RESUMO
CONTEXT: Anterior cruciate ligament (ACL) tears are a common orthopaedic injury, and the incidence of ACL reconstruction (ACLR) continues to increase. Current clinical practice guidelines (CPGs) recognize the role of psychological factors in rehabilitation, but patient-reported outcome measures (PROs) and psychological readiness are rarely incorporated into rehabilitation. OBJECTIVE: The purpose of this review was to highlight the importance of psychological health after ACL injury, understand the current metrics used to monitor psychological recovery, and outline how psychological recovery can be better incorporated in current CPGs. DATA SOURCES: A systematic review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines (PRISMA); 63 studies were identified with a PubMed search using the term "ACL Injuries/psychology". STUDY SELECTION: Exclusion criteria included lack of consideration of psychological effects or studies validating PROs after ACLR. Studies were reviewed by multiple reviewers, and a total of 38 studies were included after applying exclusion criteria. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 3b. DATA EXTRACTION: Two independent reviewers analyzed the included articles to extract sample size, psychological readiness scale or other measures used, and key results. RESULTS: Psychological outcomes, especially kinesiophobia and fear of reinjury, are seen commonly after ACLR. Psychological factors were shown to impede return to sport (RTS), alter measurable knee biomechanics, and potentially increase the risk for re-rupture. Targeted interventions such as kinesiotaping, knee bracing, and imagery training can help improve psychological and functional testing after ACLR. CONCLUSION: ACLR is often complicated by psychological factors. Psychological readiness is a crucial yet often unincorporated part of rehabilitation. Patients with higher levels of kinesiophobia and lower psychological readiness to RTS specifically should be identified to allow for administration of interventions, such as imagery training, knee bracing, or kinesiotaping, that can mitigate the negative effects of psychological outcomes and improve recovery.
RESUMO
LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung cancer (NSCLC) and cause aggressive tumor growth. Unfortunately, treatment with RAS-RAF-MEK-ERK pathway inhibitors has minimal therapeutic efficacy in LKB1-mutant KRAS-driven NSCLC. Autophagy, an intracellular nutrient scavenging pathway, compensates for Lkb1 loss to support Kras-driven lung tumor growth. Here we preclinically evaluate the possibility of autophagy inhibition together with MEK inhibition as a treatment for Kras-driven lung tumors. We found that the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and the MEK inhibitor Trametinib displays synergistic anti-proliferative activity in KrasG12D/+;Lkb1-/- (KL) lung cancer cells, but not in KrasG12D/+;p53-/- (KP) lung cancer cells. In vivo studies using tumor allografts, genetically engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) showed anti-tumor activity of the combination of HCQ and Trametinib on KL but not KP tumors. We further found that the combination treatment significantly reduced mitochondrial membrane potential, basal respiration, and ATP production, while also increasing lipid peroxidation, indicative of ferroptosis, in KL tumor-derived cell lines (TDCLs) and KL tumors compared to treatment with single agents. Moreover, the reduced tumor growth by the combination treatment was rescued by ferroptosis inhibitor. Taken together, we demonstrate that autophagy upregulation in KL tumors causes resistance to Trametinib by inhibiting ferroptosis. Therefore, a combination of autophagy and MEK inhibition could be a novel therapeutic strategy to specifically treat NSCLC bearing co-mutations of LKB1 and KRAS.