Camptothecin and khat (Catha edulis Forsk.) induced distinct cell death phenotypes involving modulation of c-FLIPL, Mcl-1, procaspase-8 and mitochondrial function in acute myeloid leukemia cell lines

<p>Abstract</p> <p>Background</p> <p>An organic extract of the recreational herb khat (<it>Catha edulis </it>Forsk.) triggers cell death in various leukemia cell lines <it>in vitro</it>. The chemotherapeutics camptothecin, a plant alkaloid topoisomerase I inhibitor, was tested side-by-side with khat in a panel of acute myeloid leukemia cell lines to elucidate mechanisms of toxicity.</p> <p>Results</p> <p>Khat had a profound effect on MOLM-13 cells inducing mitochondrial damage, chromatin margination and morphological features of autophagy. The effects of khat on mitochondrial ultrastructure in MOLM-13 correlated with strongly impaired routine respiration, an effect neither found in the khat-resistant MV-4-11 cells nor in camptothecin treated cells. Enforced expression of anti-apoptotic Bcl-2 protein provided protection against camptothecin-induced cell death and partly against khat toxicity. Khat-induced cell death in MOLM-13 cells included reduced levels of anti-apoptotic Mcl-1 protein, while both khat and camptothecin induced c-FLIP_Lcleavage and procaspase-8 activation.</p> <p>Conclusion</p> <p>Khat activated a distinct cell death pathway in sensitive leukemic cells as compared to camptothecin, involving mitochondrial damage and morphological features of autophagy. This suggests that khat should be further explored in the search for novel experimental therapeutics.</p

Triaging HPV-Positive Cervical Samples with p16 and Ki-67 Dual Stained Cytology within an Organized Screening Program—A Prospective Observational Study from Western Norway

The implementation of high-risk human papillomavirus testing (hrHPV testing) as a screening method in substitute for cytology has evoked the need for more sensitive and less objective tests for the triage of HPV-positive women. In a cohort of 1763 HPV-positive women, the potential of immunocytochemical p16 and Ki-67 dual staining as compared to cytology, alone or in combination with HPV partial genotyping, was tested for triage of women attending a cervical cancer screening program. Performance was measured using sensitivity, specificity, and positive and negative predictive values. Comparisons were assessed using logistic regression models and the McNemar test. Dual staining was evaluated in a prospectively collected study cohort of 1763 HPV-screened women. For triage of CIN2+ and CIN3+, NPV and sensitivity, 91.8% and 94.2% versus 87.9% and 89.7%, respectively, were significantly higher using dual staining together with HPV 16/18 positive, as compared to cytology (p < 0.001). The specificities, however, were lower for dual staining as compared to cytology. Conclusions: Dual staining is safer for decision-making regarding HPV-positive women’s need for follow-up with colposcopy and biopsy, as compared to cytology

Morphological evaluation of human vs xenografted mice ovarian serous adenocarcinomas.

<p>The left column shows a high-grade serous adenocarcinoma from human ovary. The right column shows a mouse with a representative ovarian xenograft derived from human SKOV-3^luc+ cells. (<b>A</b>), Formalin fixed paraffin embedded H+E stained sections of human (left) vs xenografted (right) mice (10× magnification), (<b>B–F</b>), Detection of various cancer protein biomarkers (Ber-EP4, cytokeratin, TAG72, vimentin, and WT1) by immunohistochemistry in human (left) vs xenografted (right) mice (10× magnification).</p

Surgical procedures and monitoring of tumor growth in xenografted mice by bioluminescence image analysis.

<p>(<b>A</b>), Preoperative bioluminescence imaging of a representative xenografted (SKOV-3^luc+ cells) mouse (dorsal aspect) with colour bar illustrating photon counts per raster scan point (1 mm²). (<b>B–D</b>), Illustrations of various routine surgical procedures with exposure of right tube (B), ovary (C) and after closure of the incision in the mouse abdominal wall (D). (<b>E</b>), Routine surgical resection specimen illustrating uterus (U), ovaries (O) and the ovarian tumor (T). (<b>F</b>), Immediate postoperative (dorsal view) bioluminescent negative view indicating apparent complete surgical removal of xenografted SKOV-3^luc+ cells.</p

Tumor engraftment and tumor progression.

<p>Xenograft disease characteristics. Data is derived from 10 xenografted mice.</p