Alleviating iatrogenic effects of paclitaxel via antiinflammatory treatment.

BACKGROUND: Paclitaxel (PTX) is touted as an essential medicine due to its extensive use as a chemotherapeutic agent for various cancers and an antiproliferative agent for endovascular applications. Emerging studies in cardio-oncology implicate various vascular complications of chemotherapeutic agents. METHODS: We evaluated the inflammatory response induced by the systemic administration of PTX. The investigation included RNAseq analysis of primary human endothelial cells (ECs) treated with PTX to identify transcriptional changes in pro-inflammatory mediators. Additionally, we used dexamethasone (DEX), a well-known antiinflammatory compound, to assess its effectiveness in counteracting these PTX-induced changes. Further, we studied the effects of PTX on monocyte chemoattractant protein-1 (MCP-1) levels in the media of ECs. The study also extended to in vivo analysis, where a group of mice was injected with PTX and subsequently harvested at different times to assess the immediate and delayed effects of PTX on inflammatory mediators in blood and aortic ECs. RESULTS: Our RNAseq analysis revealed that PTX treatment led to significant transcriptional perturbations in pro-inflammatory mediators such as MCP-1 and CD137 within primary human ECs. These changes were effectively abrogated when DEX was administered. In vitro experiments showed a marked increase in MCP-1 levels in EC media following PTX treatment, which returned to baseline upon treatment with DEX. In vivo, we observed a threefold increase in MCP-1 levels in blood and aortic ECs 12 h post-PTX administration. Similar trends were noted for CD137 and other downstream mediators like tissue factor, vascular cell adhesion molecule 1, and E-selectin in aortic ECs. CONCLUSION: Our findings illustrate that PTX exposure induces an upregulation of atherothrombotic mediators, which can be alleviated with concurrent administration of DEX. Considering these observations, further long-term investigations should focus on understanding the systemic implications associated with PTX-based therapies and explore the clinical relevance of DEX in mitigating such risks.

Pharmacologic Manipulation of Late SV40 Factor Suppresses Wnt Signaling and Inhibits Growth of Allogeneic and Syngeneic Colon Cancer Xenografts.

Aberrant hyperactivation of Wnt signaling, driven by nuclear ß-catenin in the colonic epithelium, represents the seminal event in the initiation and progression of colorectal cancer (CRC). Despite its established role in CRC tumorigenesis, clinical translation of Wnt inhibitors remains unsuccessful. Late SV40 factor (LSF; encoded by TFCP2) is a transcription factor and a potent oncogene. The current study identified a chemotype, named factor quinolinone inhibitors (FQIs), that specifically inhibits LSF DNA-binding, partner protein-binding, and transactivation activities. The role of LSF and FQIs in CRC tumor growth was examined. Herein, the study showed that LSF and ß-catenin interacted in several CRC cell lines irrespective of their mutational profile, which was disrupted by FQI2-34. FQI2-34 suppressed Wnt activity in CRC cells in a dose-dependent manner. Leveraging both allogeneic and syngeneic xenograft models showed that FQI2-34 suppressed CRC tumor growth, significantly reduced nuclear ß-catenin, and down-regulated Wnt targets such as axis inhibition protein 2 (AXIN-2) and SRY-box transcription factor 9, in the xenograft cells. FQI2-34 suppressed the proliferation of xenograft cells. Adenocarcinomas from a series of stage IV CRC patients revealed a positive correlation between LSF expression and Wnt targets (AXIN-2 and SRY-box transcription factor 9) within the CRC cells. Collectively, this study uncovers the Wnt inhibitory and CRC growth-suppressive effects of these LSF inhibitors in CRC cells, revealing a novel target in CRC therapeutics.

A Cost Analysis of Pathology Evaluation of Carotid Plaque after Endarterectomy.

BACKGROUND: Overtreatment and overuse of resources are leading causes of rising health care costs. Identification and elimination process of low value services is important in reducing such costs. At many institutions it is routine to send excised plaque after carotid endarterectomy (CEA) for pathology evaluation. With more than 140,000 CEAs performed annually in the United States, this represents an opportunity for potential cost savings. We set out to examine the cost and clinical use of pathology evaluation of plaque after CEA. METHODS: We performed a retrospective review of patients undergoing CEA at a single institution from 2016 to 2019. Patients were excluded if they had a prolonged postoperative length of stay or if they had a preoperative stroke. Demographics, perioperative outcomes, and billing costs were recorded. RESULTS: We identified 82 total CEAs, of which 42 were excluded according to the aforementioned exclusion criteria. We reviewed 40 CEAs. Mean age of this cohort was 67.2 (±8.3) years. Most (72.5%) were asymptomatic at the time of admission, whereas 27.5% presented with a transient ischemic attack. Mean postoperative length of stay was 1.8 days. The primary insurers were 39.5% private, 39.5% Medicare, and 21.1% Medicaid. Mean total charges for the hospitalization were $83,367 (±$42,874). Of this total, professional fees were $3,512 (±$980) and facility fees were $80,395 (±$42,886). Mean pathology charges were $285 (±$88). The pathology professional fee was $61 (±$27), which represented 1.82% (±0.88) of the professional costs. Reimbursement for the facility pathology charge was $229 (±$57) and for the professional pathology charge was $25 (±$14). All plaque samples were submitted for gross examination and hematoxylin and eosin staining. The correlation rate for the clinical and pathologic diagnosis was 100%. The pathology reports simply read "atherosclerotic plaque" and "calcific plaque" in 32.5% and 45% of samples. For the remaining plaques, 12.5% and 10% of reports also noted fibrosis and degenerative changes, respectively. There were no clinical implications or decisions made based on the pathology reports. Cost of pathology evaluation was on average $285, with an average reimbursement of $235. With 140,000 CEAs done annually, this represents a potential $32.9-$39.9 million saved to the health care system. CONCLUSIONS: Pathology evaluation of carotid plaque incurs significant costs to the health care system with no clear value for the postoperative care of the patient. Hospital policy regarding mandatory pathologic examination and surgeon preferences regarding plaque analysis should be more closely examined.

Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment.

Background: Paclitaxel is touted as an essential medicine due to its extensive use as a chemotherapeutic for various cancers and an antiproliferative agent for restenosis. Due to recent concerns related to long-term mortality, paclitaxel (PTX)-based endovascular therapy is now surrounded by controversies. Objective: Examine the inflammatory mediators driven by the systemic administration of PTX and explore the means to suppress these effects. Methods: RNAseq analysis, cell and mouse models. Results: RNAseq analysis of primary human endothelial cells (ECs) treated with PTX demonstrated transcriptional perturbations of a set of pro-inflammatory mediators, including monocyte chemoattractant protein-1 (MCP-1) and CD137, which were validated in EC lysates. These perturbations were abrogated with dexamethasone, a prototypic anti-inflammatory compound. The media of ECs pre-treated with PTX showed a significant increase in MCP-1 levels, which were reverted to baseline levels with DEX treatment. A group of mice harvested at different time points after PTX injection were analyzed for immediate and delayed effects of PTX. A 3-fold increase in MCP-1 was noted in blood and aortic ECs after 12 hours of PTX treatment. Similar changes in CD137 and downstream mediators such as tissue factor, VCAM-1 and E-selectin were noted in aortic ECs. Conclusions: Our study shows that systemic PTX exposure upregulates atherothrombotic markers, and co-delivery of DEX can subdue the untoward toxic effects. Long-term studies are needed to probe the mechanisms driving systemic complications of PTX-based therapies and evaluate the clinical potential of DEX to mitigate risk.