Kiang Wu Hospital

Genetic alterations that induce chromosomal instability (CIN) in colorectal cancer (CRC) cells result in partial impairments in a crucial cellular process, which present an opportunity for therapeutic exploitation in cancer treatment. In our effort to identify therapeutic vulnerability in PTEN-deficient CRC, we found that PTEN-deficient CRC cells exhibited elevated CIN phenotype and were hypersensitive to STAT3 inhibition. STAT3 inhibition induced a high level of abnormal spindle formation, causing mitotic arrest and death in PTEN-deficient CRC cells. Mechanistically, PTEN deficiency led to an increased phosphorylation in STAT3 and the hyperactivation of the downstream mitotic kinase PLK1, resulting in the formation of abnormal mitotic spindles and CIN. Inhibition of STAT3 strongly suppressed PLK1 phosphorylation in a STMN1-dependent manner, further inducing mitotic abnormalities in the cells. This irreparable mitotic defect triggered hyperactivation of the spindle assembly checkpoint and mitotic cell death in PTEN-deficient CRC cells. Collectively, our findings suggest that targeting STAT3-PLK1 axis represents a novel therapeutic approach for CRC cells with PTEN loss.

Brain malignancies originating from the central nervous system and metastasizing from extracerebral tumors remain incurable, while the underlying mechanisms remain unclear. In this study, we comprehensively investigated the pan-brain tumor microenvironment. We employed transgenic mice, stereotactic brain injections, flow cytometry, CRISPR/Cas9 gene editing, immunohistochemistry, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, western blotting, co-immunoprecipitation, DNA pulldown assays, and chromatin immunoprecipitation. We constructed single-cell RNA sequencing and spatial transcriptome profiles of pan-brain tumors and identified the enhanced hypoxia-inducible factor 1 (HIF-1) signaling in the intracerebral metastases compared with extracerebral parts, as well as in mesenchymal-subtype glioblastomas. Hypoxic adaptability mediated by HIF-1 signaling confers a tumor growth advantage in the brain. Integrated analysis and experimental models revealed the co-localization and mutual dependence between brain tumor hypoxic adaptability and macrophage infiltration. Hypoxic adaptive tumor cells recruit macrophages via galectin 1 (LGALS1) and induce differentiation toward the secreted phosphoprotein 1 (SPP1) + subpopulation via lactate mediated histone lactylation. SPP1 directly activates mitogen-activated protein kinase (MAPK) signaling in tumor cells to promote tumor growth and inhibits the cytotoxic activity of CD8+ T cells. Genetic SPP1 deficiency in macrophages delays hypoxic adaptive tumor growth in the brain and enhances the tumor response to anti-programmed cell death-1 (anti-PD-1) therapy. Preclinically, targeting lactate dehydrogenase A (LDHA) by stiripentol with blood-brain barrier permeability impedes brain tumor progression and synergizes with anti-PD-1 therapy. The interrelationship between hypoxic adaptive tumor cells and macrophages in the brain highlights the possibility of SPP1+ macrophage-based microenvironment remodeling in brain tumor therapy.

Background and aims:Multiple artificial intelligence (AI) systems have been developed to assist with endoscopic diagnosis. We established the first real-time AI lesion-labeling system to assist in delineating lesion margin during endoscopic submucosal dissection (ESD). We aimed to further validate the efficacy of this system in improving histological complete resection rate especially for beginners in low-volume centers.Methods:We performed this prospective cohort study in two endoscopy centers in Shanghai, China from January 2021 to December 2022. Eligible patients in a low-volume center equipped with real-time AI lesion labeling system were recruited consecutively to the AI group and underwent ESD performed mainly by beginners, while participants in a high-volume center underwent conventional ESD performed by experienced endoscopists. The primary outcome was complete lateral resection rate according to pathological examination of the specimen resected. Secondary outcomes were en-bloc resection rate, procedure duration, specimen diameter and complication rate.Results:174 patients (200 lesions) were recruited into the AI-assisted ESD group. With the use of lesion-margin labeling system, 90.0% (180/200) of ESD cases achieved negative lateral margins. The en bloc resection rate was 98.5% (197/200), and the histological complete resection rate was 87.5% (175/200). 181 patients (202 lesions) received conventional ESD in a high-volume center. There was no significant difference between AI-assisted and conventional ESD group regarding the rate of complete lateral resection (90.0% [180/200] vs 92.1% [186/202], P = 0.465). Total procedure duration (min) was significantly longer in AI-assisted group (82 [54,106]) compared with conventional group (49 [30,63], P < 0.001).Conclusion:AI lesion-labeling system showed reliable safety and efficacy in assisting to identify the margin of lesions before ESD, and potential to improve complete lateral resection rate of ESD for esophageal lesion in low-volume endoscopy centers.

Objective:To investigate the occurrence and managements of poor recovery after total endoscopic middle ear surgery. Methods:A total of 302 cases（315 ears） who underwent endoscopic middle ear surgery in our hospital from June 2020 to June 2021 were collected. Follow up by means of endoscopy, pure tone hearing threshold, tympanogram was conducted at 1 month, 3 months, 6 months and 1 year after surgery to analyze the incidence, possible causes, treatment strategies and effects of poor results tympanic membrane healing and hearing recovery. Results:Among 302 patients（315 ears） followed up, there were 28 cases with poor recovery. There were fourteen cases of poor eardrum healing, of which 10 cases achieved healing of eardrum after tympanic membrane patching in the outpatient department, with a success rate of about 71.4%. TM recurrence adhesion occurred in 4 cases after surgeries of cholesteatoma and adhesive otitis media. One case completely recovered after self eustachian tube insufflation, while 2 cases maintained the degree of eardrum subsidence, and one ineffective patient chose resurgical treatment, with an effective rate was 75.0%. Failure in hearing improvement occurred in 8 cases, all of which underwent second surgical exploration, and seven cases were improved after the second surgery, with an effective rate of 87.5%. Among the 8 patients with no improvement or aggravation of hearing loss after surgery, four cases had postoperative B-type or C-type of tympanogram, and the hearing could not improve after self eustachian tube insufflation for secondary surgical exploration. and the hearing improved after the secondary surgery. Incorrect orientation of ossicular prosthesis was accounted for another 2 cases, the hearing was improved after the ossicular orientation adjustment. One patient with lateral healing of TM and failed hearing recovery was corrected by a second operation. One case of tympanosclerosis underwent stapes release surgery, but hearing recovery still failed. One patient had recurrent postoperative cicatricial atresia of external auditory canal, and the patient was reluctant to undergo reoperation. Postoperative delayed facial paralysis occurred in 1 case, and the facial paralysis recovered recovered after conservative treatments. Conclusion:Eardrum patch and eustachian tube autoflation are simple and effective early outpatient treatment for patient with poor recovery. For those who failed with conservative treatments such as eardrum patch or eustachian tube and poor hearing recovery, the second surgical exploration is safe and effective. Regular follow up after endoscopic middle ear surgery is necessary for the managements of poor recovery.

Monitoring the effectiveness of COVID-19 vaccination is critical for understanding if the vaccinated population, especially the elderly, is adequately protected from the emergence of new SARS-CoV-2 variants. This study aimed to investigate the effects of COVID-19 vaccination on the severity of symptoms and mortality in hospitalized geriatric patients during the Omicron BF.7 surge in Macao. Data from electronic health records and vaccination registry of inpatients aged 60 years or above admitted to Kiang Wu Hospital from 12 December 2022 to 12 March 2023 were retrospectively analyzed. The study involved 848 people, including 426 vaccinated and 422 unvaccinated individuals. The mean CXR scores (8.95 ± 9.49 vs. 11.41 ± 10.81, p < 0.001) and the mean MEWS scores (0.96 ± 2.01 vs. 1.49 ± 2.45, p < 0.001) were lower in the vaccinated group. By comparing the dose counts, no significant difference was seen in the odds of death. Based on the time of the last vaccination, 128 people were categorized as complete and 298 as incomplete vaccination. The complete vaccination group showed a 54% (95% CI 0.23-0.91) reduction in mortality risk (p = 0.026). The study findings not only reconfirm the effectiveness of COVID-19 vaccination but, more importantly, highlight the importance of vaccination timing to maximize vaccines' protective effect.

Abstract Background This study acquired data pertaining to individuals diagnosed with Thyroid Cancer (TC) from the Surveillance, Epidemiology, and End Results (SEER) database. Subsequently, a deep learning and neural network model known as DeepSurv was employed to forecast the survival rate of TC patients and assess its efficacy. Methods Information on individuals diagnosed with TC from the years 2000 to 2019 was collected from the SEER database. The individuals in question were subsequently allocated into training and testing cohorts through a random selection process, maintaining a ratio of 7:3. The outcomes of the DeepSurv model were compared to those of the Cox proportional-hazards (CoxPH) model in order to estimate the chances of survival for TC patients. The accuracy of the model's predictions was evaluated through the examination of calibration curves, the time-dependent area under the receiver operating characteristic curve (AUC), and the concordance index (C-index). Results A total of 25,797 individuals diagnosed with TC were included in this study, with 18,057 comprising the training group and 7,740 forming the testing cohort. The CoxPH model exhibited robust correlations between age, gender, marital status, surgical intervention, radiation therapy, tumor extension, and the survival outcomes of TC patients. Notably, the C-index for the CoxPH model was 0.884, indicating a high level of predictive accuracy. Additionally, the training cohort data were used to create the DeepSurv model, which produced a higher C-index of 0.904. The predictive performance of both models was assessed, and the 3-, 5-, and 8-year AUC values were calculated. Regarding the CoxPH model, the corresponding area under the receiver operating characteristic curve (AUC) values were determined to be 0.835, 0.797, and 0.756, respectively. In comparison, the DeepSurv model achieved higher AUC values of 0.942, 0.918, and 0.906. The DeepSurv model demonstrated superior predictive ability for TC patients, as indicated by both the AUC values and the calibration curve, suggesting higher reliability compared to the CoxPH model. Conclusion Using TC patient data from the SEER database for research, we built the DeepSurv model, which performed better than the CoxPH model in estimating the survival time of TC patients.

Loss of PTEN tumor suppressor is an important event during colorectal cancer (CRC) development and is a target for therapeutic exploitation. This study reports that bromodomain and extra-terminal motif (BET) is a synthetic lethal partner of PTEN in CRC. BET inhibition (BETi) selectively induced G1 cell cycle arrest and apoptosis in PTEN-/- CRC. Further, BETi selectively and dose-dependently suppressed the growth of PTEN-/- CRC tumor xenografts in mice and patient-derived organoids. Mechanistically, PTEN-deficient CRC cells elevated the level of cytoplasmic p21CIP1/WAF1 that is hyper-phosphorylated at Thr145 by AKT. BETi suppressed AKT activation in PTEN-deficient CRC cells, followed by the reduction in p21 phosphorylation at Thr145, thereby promoting its nuclear translocation. In addition, BETi suppressed MYC level and this in turn increased the total p21 level in the nuclei. Over-expression of a phospho-mimetic p21 mutant (T145D) significantly rescued the BETi effect on PTEN-deficient CRC. These results suggest that BETi has a dual action on p21: elevating the level of p21 by inhibiting MYC and converting the oncogenic (cytoplasmic) p21 into the tumor-suppressive (nuclear) p21 by inhibiting AKT. Taken together, this study identified the synthetic lethal interaction between PTEN and BET, and provides a potential actionable target for CRC with PTEN loss.