Comparisons in analgesic effects between ultrasound-guided erector spinae plane block and surgical intercostal nerve block after video-assisted thoracoscopic surgery: A randomized controlled trial.

STUDY OBJECTIVE: This study aimed to compare the analgesic effects of anesthesiologist-administrated erector spinae plane block (ESPB) and surgeon-administrated intercostal nerve block (ICNB) following video-assisted thoracoscopic surgery (VATS). DESIGN: Randomized, controlled, double-blinded study. SETTING: Operating room, postoperative recovery room and ward in two centers. PATIENTS: One hundred patients, ASA I-III and scheduled for elective VATS. INTERVENTIONS: The anesthesiologist-administrated ESPB under ultrasound guidance or surgeon-administrated ICNB under video-assisted thoracoscopy was randomly provided during VATS. Regular oral non-opioid analgesic combined with intravenous rescue morphine were prescribed for multimodal analgesia after surgery. MEASUREMENTS: The primary outcomes were the pain score and morphine consumption during 48 h after surgery. Postoperative pain intensity were assessed using the 10-cm visual analogue scale at 1 h, 24 h, and 48 h after surgery. Morphine consumption at these time points was compared between the two study groups. Furthermore, oral weak opioid rescue analgesic was also provided at 24 h after surgery. Postoperative quality of recovery at 24 h was also assessed using the QoR-15 questionnaire, along with duration of chest tube drainage and hospital stay were compared as secondary outcomes. MAIN RESULTS: Patients in the two study groups had comparable baseline characteristics, and surgical types were also similar. Postoperative VAS changes at 1 h, 24 h, and 48 h after surgery were also comparable between the two study groups. Both groups had low median scores (<4.0) at all time points (all p > 0.05). Patients in the ESPB group required statistically non-significant higher 48-h morphine consumption [3 (0-6) vs. 0 (0-6) mg in the ESPB group and ICNB group respectively; p = 0.135] and lower numbers of oral rescue analgesic (0.4 ± 1.2 vs. 1.0 ± 1.8 in the ESPB group and ICNB group respectively; p = 0.059). Additionally, patients in the two study groups had similar QoR15 scores and lengths of hospital stay. CONCLUSIONS: Both anesthesiologist-administered ultrasound-guided ESPB and surgeon-administered VATS ICNB were effective analgesic techniques for patients undergoing VATS for tumor resection.

Surgical strategy for colorectal cancer with synchronous liver and extrahepatic metastases: A scoring system and decision tree model.

BACKGROUND: The role of hepatectomy in a specific group of patients with synchronous colorectal cancer with liver metastases (SCRLM) and synchronous extrahepatic disease (SEHD) is still unclear. The aim of this study was to evaluate the efficacy of liver surgery and define the selection criteria for surgical candidates in patients with SCRLM + SEHD. METHODS: Between July 2007 and October 2018, 475 patients with colorectal cancer with liver metastases (CRLM) who underwent liver resection were retrospectively reviewed. Sixty-five patients with SCRLM + SEHD were identified and included in the study. Clinical pathological data of these patients were analyzed to evaluate the influence on survival. Important prognostic factors were identified by univariate and multivariate analyses. The risk score system and decision tree analysis were generated according to the important prognostic factors for better patient selection. RESULTS: The 5-year survival rate of patients with SCRLM + SEHD was 21.9%. The most important prognostic factors were SCRLM number of more than five, site of SEHD other than the lung only, inability to achieve SCRLM + SEHD R0 resection, and BRAF mutation of cancer cells. The proposed risk score system and decision tree model easily discriminated between patients with different survival rates and identified the profile of suitable surgical patients. CONCLUSION: Liver surgery should not be a contraindication for patients with SCRLM + SEHD. Patients with complete SCRLM + SEHD R0 resection, SCRLM number less than or equal to five, SEHD confined to the lung only, and wild-type BRAF could have favorable survival outcomes. The proposed scoring system and decision tree model may be beneficial to patient selection in clinical use.

Old age and EGFR mutation status in inoperable early-stage non-small cell lung cancer patients receiving stereotactic ablative radiotherapy: A single institute experience of 71 patients in Taiwan.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is now the standard of care for patients with inoperable early-stage lung cancer. Many of these patients are elderly. EGFR (epidermal growth factor receptor) mutation is also common in the Asian population. METHODS: To evaluate the effects of old age and EGFR mutation on treatment outcomes and toxicity, we reviewed the medical records of 71 consecutive patients with inoperable early-stage non-small cell lung cancer (NSCLC) who received SABR at Taipei Veterans General Hospital between 2015 and 2021. RESULTS: The study revealed that median age, follow-up, Charlson comorbidity index, and ECOG score were 80 years, 2.48 years, 3, and 1, respectively. Of these patients, 37 (52.1%) were 80 years or older, and 50 (70.4%) and 21 (29.6%) had T1 and T2 diseases, respectively. EGFR mutation status was available for 33 (46.5%) patients, of whom 16 (51.5%) had a mutation. The overall survival rates at 1, 3, and 5 years were 97.2, 74.9, and 58.3%, respectively. The local control rate at 1, 3, and 5 years was 97.1, 92.5, and 92.5%, respectively. Using Cox proportional hazards regression we found that male sex was a risk factor for overall survival (p = 0.036, 95% CI: 1.118-26.188). Two patients had grade 2 pneumonitis, but no other grade 2 or higher toxicity was observed. We did not find any significant differences in treatment outcomes or toxicity between patients aged 80 or older and those with EGFR mutations in this cohort. CONCLUSION: These findings indicate that age and EGFR mutation status do not significantly affect the effectiveness or toxicity of SABR for patients with inoperable early-stage NSCLC.

Overall Survival for Esophageal Squamous Cell Carcinoma with Multiple Primary Cancers after Curative Esophagectomy-A Retrospective Single-Institution Study.

Background: Advances in surgical techniques and treatment modalities have improved the outcomes of esophageal cancer, yet difficult decision making for physicians while encountering multiple primary cancers (MPCs) continues to exist. The aim of this study was to evaluate long-term survival for esophageal squamous cell carcinoma (SCC) associated with MPCs. Methods: Data from 544 patients with esophageal SCC who underwent surgery between 2005 and 2017 were reviewed to identify the presence of simultaneous or metachronous primary cancers. The prognostic factors for overall survival (OS) were analyzed. Results: Three hundred and ninety-seven patients after curative esophagectomy were included, with a median observation time of 44.2 months (range 2.6−178.6 months). Out of 52 patients (13.1%) with antecedent/synchronous cancers and 296 patients without MPCs (control group), 49 patients (12.3%) developed subsequent cancers after surgery. The most common site of other primary cancers was the head and neck (69/101; 68.3%), which showed no inferiority in OS. Sex and advanced clinical stage (III/IV) were independent risk factors (p = 0.031 and p < 0.001, respectively). Conclusion: Once curative esophagectomy can be achieved, surgery should be selected as a potential therapeutic approach if indicated, even with antecedent/synchronous MPCs. Subsequent primary cancers were often observed in esophageal SCC, and optimal surveillance planning was recommended.

Post-recurrence survival analysis in patients with oligo-recurrence after curative esophagectomy.

BACKGROUND: Recurrent esophageal cancer is associated with dismal prognosis. There is no consensus about the role of surgical treatments in patients with limited recurrences. This study aimed to evaluate the role of surgical resection in patients with resectable recurrences after curative esophagectomy and to identify their prognostic factors. METHODS: We retrospectively reviewed patients with recurrent esophageal cancer after curative esophagectomy between 2004 and 2017 and included those with oligo-recurrence that was amenable for surgical intent. The prognostic factors of overall survival (OS) and post-recurrence survival (PRS), as well as the survival impact of surgical resection, were analyzed. RESULTS: Among 654 patients after curative esophagectomies reviewed, 284 (43.4%) had disease recurrences. The recurrences were found resectable in 63 (9.6%) patients, and 30 (4.6%) patients received surgery. The significant prognostic factors of PRS with poor outcome included mediastinum lymph node (LN) recurrence and pathologic T3 stage. In patients with and without surgical resection for recurrence cancer, the 3-year OS rates were 65.6 and 47.6% (p = 0.108), while the 3-year PRS rates were 42.9 and 23.5% (p = 0.100). In the subgroup analysis, surgery for resectable recurrence, compared with non-surgery, could achieve better PRS for patients without any comorbidities (hazard ratio 0.36, 95% CI: 0.14 to 0.94, p = 0.038). CONCLUSIONS: Mediastinum LN recurrence or pathologic T3 was associated with worse OS and PRS in patients with oligo-recurrences after curative esophagectomies. No definite survival benefit was noted in patients undergoing surgery for resectable recurrence, except in those without comorbidities.

PD-L1 Expression in Monocytes Correlates with Bacterial Burden and Treatment Outcomes in Active Pulmonary Tuberculosis.

The PD-1/PD-L1 pathway is critical in T cell biology; however, the role of the PD-1/PD-L1 pathway in clinical characteristics and treatment outcomes in pulmonary tuberculosis (PTB) patients is unclear. We prospectively enrolled PTB, latent TB infection (LTBI), and non-TB, non-LTBI subjects. The expression of PD-1/PD-L1 on peripheral blood mononuclear cells (PBMCs) was measured and correlated with clinical characteristics and treatment outcomes in PTB patients. Immunohistochemistry and immunofluorescence were used to visualize PD-1/PD-L1-expressing cells in lung tissues from PTB patients and from murine with heat-killed MTB (HK-MTB) treatment. A total of 76 PTB, 40 LTBI, and 28 non-TB, non-LTBI subjects were enrolled. The expression of PD-1 on CD4+ T cells and PD-L1 on CD14+ monocytes was significantly higher in PTB cases than non-TB subjects. PTB patients with sputum smear/culture unconversion displayed higher PD-L1 expression on monocytes. PD-L1-expressing macrophages were identified in lung tissue from PTB patients, and co-localized with macrophages in murine lung tissues. Mycobacterium tuberculosis (MTB) whole cell lysate/EsxA stimulation of human and mouse macrophages demonstrated increased PD-L1 expression. In conclusion, increased expression of PD-L1 on monocytes in PTB patients correlated with higher bacterial burden and worse treatment outcomes. The findings suggest the involvement of the PD-1/PD-L1 pathway in MTB-related immune responses.

Preoperative consolidation-to-tumor ratio is effective in the prediction of lymph node metastasis in patients with pulmonary ground-glass component nodules.

BACKGROUND: Preoperative positron emission tomography/computed tomography (PET/CT) is recommended as a guideline for staging of lung cancer. However, for patients with pulmonary ground-glass opacity (GGO) nodules who are supposed to have a relatively low risk of incidence of lymphatic metastasis, it remains uncertain whether PET/CT is more effective than consolidation-to-tumor ratio (CTR) in the prediction of regional lymphatic metastasis. METHODS: The data on patients who underwent surgery for lung cancer from 2011 to 2016 were collected retrospectively, which included CTR, results of PET/CT, and pathological characteristics. The patients who had undergone preoperative PET/CT were identified to find the risk factors for lymphatic metastasis. A receiver operating characteristic (ROC) curve and multiple logistic regression was utilized to clarify the predictive value of CTR and main tumor maximal standardized uptake value (SUVmax). RESULTS: Among 217 patients who had PET/CT before lobectomy, chest computed tomography revealed that 75 patients had CTR greater than 62%. The patients with lymphatic metastasis were shown to have higher CTR and higher main tumor SUVmax. Multiple logistic regression showed that younger age (<60 years), higher main tumor SUVmax on PET/CT, and greater CTR were independent predictive factors for lymphatic metastasis. The area under the ROC curve was comparable, 0.817 for CTR, and 0.816 for main tumor SUVmax. CONCLUSIONS: The present study revealed that CTR was not inferior to main tumor SUVmax considering the predictive power for lymphatic metastasis preoperatively in lung cancer patients with a GGO component. PET/CT might not be necessary preoperatively in selected patients.

The precaution strategy toward the COVID-19 pandemic in the operating room of a tertiary hospital in Taiwan.

BACKGROUND: The pandemic of SARS-CoV-2 (COVID-19), which began in December 2019, spread mostly from person to person through respiratory droplets. A recommendation was issued to postpone all elective surgical practices. However, some confirmed or suspected COVID-19 patients required life-saving emergent surgeries. METHODS: To facilitate emergent surgical interventions for these patients, we have reviewed the current literature and established an algorithm of precautions to be taken by operating room team members during the COVID-19 pandemic. RESULTS: The initial algorithm of preparation for surgical intervention during the COVID-19 pandemic was relatively simple. However, the abrupt increase of confirmed COVID-19 cases due to returned overseas travelers since mid-March 2020 disrupted the routine hospital clinical service. Due to the large number of febrile patients, the algorithm was therefore revised according to travel history, occupation, contact and cluster history (TOCC), unexplained fever/symptoms, and emergent/nonemergent surgery. TOCC (+) patients presenting with otherwise unexplained fever/symptoms would be regarded as belonging to the fifth category of "severe special infectious pneumonia." If the patient requires emergent surgery to relieve the non-life-threatening disorders, two times of negative COVID-19 tests are necessary before the operation is approved. For life-threatening situations without two negative results of COVID-19 tests, the operation schedule should be approved by the Chairman of Surgery Management Committee. CONCLUSION: The application of a clear and integrated algorithm for operating room team members aids in effective personal protective equipment facilitation to keep both healthcare providers and patients safe as well as to prevent hospital-based transmission of COVID-19.

Lymphadenectomy is Unnecessary for Pure Ground-Glass Opacity Pulmonary Nodules.

BACKGROUND: Lobectomy plus lymph node dissection is the standard treatment of early-stage lung cancer, but the low lymph node metastasis rate with ground-glass opacity (GGO) makes surgeons not perform lymphadenectomy. This study aimed to re-evaluate the lymph node metastasis rate of GGO to help make a clinical judgment. METHODS: We performed this retrospective study to enroll patients who received lung cancer surgery from 2011 to 2016. Patient characteristics collected included tumor size, solid part size and lymph node metastasis rate. These patients were categorized into pure GGO and part solid GGO groups to undergo analysis. RESULTS: Lymph node metastasis rates were 0%, 3.8% and 6.9% in order of the pure GGO group, the GGO predominant group and the solid predominant group. In the lobectomy patients, the solid predominant group still showed to have the highest lymph node metastasis rate and recurrence rate (8.3% and 10.1%). CONCLUSION: It is unnecessary to perform lymphadenectomy for patients with pure GGO in view of the 0% lymph node metastasis rate. The higher lymph node metastasis rate in the patients with the solid predominant group, 6.9%, suggested that surgeons should choose a rational lymphadenectomy method according to their GGO property and clinical judgment.

Electromagnetic navigation-guided versus computed tomography-guided percutaneous localization of small lung nodules before uniportal video-assisted thoracoscopic surgery: a propensity score-matched analysis.

OBJECTIVES: An optimal method for preoperative localization of small lung nodules is yet to be established, and there are few comparative studies in the literature. In the present study, we aimed to compare electromagnetic navigation-guided and computed tomography (CT)-guided methods of percutaneous transthoracic localization. METHODS: The clinical, radiographic, surgical and pathological data of patients who underwent electromagnetic navigation-guided localization (EMNGL) and CT-guided localization (CTGL) before uniportal video-assisted thoracic surgery (VATS) were reviewed. Propensity score matching analysis was performed to compare the localization and surgical results. RESULTS: After matching, 25 EMNGL and 50 CTGL patients were included in the analysis. In the CTGL group, pulmonary haemorrhage and pneumothorax were noted in 56% and 34% of patients, respectively, on postprocedural CT scans. Successful localization was achieved in 96% and 100% of patients in the EMNGL and CTGL groups, respectively (P = 0.333). The median time in the operation room was significantly shorter in the CTGL group {142.5 [interquartile range (IQR) 123.8-175.0] vs 205.0 [IQR 177.5-290.0] min, P < 0.001}. In contrast, EMNGL significantly decreased the total time [205.0 (IQR 177.5-290.0) vs 324.0 (IQR 228.3-374.0) min, P = 0.002]. The median duration of chest drainage was 1 day shorter in the EMNGL group [2.0 (IQR 1.5-2.5) vs 3.0 (IQR 2.0-3.0), P = 0.002]; the surgical complication rates were comparable between the 2 groups. CONCLUSIONS: The localization and surgical results were similar between the EMNGL and CTGL groups. EMNGL is comparable to conventional CTGL with respect to preoperative localization of small lung nodules before uniportal VATS.

Author Correction: Overexpression of Aiolos promotes epithelial-mesenchymal transition and cancer stem cell-like properties in lung cancer cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Overexpression of Aiolos promotes epithelial-mesenchymal transition and cancer stem cell-like properties in lung cancer cells.

Aiolos/Ikaros family zinc finger 3 (IKZF3), a member of the Ikaros family of lymphocyte maturation-driving transcription factors, is highly expressed in hematopoietic malignancies. However, its role in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like properties in lung cancer remains unknown. Human lung cancer cell lines H1299 with overexpressing Aiolos (H1299-Aiolos) and A549 with overexpressing Aiolos (A549-Aiolos) were generated by stable transfection. Cell migration and invasion assays were done to demonstrate their invasion and migration ability. Sphere formation assay was used to determine their tumor-initiating capability. Aiolos overexpression induced EMT and increased migration/invasiveness in H1299 and A549 cells. Aiolos overexpression also increased metastatic ability in vivo. Aiolos overexpression upregulated the expression of Twist and matrix metalloproteinase 16 (MMP16). By using knockdown of Twist or an inhibitor of phosphatidylinositol (PI) 3-kinase, EMT, migration/invasiveness ability, and MMP16 expression were reversed in H1299-Aiolos and A549-Aiolos cells. Overexpression of Aiolos upregulated the CSC-like properties in lung cancer cells, and were also reversed by an inhibitor of PI 3-kinase. For lung cancer cells, Aiolos overexpression promotes EMT and CSC-like properties through upregulating the PI 3-kinase/Akt pathway. The information is helpful for developing therapeutic strategies targeting Aiolos expression for lung cancer treatment.

Prognostic significance of basal versus superior segment in patients with completely resected lung adenocarcinoma in the lower lobe.

BACKGROUND: Although the lower lobes of the lungs occupy half of the chest on both sides, the prognostic value of tumor location in lung cancer in the lower lobe has not been well demonstrated. This study investigated the prognostic value of tumor location (basal vs. superior) in patients with resected lung adenocarcinoma in the lower lobe. METHODS: A total of 207 patients undergoing lobectomy for lung adenocarcinoma in the lower lobe were included in the study. The association between tumor location and mediastinal lymph node metastasis was analyzed. Prognostic factors of overall survival and probability of freedom from recurrence (FFR) were also investigated. RESULTS: During follow-up, 71 (34.3%) patients developed recurrence. Patients with basal segment tumors had a significantly higher possibility of developing N2 lymph node metastasis than those with superior segment tumors (P = 0.025). Univariate analysis showed that location in the basal (vs. superior) segment was a significant prognostic factor for a lower probability of FFR (P = 0.013). Basal (vs. superior) segment remained a significant prognostic factor for a lower probability of FFR (P = 0.010) in multivariate analysis. CONCLUSIONS: Basal segment tumors have a significantly higher possibility of developing N2 lymph node metastasis than superior segment tumors in resected lung adenocarcinoma in the lower lobe. Tumor location at the basal segment was a significant prognostic factor for a lower probability of FFR. This information is useful for patient stratification of risk of postoperative recurrence.

Prognostic significance of AKR1B10 in patients with resected lung adenocarcinoma.

BACKGROUND: Aldo-keto reductases (AKRs) modify carbonyl groups on aldehyde or ketones to form primary or secondary alcohols, which are then conjugated with sulfates or glucuronide for excretion. The AKR1B10 gene encodes a member of the AKR superfamily. Overexpression of AKR1B10 plays an important role in the tumorigenesis of lung cancer cells; however, the prognostic value of AKR1B10 expression in patients with lung adenocarcinoma has not been well demonstrated. METHODS: A total of 96 patients with resected lung adenocarcinoma were included in the study. AKR1B10 expression was determined by immunohistochemistry in tumor specimens. The prognostic value of AKR1B10 overexpression and its relationship with clinicopathological variables were investigated. RESULTS: AKR1B10 overexpression was identified in 22 (22.9%) of the 96 patients and tended to be significantly associated with N1 or N2 status (P = 0.055). AKR1B10 overexpression was not a significant prognostic factor for overall survival (P = 0.301) but was a significant prognostic factor for poor recurrence-free survival (P = 0.015). T status (T3 or T4 vs. T1 or T2; P = 0.020), N1 or N2 (vs. N0; P = 0.019), predominant pattern group (lepidic/acinar/papillary vs. micropapillary/solid; P = 0.023), and AKR1B10 overexpression (P = 0.013) were significant prognostic factors for poor recurrence-free survival in multivariate analysis. CONCLUSIONS: AKR1B10 overexpression was a significant prognostic factor for poor recurrence-free survival in patients with resected lung adenocarcinoma. This information is useful to stratify patients at high-risk of recurrence after lung adenocarcinoma resection.

Generating a robust prediction model for stage I lung adenocarcinoma recurrence after surgical resection.

Lung cancer mortality remains high even after successful resection. Adjuvant treatment benefits stage II and III patients, but not stage I patients, and most studies fail to predict recurrence in stage I patients. Our study included 211 lung adenocarcinoma patients (stages I-IIIA; 81% stage I) who received curative resections at Taipei Veterans General Hospital between January 2001 and December 2012. We generated a prediction model using 153 samples, with validation using an additional 58 clinical outcome-blinded samples. Gene expression profiles were generated using formalin-fixed, paraffin-embedded tissue samples and microarrays. Data analysis was performed using a supervised clustering method. The prediction model generated from mixed stage samples successfully separated patients at high vs. low risk for recurrence. The validation tests hazard ratio (HR = 4.38) was similar to that of the training tests (HR = 4.53), indicating a robust training process. Our prediction model successfully distinguished high- from low-risk stage IA and IB patients, with a difference in 5-year disease-free survival between high- and low-risk patients of 42% for stage IA and 45% for stage IB (p < 0.05). We present a novel and effective model for identifying lung adenocarcinoma patients at high risk for recurrence who may benefit from adjuvant therapy. Our prediction performance of the difference in disease free survival between high risk and low risk groups demonstrates more than two fold improvement over earlier published results.

Prognostic Factors in Completely Resected Node-Negative Lung Adenocarcinoma of 3 cm or Smaller.

INTRODUCTION: The role of adjuvant chemotherapy for patients with stage I NSCLC remains unknown. The prognostic value of histological subtypes in resected node-negative small lung adenocarcinoma has not been widely investigated. This study investigated the prognostic factors in patients with node-negative lung adenocarcinoma 3 cm or smaller to find potential candidates for adjuvant chemotherapy. METHODS: A total of 726 patients with completely resected node-negative lung adenocarcinoma 3 cm or smaller were included in the study. Prognostic factors for overall survival or probability of freedom from recurrence (FFR) were investigated. RESULTS: During follow-up, recurrence developed in 59 patients (8.1%). Univariate analysis showed that the micropapillary/solid predominant pattern group was associated with a significantly lower probability of FFR (p = 0.001) in node-negative lung adenocarcinoma 3 cm or smaller. Those with greater tumor size (p = 0.001) and the micropapillary/solid predominant pattern group (p = 0.035) had a significantly lower probability of FFR in multivariate analysis. For tumors 2 cm or smaller, the micropapillary/solid predominant pattern group had a trend toward a lower probability of FFR (p = 0.053) in multivariate analysis. Presence of the solid pattern was a prognostic factor for lower probability of FFR (p = 0.001) in multivariate analysis. CONCLUSIONS: The new adenocarcinoma classification has significant impact on recurrence in node-negative lung adenocarcinoma 3 cm or smaller. Patients with the micropapillary/solid predominant pattern have a significantly higher risk for recurrence. For tumors 2 cm or smaller, presence of the solid pattern was a prognostic factor for higher probability of recurrence. This information is useful for patient stratification for adjuvant therapy.

K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression.

Intratumoural hypoxia induces HIF-1α and promotes tumour progression, metastasis and treatment resistance. HIF-1α stability is regulated by VHL-E3 ligase-mediated ubiquitin-dependent degradation; however, the hypoxia-regulated deubiquitinase that stabilizes HIF-1α has not been identified. Here we report that HAUSP (USP7) deubiquitinase deubiquitinates HIF-1α to increase its stability, induce epithelial-mesenchymal transition and promote metastasis. Hypoxia induces K63-linked polyubiquitinated HAUSP at lysine 443 to enhance its functions. Knockdown of HAUSP decreases acetylation of histone 3 lysine 56 (H3K56Ac). K63-polyubiquitinated HAUSP interacts with a ubiquitin receptor CBP to specifically mediate H3K56 acetylation. ChIP-seq analysis of HAUSP and HIF-1α binding reveals two motifs responsive to hypoxia. HectH9 is the E3 ligase for HAUSP and a prognostic marker together with HIF-1α. This report demonstrates that hypoxia-induced K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and causes CBP-mediated H3K56 acetylation on HIF-1α target gene promoters to promote EMT/metastasis, further defining HAUSP as a therapeutic target in hypoxia-induced tumour progression.

WITHDRAWN: Prognostic Significance of Programmed Cell Death-Ligand 1 Expression in Patients With Resected Lung Adenocarcinoma.

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