Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer

TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations

Exploring the Mechanism of Immunological Responses in Liver Transplantation–From Rejection to Tolerance in DA-PVG Model

在這篇論文中，我們建立了一個自發性耐受的模式，兩種不同品系的大鼠DA與PVG在進行異體肝臟移植後，可以在不外加任何免疫抑制的處理下，自發性的對外來器官產生耐受的反應。利用功能性蛋白質體學分析在異體肝臟移植中有不同表現量的血清蛋白質，發現在這些不同表現量的蛋白質中，包括血紅素結合蛋白 (haptoglobin)以及激肽原 (kininogen)皆有報告提出具有抑制淋巴球細胞的增生能力，而因此可能降低細胞調控的排斥反應。根據這些不同表現量的蛋白質，透過生物資訊分析統計上有顯著差異的網絡 (network)，發現介白質6 (Interleukin-6)可能參與這個自發性耐受的模式。介白質6是一種具有肝臟保護能力的白血球細胞生長激素，它可以促進肝臟的再生、減少肝臟的受損以及提高具有免疫抑制能力的蛋白質例如血紅素結合蛋白的表現量。有趣的是，在這個模式中，介白質6表現的時間點正好是器官移植排斥最嚴重的時期，因此我們推測介白質6可能在這個自發性耐受上扮演關鍵的角色。此外，介白質6可以提高岩澡糖基化 (fucosylation)調控基因的表現，也支持我們所觀察到在模式中，血清蛋白質的岩澡糖基化程度有上升的情形，但是岩澡糖基化在這個模式中可能的相關功能目前尚不清楚。這些觀察到的現象暗示介白質6在異體移植中扮演著保護的角色。In this report, we have established a spontaneous tolerance model in which rats could develop spontaneous tolerance without any immunosuppressive treatments after orthotopic liver transplantion between DA (RT-1a) and PVG (RT-1c) rats. Functional proteomics analysis was introduced to investigate the differently expressed proteins involved in allograft liver transplantation. Among these different-expressed proteins, both haptoglobin and kininogen were reported to inhibit the proliferation of lymphocytes, suggesting a possible role of these two proteins in down-regulate cell-mediated graft rejection. Bioinformatics analysis of the statistically significant networks based on these differently expressed proteins indicated that the IL-6 signaling pathway might be involved in this model. IL-6 is a hepatoprotective cytokine that promotes liver regeneration, reduces liver injury and up-regulates the immune- suppressive proteins such as haptoglobin. Interestingly in this model, the highest expression of IL-6 occurred at the most severe stage of allograft rejection; thus we hypothesize that IL-6 might be the key contributor to spontaneous tolerance. Furthermore, it has been previously shown that IL-6 can also up-regulate the fucosylation regulatory genes, which supports our observation of an increase of fucosylation levels in serum protein; yet the related functions of fucosylation in this model remained unclear. These observations suggest that IL-6 plays a protective role in the spontaneous tolerance DA/PVG OLT model.Acknowledgements 2bstract (Chinese) 4bstract (English) 5bbreviations 10ists of Figures 12ists of Figures 13. Introduction 14.1. Organ transplantation 14.2. Transplantation rejection and immunosuppressive therapy 15.3. Spontaneous tolerance orthotopic liver transplantation 16.4. Functional proteomics analysis 17.5. Investigation of IL-6 related responses in DA/PVG OLT model 19. Materials and Methods 21.1. Orthotopic liver transplantation 21.2. Sample preparation 21.3. Two-dimensional gel electrophoresis (2DE) 21.4. Two-dimensional difference gel electrophoresis (2D-DIGE) 22.5. In-gel digestion for protein identification 23.6. Mass spectrometry analysis 24.7. Bioinformatics analysis 25.8. Enzyme-linked immunosorbent assay (ELISA) of IL-6 26.9. Western blot assay 26.10. Lectin blot assay 27. Results 29.1. Analysis of protein expression in DA/PVG OLT model 29.2. Identification of different-expressed serum protein 29.3. Functional networks analysis of DA/PVG OLT model 30.4. ELISA Quantification of IL-6 30.5. The expression time course of haptoglobin,α1-antitrypsin, and ceruloplasmin 31.6. Lectin blot analysis the fucosylation of serum protein 31. Discussion 33.1. Functional proteomics analysis in DA/PVG OLT model 33.2. Potential immunosuppressive proteins 33.3. Bioinformatics network analysis in DA/PVG OLT model 34.4. Il-6 signaling pathway 35.5. Role of IL-6 in organ transplantation 36.6. IL-6 regulated proteins 37.7. The expression time course of IL-6 and IL-6 regulated proteins 38.8. Glycan modification in DA/PVG OLT model 39.9. Conculsion 40. Reference 42. Figures 51. Tables 6

Opioid-sparing anesthesia with dexmedetomidine provides stable hemodynamic and short hospital stay in non-intubated video-assisted thoracoscopic surgery: a propensity score matching cohort study

Abstract Objectives Dexmedetomidine is an alpha-2 agonist with anti-anxiety, sedative, and analgesic effects and causes a lesser degree of respiratory depression. We hypothesized that the use of dexmedetomidine in non-intubated video-assisted thoracic surgery (VATS) may reduce opioid-related complications such as postoperative nausea and vomiting (PONV), dyspnea, constipation, dizziness, skin itching, and cause minimal respiratory depression, and stable hemodynamic status. Methods Patients who underwent non-intubated VATS lung wedge resection with propofol combined with dexmedetomidine (group D) or alfentanil (group O) between December 2016 and May 2022 were enrolled in this retrospective propensity score matching cohort study. Intraoperative vital signs, arterial blood gas data, perioperative results and treatment outcomes were analyzed. Of 100 patients included in the study (group D, 50 and group O, 50 patients), group D had a significantly lower degree of decrement in the heart rate and the blood pressure than group O. Intraoperative one-lung arterial blood gas revealed lower pH and significant ETCO2. The common opioid-related side effects, including PONV, dyspnea, constipation, dizziness, and skin itching, all of which occurred more frequently in group O than in group D. Patients in group O had significantly longer postoperative hospital stay and total hospital stay than group D, which might be due to opioid-related side effects postoperatively. Conclusions The application of dexmedetomidine in non-intubated VATS resulted in a significant reduction in perioperative opioid-related complications and maintenance with acceptable hemodynamic performance. These clinical outcomes found in our retrospective study may enhance patient satisfaction and shorten the hospital stay

Integrating FSE and AHP to Identify Valuable Customer Needs by Service Quality Analysis

In this study, we explore the needs of different valuable customer groups for service quality and how limited resources are allocated to enhance service quality. Accordingly, we propose a hybrid multi-criteria decision-making (MCDM) tool that uses fuzzy synthetic evaluation (FSE) in combination with the analytic hierarchy process (AHP) to help companies enhance understanding of quantitative data (the weights of the factors that affect service quality) and qualitative information to identify valuable customers. Fifty-three experts and 304 consumers at convenience stores (CVS) comprise the data set. We employed the AHP to obtain index weights in the second step of FSE and conducted FSE to determine the importance of various valuable customer groups. The results demonstrate that different valuable customer groups have dissimilar perceptions and feelings about service quality. The findings indicate that customers between “20 to 29 years old” are the most valuable customer group and that most consumers do not care much about “problem solving”. The analysis is distinct from extant work in that it examines the effect of receiving service quality from a consumer viewpoint, as we conducted a comprehensive analysis from both customer and expert perspectives

En Bloc Resection for Lung Cancer with Chest Wall Invasion

The aim of this study was to retrospectively assess the results of en bloc chest wall plus lung resection for patients with non-small cell lung cancer (NSCLC) invading the chest wall. Methods: From January 1986 to December 2000, of 1,820 patients having surgery for NSCLC, 42 (2.3%) patients with neoplasms involving the chest wall underwent en bloc chest wall and lung resection. Patient demographics, preoperative symptoms, operative procedures, tumor cell type and size, removed nodal status, and pathologic stage were summarized. The 5-year survival rates of the groups were compared. Results: Postoperative staging revealed 28 were T3N0M0, 4 were T3N1M0, and 10 were T3N2M0. The in-hospital mortality rate was 11.9% (5/42). The mean age was 79.0 ± 2.8 years in the patients who died of complications, which was significantly older than the mean age of 67.9 ± 8.1 years in the patients who survived the surgery (p = 0.005). The overall 5-year survival was 28.4%. The 5-year survival was significantly longer in the patients with negative (N0) nodal metastasis than in those with N1 and/or N2 nodal metastasis (39.6% versus 7.1%, p = 0.01). Eleven patients had tumor involvement of the parietal pleura. Thirty-one patients had tumor involvement of the soft tissue and/or bone. There was no significant difference of 5-year survival rate between the patients with involvement of the parietal pleura only and the patients with involvement of the parietal pleura and the soft tissue and/or bone (10.9% versus 33.5%, p = 0.94). Conclusion: En bloc resection for bronchogenic carcinoma invading the chest wall provides a favorable prognosis in cases without nodal metastasis. Significant postoperative mortality is associated with old age (> 80 years). The 5-year survival rate is not significantly different between the patients with involvement of the parietal pleura only and the patients with involvement of the parietal pleura and the soft tissue and/or bone

Treatment With Propranolol for Infantile Hemangioma in 13 Taiwanese Newborns and Young Infants

Hemangioma in infants has a benign self-limited course, but the 10% of cases with complications need further treatment. Successful treatment with propranolol in western countries has been reported over the past few years. We evaluated the efficacy of propranolol for treating infantile hemangioma in Taiwanese newborns and young infants. Methods: Patients below 1 year of age treated with propanolol between November 2009 and March 2011 were enrolled. Demographic data, clinical features, imaging findings, treatment regimens of propranolol, and outcome were investigated. Results: Thirteen patients were treated with propranolol at a dose of 2–3 mg/kg/day. Seven (53.8%) patients had solitary hemangioma and six had multiple ones. The indications for treatment were risk of local event in nine patients, functional risk in four, local complication in one, and life-threatening complication in one. The median age for starting propranolol was 4 months (range: 1–11 months). Responses to propranolol, such as decolorization, regression in tumor size, or improvement of hemangioma-associated complications were observed in all patients within 1–2 weeks after treatment. Propranolol-associated adverse effects occurred in two patients. One infant had occasional tachypnea, and the other had occasional pale-looking appearance. The symptoms resolved after dosage tapering. Conclusion: Propranolol may be a promising therapeutic modality for infantile hemangioma. Therapeutic strategies are needed to evaluate the optimal treatment protocol and long-term adverse effects

Salivary Pro-Inflammatory Markers and Smoking Status Influences the Treatment Effectiveness of Periodontal Disease Patients with Hypertension

Background: Hypertension and periodontal diseases share several risk factors. Inflammation biomarkers in saliva are related to hypertension and periodontal disease. The aim of this study was to explore the role of the salivary inflammatory biomarkers in the treatment effectiveness of patients with hypertension and periodontal disease. Methods: This observational study enrolled 160 subjects diagnosed with periodontitis, 40 of which had a history of hypertension. All subjects had completed scaling and root planning therapeutic procedures within four weeks. The clinical periodontal parameters (i.e., bleeding on probing, plaque control record (PCR), and probing depth (PD)) were evaluated before and after the treatment. Pro-inflammatory markers were determined using a commercial kit. Results: The recovery rate (PD 4–9 mm) in non-hypertensive subjects was significantly higher than in hypertensive subjects (60.47% vs. 52.60%, respectively; p = 0.04). All clinical parameters, excluding PCR, positively correlated with salivary IL-1β at baseline and after completing treatment. Our results showed that increased salivary IL-1β levels were positively associated with decreased PCR (β = −27.65 and p = 0.05) and PD recovery rate (β = −17.05 and p = 0.02) in hypertensive subjects. Conclusions: The present study sheds important light on the clinical use of salivary pro-inflammatory cytokines as valuable biomarkers for predicting the treatment effectiveness of patients suffering from hypertension and periodontitis

Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas

International audienceThe TP53 tumor suppressor gene is frequently mutated in human cancers. An analysis of five data platforms in 10,225 patient samples from 32 cancers reported by The Cancer Genome Atlas (TCGA) enables comprehensive assessment of p53 pathway involvement in these cancers. More than 91% of TP53-mutant cancers exhibit second allele loss by mutation, chromosomal deletion, or copy-neutral loss of heterozygosity. TP53 mutations are associated with enhanced chromosomal instability, including increased amplification of oncogenes and deep deletion of tumor suppressor genes. Tumors with TP53 mutations differ from their non-mutated counterparts in RNA, miRNA, and protein expression patterns, with mutant TP53 tumors displaying enhanced expression of cell cycle progression genes and proteins. A mutant TP53 RNA expression signature shows significant correlation with reduced survival in 11 cancer types. Thus, TP53 mutation has profound effects on tumor cell genomic structure, expression, and clinical outlook

RNA Modifications and Epigenetics in Modulation of Lung Cancer and Pulmonary Diseases

Lung cancer is the leading cause of cancer-related mortality worldwide, and its tumorigenesis involves the accumulation of genetic and epigenetic events in the respiratory epithelium. Epigenetic modifications, such as DNA methylation, RNA modification, and histone modifications, have been widely reported to play an important role in lung cancer development and in other pulmonary diseases. Whereas the functionality of DNA and chromatin modifications referred to as epigenetics is widely characterized, various modifications of RNA nucleotides have recently come into prominence as functionally important. N6-methyladosine (m6A) is the most prevalent internal modification in mRNAs, and its machinery of writers, erasers, and readers is well-characterized. However, several other nucleotide modifications of mRNAs and various noncoding RNAs have also been shown to play an important role in the regulation of biological processes and pathology. Such epitranscriptomic modifications play an important role in regulating various aspects of RNA metabolism, including transcription, translation, splicing, and stability. The dysregulation of epitranscriptomic machinery has been implicated in the pathological processes associated with carcinogenesis including uncontrolled cell proliferation, migration, invasion, and epithelial-mesenchymal transition. In recent years, with the advancement of RNA sequencing technology, high-resolution maps of different modifications in various tissues, organs, or disease models are being constantly reported at a dramatic speed. This facilitates further understanding of the relationship between disease development and epitranscriptomics, shedding light on new therapeutic possibilities. In this review, we summarize the basic information on RNA modifications, including m6A, m1A, m5C, m7G, pseudouridine, and A-to-I editing. We then demonstrate their relation to different kinds of lung diseases, especially lung cancer. By comparing the different roles RNA modifications play in the development processes of different diseases, this review may provide some new insights and offer a better understanding of RNA epigenetics and its involvement in pulmonary diseases

Circular RNAs Modulate Cancer Hallmark and Molecular Pathways to Support Cancer Progression and Metastasis

Circular RNAs (circRNAs) are noncoding products of backsplicing of pre-mRNAs which have been established to possess potent biological functions. Dysregulated circRNA expression has been linked to diseases including different types of cancer. Cancer progression is known to result from the dysregulation of several molecular mechanisms responsible for the maintenance of cellular and tissue homeostasis. The dysregulation of these processes is defined as cancer hallmarks, and the molecular pathways implicated in them are regarded as the targets of therapeutic interference. In this review, we summarize the literature on the investigation of circRNAs implicated in cancer hallmark molecular signaling. First, we present general information on the properties of circRNAs, such as their biogenesis and degradation mechanisms, as well as their basic molecular functions. Subsequently, we summarize the roles of circRNAs in the framework of each cancer hallmark and finally discuss the potential as therapeutic targets