Notch signaling represents a key mechanism mediating cancer metastasis and stemness. To understand how Notch signaling is overactivated to couple tumor metastasis and self-renewal in NSCLC cells, we performed the current study and showed that RFC4, a DNA replication factor amplified in more than 40% of NSCLC tissues, directly binds to the Notch1 intracellular domain (NICD1) to competitively abrogate CDK8/FBXW7-mediated degradation of NICD1. Moreover, RFC4 is a functional transcriptional target gene of Notch1 signaling, forming a positive feedback loop between high RFC4 and NICD1 levels and sustained overactivation of Notch signaling, which not only leads to NSCLC tumorigenicity and metastasis but also confers NSCLC cell resistance to treatment with the clinically tested drug DAPT against NICD1 synthesis. Furthermore, together with our study, analysis of two public datasets involving more than 1500 NSCLC patients showed that RFC4 gene amplification, and high RFC4 and NICD1 levels were tightly correlated with NSCLC metastasis, progression and poor patient prognosis. Therefore, our study characterizes the pivotal roles of the positive feedback loop between RFC4 and NICD1 in coupling NSCLC metastasis and stemness properties and suggests its therapeutic and diagnostic/prognostic potential for NSCLC therapy.

Background: This study aimed to investigate independent risk factors of postoperative hypoxemia in patients with acute type A aortic dissection (ATAAD).Methods: A single-center retrospective study was conducted with enrolled 75 ATAAD patients following surgery, which were stratified into three groups on the basis of the postoperative PaO 2 /FiO 2 ratio: severe hypoxemia group (PaO 2 /FiO 2 ratio ≤100 mmHg); moderate hypoxemia group (100 mmHg < PaO 2 /FiO 2 ratio ≤200 mmHg); and non-hypoxemia group (PaO 2 /FiO 2 ratio >200 mmHg). The patient's demography, perioperative laboratory results, operative details, clinical outcomes were collected and analyzed. Univariable and multivariable analyses were performed and logistic regression model was established. Results:The incidence of postoperative severe hypoxemia and hypoxemia was 32% and 52%, respectively. Among the three groups, severe hypoxemia group exhibited a high significance of body mass index (BMI) and preoperative white blood cell (WBC) and main distribution of hypertension; meanwhile, Marfan syndrome was mainly distributed in non-hypoxemia group. On intensive care unit (ICU) admission, severe hypoxemia group exhibited a high significance of Acute Physiology and Chronic Health Evaluation (APACHE II) score of postoperative patients, and more patients would present shock. Moreover, severe hypoxemia group patients had a higher incidence of postoperative acute kidney injury (AKI) and usage of renal replacement therapy, longer length of stay (LOS) of ICU, and shorter 28 days ventilator-free days (VFDs). Conclusions:The incidence of postoperative hypoxemia was high in ATAAD patients owing to comprehensive high-risk factors. Besides, postoperative complications negatively impacted their clinical outcomes.

We explored the efficacy of an interspace between the popliteal artery and capsule of the posterior knee (IPACK) block when added to an established enhanced recovery after surgery (ERAS) pathway to assist with posterior knee analgesia and functional mobility after total knee arthroplasty (TKA). We recruited participants undergoing TKA in our prospective, randomized, triple-blinded controlled trial. All study patients participated in our ERAS pathway consisting of a primary spinal anesthetic, adductor canal nerve catheter, and periarticular joint infiltration. Patients were randomized to receive an IPACK block or no block. The primary outcome was total postoperative opioid consumption. Secondary outcomes included pain scores, recovery unit length of stay, time to first opioid use, the incidence of posterior knee pain, ambulation distance and activities of daily living on postoperative day 1, and hospital length of stay. A total of 96 patients were randomized to the control and IPACK groups. There were no statistical differences in primary or majority of secondary outcomes. There was a lower incidence of posterior knee pain (39%) in the IPACK group when compared with controls (8.7%), p < 0.01. In terms of opioid consumption and a majority of functional outcomes, our study demonstrates no overall benefits of adding an IPACK block in this ERAS pathway in TKA. Nevertheless, IPACK may have the potential of mitigating posterior knee pain after TKA. Level of evidence: level 1.Clinical trial number and registry URL: NCT03653416. www.clinicaltrials.gov.

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