Genomic and Immunological Features of Micropapillary Pattern in Lung Adenocarcinoma

Background: Lung adenocarcinoma (LUAD) usually contain heterogeneous histological subtypes, among which the micropapillary (MIP) subtype was associated with poor prognosis while the lepidic (LEP) subtype possessed the most favorable outcome. A more comprehensive analysis involving discovery and public validation cohorts on the two subtypes could better decipher the key biological and evolutionary mechanisms.Methods: We firstly retrospectively studied the survival status of 286 LUAD patients with different subtypes. MIP and LEP components were micro-dissected for whole-exome sequencing (WES). Shared and private alterations as well as genomic alternation characteristics between the two components were investigated. Four public cohorts containing LEP and MIP samples were further selected for genomic profile comparison, novel therapeutic target investigation and immune infiltration quantification.Results: LEP and MIP subtypes exhibited largest disease free survival (DFS) in our patients. A total of 2035 SNV and 2757 InDels were identified in the sequenced LEP and MIP components. EGFR was found with highest mutation frequency. Distinct biological processes or pathways were involved in the evolutionary of the two components. Besides, analyses on copy number variation (CNV) and intratumor heterogeneity further discovered the possible immunosurveillance escape, the discrepancy between mutation and CNV level ITH and the pervasive DNA Damage Response as well as WNT pathway gene alternations in MIP component. Phylogenetic analysis on 5 pairs of LEP and MIP components further confirmed the presence of ancestral EGFR mutations. Through comprehensive analysis in our samples and public cohorts, PTP4A3, NAPRT and RECQL4 were identified as novel therapeutic and diagnostic targets in MIP subtype. Immunosuppression prevalence in MIP component was finally confirmed by multi-omics data.Conclusion: We identified genetic differences responsible for variated prognosis. The subtype evolution trajectory was additionally unraveled. Novel gene targets and the immunological analyses also provided therapeutic suggestions for MIP subtype.

International practice variation in perioperative laboratory testing in glioblastoma patients—a retrospective cohort study

Purpose Although standard-of-care has been defined for the treatment of glioblastoma patients, substantial practice variation exists in the day-to-day clinical management. This study aims to compare the use of laboratory tests in the perioperative care of glioblastoma patients between two tertiary academic centers—Brigham and Women’s Hospital (BWH), Boston, USA, and University Medical Center Utrecht (UMCU), Utrecht, the Netherlands. Methods All glioblastoma patients treated according to standard-of-care between 2005 and 2013 were included. We compared the number of blood drawings and laboratory tests performed during the 70-day perioperative period using a Poisson regression model, as well as the estimated laboratory costs per patient. Additionally, we compared the likelihood of an abnormal test result using a generalized linear mixed effects model. Results After correction for age, sex, IDH1 status, postoperative KPS score, length of stay, and survival status, the number of blood drawings and laboratory tests during the perioperative period were 3.7-fold (p < 0.001) and 4.7-fold (p < 0.001) higher, respectively, in BWH compared to UMCU patients. The estimated median laboratory costs per patient were 82 euros in UMCU and 256 euros in BWH. Furthermore, the likelihood of an abnormal test result was lower in BWH (odds ratio [OR] 0.75, p < 0.001), except when the prior test result was abnormal as well (OR 2.09, p < 0.001). Conclusions Our results suggest a substantially lower clinical threshold for ordering laboratory tests in BWH compared to UMCU. Further investigating the clinical consequences of laboratory testing could identify over and underuse, decrease healthcare costs, and reduce unnecessary discomfort that patients are exposed to.

SURVIVAL AND NATURAL REGENERATION OF FOREST ESSENCES CULTIVATED IN ALTERED AREAS THIRTY-FIVE YEARS AFTER PLANTING

The evaluation of the survival and natural regeneration of tree species in a 35-year-old plantation was carried out to identify the species established in the area, aiming at their recommendation in forest restoration plantations in the State of Acre. In the 1980s, 138 forest species were planted in two experimental units (EU), of 1.38 ha each, in the Zoobotanical Park (ZP) of the Federal University of Acre, Rio Branco campus. The main activities carried out in the area, prior to planting, were agriculture and cattle raising. Survival status was measured through a census of all individuals planted at the time, who were still alive. In addition, all regenerating individuals from planted species were surveyed in the effective planting area of the experimental units. At the time of evaluation, living individuals of 41 and 46 species were found in experimental units 1 (EU-1) and 2 (EU-2), respectively. The species Syagrus sancona, Talisia esculenta, Acacia polyphylla, Couepia bracteosa, Mangifera indica, Syzygium cumini and Copaifera multijuga showed survival rates above 90% in at least one of the experimental units. Only Syagrus sancona and Handroanthus serratifolius presented high survival rates in both experimental. Regenerating individuals of the species Aspidosperma vargasii, Couepia bracteosa, Euterpe precatoria, Handroanthus serratifolius, Oenocarpus mapora, Onychopetalum periquino and Stryphnodendron pulcherrimum were found in the two EU.

Association of Acute Perioperative Myocardial Injury With All-Cause Mortality Within 90 Days After Hip Fracture Repair in the Elderly: A Prospective Study

Introduction It remains unclear whether acute perioperative myocardial injury (APMI) increases mortality in the elderly. This study aimed to investigate APMI’s association with mortality within 90 days after hip fracture repair in elderly patients. Materials and Methods This prospective study enrolled elderly patients admitted to the department of Traumatology and Orthopaedics in XXX Hospital, who underwent surgery in 2018–2019 with a 90-day follow-up. According to survival status within 90 days, survival and death groups were constituted. Clinical, demographic, and laboratory indicators and 90-day mortality post-surgery were recorded. APMI’s association with 90-day mortality post-surgery was analyzed by logistic regression. Results Totally 248 participants were enrolled, including 224 and 24 in the survival and death groups, respectively, for a mortality rate of 9.7%. Compared with surviving individuals, the death group was older [81 (75–86) vs 87 (82–89) years], and had higher incidence rates of APMI (24.6% vs 58.3%), intertrochanteric fractures (41.1% vs 62.5%), preoperative atrial fibrillation (8.9% vs 29.2%), and dementia (73.7% vs 95.8%) (all P<.05). They also showed higher pre-injury frail scale scores [1 (0–2) vs 3 (1–4)] and Nottingham hip fracture scores (NHFSs) [4 (4–5) vs 6.5 (5–7)], lower Glomerular filtration [62 (46.1–78.6) vs 44.37 (35–61.92) ml/min], and reduced odds of glomerular filtration rate <60 mL/min (75.0% vs 46.9%) (all P < .05). APMI (OR = 3.294, 95% CI: 1.217–8.913) and NHFS (OR = 2.089, 95% CI: 1.353–3.225) independently predicted 90-day mortality post-surgery (all P<.05). Conclusions APMI is associated with increased mortality risk within 90 days after hip fracture repair in elderly patients.

Analysis and Study on the Quality of Life of Patients Undergoing Transcatheter Aortic Valve Replacement

Objective. Explore the factors affecting the QO of life after transcatheter aortic valve replacement (TAVR) and analyze and evaluate their surgical efficacy and postoperative survival status. Methods. Through correlation analysis and multiple regression analysis, we predict various clinical characteristics and postoperative quality and predict clinical changes in L postoperative quality. Results. The quality of life of patients with the disease has gradually improved and improved from 6 months after surgery. The differences in the three aspects of its physiological mechanism function, physiological function function, overall health, and vitality are statistically significant ( p < 0.05 ). Conclusion. Compared with traditional open-thoracic aortic valve (AV) surgery, TAVR has the significant advantages of smaller surgical incision and less trauma to the patient, which has become one of the reasons why patients are willing to accept it.

ICU delirium burden predicts functional neurologic outcomes

Background We investigated the effect of delirium burden in mechanically ventilated patients, beginning in the ICU and continuing throughout hospitalization, on functional neurologic outcomes up to 2.5 years following critical illness. Methods Prospective cohort study of enrolling 178 consecutive mechanically ventilated adult medical and surgical ICU patients between October 2013 and May 2016. Altogether, patients were assessed daily for delirium 2941days using the Confusion Assessment Method for the ICU (CAM-ICU). Hospitalization delirium burden (DB) was quantified as number of hospital days with delirium divided by total days at risk. Survival status up to 2.5 years and neurologic outcomes using the Glasgow Outcome Scale were recorded at discharge 3, 6, and 12 months post-discharge. Results Of 178 patients, 19 (10.7%) were excluded from outcome analyses due to persistent coma. Among the remaining 159, 123 (77.4%) experienced delirium. DB was independently associated with >4-fold increased mortality at 2.5 years following ICU admission (adjusted hazard ratio [aHR], 4.77; 95% CI, 2.10–10.83; P < .001), and worse neurologic outcome at discharge (adjusted odds ratio [aOR], 0.02; 0.01–0.09; P < .001), 3 (aOR, 0.11; 0.04–0.31; P < .001), 6 (aOR, 0.10; 0.04–0.29; P < .001), and 12 months (aOR, 0.19; 0.07–0.52; P = .001). DB in the ICU alone was not associated with mortality (HR, 1.79; 0.93–3.44; P = .082) and predicted neurologic outcome less strongly than entire hospital stay DB. Similarly, the number of delirium days in the ICU and for whole hospitalization were not associated with mortality (HR, 1.00; 0.93–1.08; P = .917 and HR, 0.98; 0.94–1.03, P = .535) nor with neurological outcomes, except for the association between ICU delirium days and neurological outcome at discharge (OR, 0.90; 0.81–0.99, P = .038). Conclusions Delirium burden throughout hospitalization independently predicts long term neurologic outcomes and death up to 2.5 years after critical illness, and is more predictive than delirium burden in the ICU alone and number of delirium days.

Is Olfactory Impairment Associated With 10-year Mortality Mediating by Neurodegenerative Diseases in Older Adults? The Four-Way Decomposition Analysis

Background: Literature shows that olfactory impairment (OI) is associated not only with neurodegenerative diseases (NDDs), but also with increased mortality. In this study, we analyzed data collected from the prospective phase of the 10-year follow-up of the Shanghai Aging Study (SAS) to explore the mediation effect of NDDs on the OI-mortality relationship.Methods: We analyzed data collected from the prospective phase of the 10-year follow-up of the SAS. We included 1,811 participants aged 60 years or older who completed both an olfactory identification test and a cognitive assessment at baseline (2010–2011). Survival status of the participants from baseline to December 31, 2019 was obtained from the local mortality surveillance system. We used the four-way decomposition method to attribute effects to interaction and mediation and to explore the mediation effect of NDDs on the OI-mortality relationship.Results: The four-way decomposition method revealed a statistically significant association of OI with death. Overall, 43% higher risk for death was associated with OI [excess relative risk (ERR) = 0.43, 95% CI: 0.06–0.80, p = 0.023]. Excluding the mediation from NDDs and interaction between OI and NDDs, the controlled direct effect of OI on death was even higher in NDDs participants, with an ERR of 77% (95% CI: 0.00–1.55, p = 0.050). Statistically significant association was found for failure to identify coffee (ERR = 0.77, 95% CI: 0.18–1.36, p = 0.010) and marginally significant associations were found for failure to identify cinnamon (ERR = 0.33, 95% CI: −0.02–0.68, p = 0.068) and rose (ERR = 0.33, 95% CI: −0.01–0.67, p = 0.054) with death.Conclusion: OI was associated with the long-term mortality in older adults and the association was even stronger in those with NDDs. Failure to identify coffee or rose was associated with a higher mortality risk, and the association was mediated by NDDs.

Multimodal Deep Learning for Prognosis Prediction in Renal Cancer

BackgroundClear-cell renal cell carcinoma (ccRCC) is common and associated with substantial mortality. TNM stage and histopathological grading have been the sole determinants of a patient’s prognosis for decades and there are few prognostic biomarkers used in clinical routine. Management of ccRCC involves multiple disciplines such as urology, radiology, oncology, and pathology and each of these specialties generates highly complex medical data. Here, artificial intelligence (AI) could prove extremely powerful to extract meaningful information to benefit patients.ObjectiveIn the study, we developed and evaluated a multimodal deep learning model (MMDLM) for prognosis prediction in ccRCC.Design, Setting, and ParticipantsTwo mixed cohorts of non-metastatic and metastatic ccRCC patients were used: (1) The Cancer Genome Atlas cohort including 230 patients and (2) the Mainz cohort including 18 patients with ccRCC. For each of these patients, we trained the MMDLM on multiscale histopathological images, CT/MRI scans, and genomic data from whole exome sequencing.Outcome Measurements and Statistical AnalysisOutcome measurements included Harrell’s concordance index (C-index) and also various performance parameters for predicting the 5-year survival status (5YSS). Different visualization techniques were used to make our model more transparent.ResultsThe MMDLM showed great performance in predicting the prognosis of ccRCC patients with a mean C-index of 0.7791 and a mean accuracy of 83.43%. Training on a combination of data from different sources yielded significantly better results compared to when only one source was used. Furthermore, the MMDLM’s prediction was an independent prognostic factor outperforming other clinical parameters.InterpretationMultimodal deep learning can contribute to prognosis prediction in ccRCC and potentially help to improve the clinical management of this disease.Patient SummaryAn AI-based computer program can analyze various medical data (microscopic images, CT/MRI scans, and genomic data) simultaneously and thereby predict the survival time of patients with renal cancer.

A network pharmacology approach to reveal the pharmacological targets and biological mechanism of compound kushen injection for treating pancreatic cancer based on WGCNA and in vitro experiment validation

Background Compound kushen injection (CKI), a Chinese patent drug, is widely used in the treatment of various cancers, especially neoplasms of the digestive system. However, the underlying mechanism of CKI in pancreatic cancer (PC) treatment has not been totally elucidated. Methods Here, to overcome the limitation of conventional network pharmacology methods with a weak combination with clinical information, this study proposes a network pharmacology approach of integrated bioinformatics that applies a weighted gene co-expression network analysis (WGCNA) to conventional network pharmacology, and then integrates molecular docking technology and biological experiments to verify the results of this network pharmacology analysis. Results The WGCNA analysis revealed 2 gene modules closely associated with classification, staging and survival status of PC. Further CytoHubba analysis revealed 10 hub genes (NCAPG, BUB1, CDK1, TPX2, DLGAP5, INAVA, MST1R, TMPRSS4, TMEM92 and SFN) associated with the development of PC, and survival analysis found 5 genes (TSPOAP1, ADGRG6, GPR87, FAM111B and MMP28) associated with the prognosis and survival of PC. By integrating these results into the conventional network pharmacology study of CKI treating PC, we found that the mechanism of CKI for PC treatment was related to cell cycle, JAK-STAT, ErbB, PI3K-Akt and mTOR signalling pathways. Finally, we found that CDK1, JAK1, EGFR, MAPK1 and MAPK3 served as core genes regulated by CKI in PC treatment, and were further verified by molecular docking, cell proliferation assay, RT-qPCR and western blot analysis. Conclusions Overall, this study suggests that the optimized network pharmacology approach is suitable to explore the molecular mechanism of CKI in the treatment of PC, which provides a reference for further investigating biomarkers for diagnosis and prognosis of PC and even the clinical rational application of CKI.