Emerging roles of Aurora-A kinase in cancer therapy resistance

Aurora kinase A (Aurora-A), a serine/threonine kinase, plays a pivotal role in various cellular processes, including mitotic entry, centrosome maturation and spindle formation. Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer, including lung cancer, colorectal cancer, and breast cancer. Alteration of Aurora-A impacts multiple cancer hallmarks, especially, immortalization, energy metabolism, immune escape and cell death resistance which are involved in cancer progression and resistance. This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance, including chemoresistance (taxanes, cisplatin, cyclophosphamide), targeted therapy resistance (osimertinib, imatinib, sorafenib, etc.), endocrine therapy resistance (tamoxifen, fulvestrant) and radioresistance. Specifically, the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair, feedback activation bypass pathways, resistance to apoptosis, necroptosis and autophagy, metastasis, and stemness. Noticeably, our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1, ARID1A and MYC gene mutation tumors, and potential synergistic strategy for mTOR, PAK1, MDM2, MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase. In addition, we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.

Efficacy and longevity of immune response to 3rd COVID-19 vaccine and effectiveness of a 4th dose in severely immunocompromised patients with cancer

Cancer patients show increased morbidity with COVID-19 and need effective immunization strategies. We demonstrate that a 3rd dose of COVID-19 vaccine leads to seroconversion in 57% of patients that were seronegative after primary vaccination. The immune response is durable as assessed by anti-S antibody titers, T-cell activity and neutralization activity against wild-type SARS-CoV2 and BA1.1.529 at 6 months of follow up. A subset of severely immunocompromised hematologic malignancy patients were unable to mount adequate immune response after the 3rd dose and were treated with a 4th dose in a prospective clinical trial which led to adequate immune-boost in 67% of patients. Low baseline IgM levels and CD19 counts were associated with inadequate seroconversion. Booster doses induced limited neutralization activity against the Omicron variant. These results indicate that vaccine booster-induced immunity is durable in cancer patients and additional doses can further stimulate immunity in a subset of hematologic malignancy patients. Statement of significanceWe demonstrate that a 3rd dose of vaccine leads to seroconversion in 57% of negative patients with durable immune responses at 6 months. A 4th dose of vaccine can seroconvert hematologic malignancy patients with higher baseline IgM and CD19 levels.

Direct Carotid Puncture for Mechanical Thrombectomy in Acute Ischemic Stroke: Literature Review and a Single-Center Experience.

BACKGROUND: Endovascular thrombectomy (EVT) for acute ischemic stroke via direct carotid puncture (DCP) has been commonly reported as case reports and series in the literature. However, the reported procedural risk and therapeutic outcome associated with this approach were variable. In this study, we aim to establish the role and safety profile of this alternative access technique by describing our single-center experience and conducting a comprehensive review of the literature. METHODS: We conducted a retrospective review of consecutive patients at our center with large vessel occlusion (LVO) treated between 2018 and 2020 with DCP access. In addition, a literature review of studies published from 2012-2021 following PRISMA guidelines was conducted. RESULTS: During the 3-year period, 11 patients with LVO were treated with EVT using DCP technique in our local cohort. A total of 216 cases were found in the literature search. A combined total of 227 cases were reviewed separately and collectively. Combining the data, DCP access was successfully achieved in 93.3% of the cases; 76.6% achieved satisfactory recanalization (mTICI ≥2b). DCP-related complications were seen in 20.3% of cases. A total of 32.4% patients were functionally independent (mRS ≤2) upon follow-up. CONCLUSIONS: Results from the literature review and our experience illustrate DCP as a feasible approach for EVT. The role of DCP as a bailout is iterated despite a higher complication risk, which may be imperative in low-volume stroke centers. Further studies to evaluate the role of DCP as a primary vascular access technique for EVT in selected cases could be explored.

Endovascular Intervention for Early Postoperative Stenosis of Extracranial-Intracranial Bypass Graft: Case Report and Review of the Literature.

BACKGROUND: Bypass graft stenosis following extracranial-intracranial bypass surgery carries significant risks for morbidity and mortality. In case of graft failure, treatment options include surgical revision and endovascular intervention. Whereas endovascular intervention following coronary artery bypass is well established, the role of endovascular therapy in cerebral bypass conduits is rarely reported. We present a case of extracranial-intracranial bypass graft stenosis in the early postoperative period that was successfully treated by endovascular angioplasty and stenting. CASE DESCRIPTION: A middle-aged patient presented with a malignant skull base tumor with internal carotid artery invasion. Extracranial-intracranial bypass surgery was performed for flow preservation before tumor removal. Autologous radial artery was used as the bypass graft conduit. Symptomatic graft stenosis was encountered in the immediate postoperative period. Treatments in the form of intra-arterial vasodilator infusion and balloon angioplasty led to only minor flow improvement. The narrowing was eventually salvaged by endovascular stenting. Good clinical and radiologic outcomes were achieved at 6-month follow-up. CONCLUSIONS: Endovascular intervention is a feasible treatment option in management of graft stenosis after cerebral revascularization surgery. Our case adds evidence to the safety and role of endovascular intervention in early cerebral bypass conduit failure. In addition, endovascular stenting can be considered as a salvage option for cases that are refractory to angioplasty.