. Complementation required the defective variants to be coexpressed in the same cell. The observed complementation activities were highly dependent on the assay system. The most robust activities were obtained with a vaccinia virus-based expression and reporter gene activation assay for cell fusion. In an alternative system involving Env expression from integrated provirus, complementation was detected in cell fusion assays, but not in virus particle entry assays.</p> <p>Conclusion</p> <p>Our results indicate that Env function does not require every subunit in the trimer to be competent for all essential activities. Through cross-talk between subunits, the functional determinants on one defective protomer can cooperatively interact to trigger the functional determinants on an adjacent protomer(s) harboring a different defect, leading to fusion. Cooperative subunit interaction is a general feature of the Env trimer, based on complementation activities observed for a highly diverse range of functional defects.</p