F10 cytotoxicity via topoisomerase I cleavage complex repair consistent with a unique mechanism for thymineless death

DNA topoisomerase I (Top1) is the sole target of camptothecin (CPT) and other Top1 poisons [1] that are widely used drugs for treatment of colon cancer and other malignancies. Our previous studies have shown that Top1 is also an important target for the fluoropyrimidine polymer F10 reviewed in [2], and that Top1 poisoning plays an important, but relatively undefined role in thymineless death (TLD), the process by which inhibiting de novo thymidylate synthesis causes DNA damage and cell death. While Top1 poisoning is an important aspect of TLD, thymidine deprivation may also cause DNA damage by Top1-independent pathways, such as replication fork collapse, and these multiple sources of DNA damage may provide the basis for the very strong potency of F10 relative to alternative DNA damaging agents observed for many types of malignant cells. Elucidating the DNA repair pathways activated in cells treated with F10 relative to CPT can provide insight into how Top1 poisoning induced by fluoropyrimidine drugs differs from traditional Top1 poisons, and also clarify which aspects of the DNA damage response are activated by Top1-independent processes

Comparative effectiveness and safety of anticoagulants for the treatment of heparin‐induced thrombocytopenia

BACKGROUND The effectiveness and safety of non-heparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT) are not fully established, and the optimal treatment strategy is unknown. In a systematic review and meta-analysis, we aimed to determine precise rates of platelet recovery, new or progressive thromboembolism (TE), major bleeding, and death for all non-heparin anticoagulants and to study potential sources of variability. METHODS Following a detailed protocol (PROSPERO: CRD42020219027), EMBASE and Medline were searched for all studies reporting clinical outcomes of patients treated with non-heparin anticoagulants (argatroban, danaparoid, fondaparinux, direct oral anticoagulants [DOAC], bivalirudin, and other hirudins) for acute HIT. Proportions of patients with the outcomes of interest were pooled using a random-effects model for each drug. The influence of the patient population, the diagnostic test used, the study design, and the type of article was assessed. RESULTS Out of 3194 articles screened, 92 studies with 119 treatment groups describing 4698 patients were included. The pooled rates of platelet recovery ranged from 74% (bivalirudin) to 99% (fondaparinux), TE from 1% (fondaparinux) to 7% (danaparoid), major bleeding from 1% (DOAC) to 14% (bivalirudin), and death from 7% (fondaparinux) to 19% (bivalirudin). Confidence intervals were mostly overlapping, and results were not influenced by patient population, diagnostic test used, study design, or type of article. DISCUSSION Effectiveness and safety outcomes were similar among various anticoagulants, and significant factors affecting these outcomes were not identified. These findings support fondaparinux and DOACs as viable alternatives to conventional anticoagulants for treatment of acute HIT in clinical practice

Tumorigenic role of podoplanin in esophageal squamous-cell carcinoma

Background. Podoplanin, a mucin-type transmembrane glycoprotein, is thought to be one of the cancer stem cell markers for squamous-cell carcinoma of the vulva. The objectives of the present study were to examine the role of podoplanin in esophageal squamous-cell carcinoma (ESCC). Methods. Expression of podoplanin was examined immunohistochemically in 61 cases of ESCC that had not been treated with chemotherapy or radiotherapy before surgery. Because cancer stem-cell quantities have been reported to increase with chemotherapy and radiotherapy, cases in patients who did not receive such prior therapies were included in this study. Cases with[10% tumor cells showing signals for podoplanin were categorized as podoplanin high, and the others were classified as podoplanin low. The effects of podoplanin on the behavior of cancer cells were evaluated in ESCC cell lines in which podoplanin expression was knocked down. Results. To examine whether podoplanin could be used as a cancer stem cell marker for ESCC, podoplanin-positive and podoplanin-negative fractions were sorted separately from the ESCC cell line and cultured. Podoplanin-positive ESCC cells yielded both podoplanin-positive and podoplanin- negative cells, whereas few cells were obtained from podoplanin-negative ESCC cells. When podoplanin expression was knocked down, ESCC cell lines became vulnerable to anticancer drugs and showed defective invasion and tumorigenic activities. Nineteen (31.1%) of 61 cases were categorized as podoplanin high. Podoplaninhigh cases were correlated with T category, stage of disease, lymphatic and vascular invasion, recurrence, and prognosis of patients. Podoplanin-low cases showed better overall and disease-free survival. Conclusions. There is a role for podoplanin in tumorigenesis and malignant progression in ESCC. Cancer cells comprise a heterogeneous group of cells, among which only a small population of cells possesses the ability to reconstitute a whole tumor.1–3 This population, called cancer stem cells (CSCs), efficiently forms colonies in semisolid culture and is xenotransplantable in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice.4 CSCs were first identified in leukemia and subsequently isolated from solid tumors, such as those of breast, brain, prostate, melanoma, colon, pancreas, head/neck, liver, and gastric cancers.5–15 CSCs are known to be resistant to chemotherapy and radiotherapy and are more invasive than non-CSCs. Recognition of CSCs and their efficient elimination may be a valuable strategy for treatment of cancers. Therefore, studies to search for markers of CSCs have been performed. First, successful isolation of CD34? CD38- leukemic stem cells was reported.5 However, subsequent studies showed that markers for CSCs differ among cancers originating from different organs. Atsumi et al. reported that podoplanin, a mucin-type transmembrane glycoprotein, is a possible candidate CSC marker for squamous-cell carcinoma (SCC).16 Cultured cells from the SCC cell line A431, which is derived from the vulva, consist of two populations: podoplanin-positive and podoplanin-negative cells. CSCs are known to produce both CSC and non-CSC