Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct ...disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.
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•First deep proteogenomic landscape of non-smoking lung adenocarcinoma in East Asia•Identified age, sex-related endogenous, and environmental carcinogen mutagenic processes•Proteome-informed classification distinguished clinical features within early stages•Protein networks identified tumorigenesis hallmarks, biomarkers, and druggable targets
Deep proteogenomic landscape of early stage lung adenocarcinoma in a cohort of mostly non-smokers reveals unique drivers and biomarkers, as well as gender-associated mutagenesis.
Prostate cancer has high metastatic potential. Men with higher urinary levels of the sleep hormone melatonin are much less likely to develop advanced prostate cancer compared with men with lower ...levels of melatonin. Melatonin has shown anticancer activity in experimental investigations. Nevertheless, the therapeutic effect of melatonin in metastatic prostate cancer has largely remained a mystery. Analyses of Gene Expression Omnibus data and human tissue samples indicated that levels of matrix metallopeptidase 13 (MMP‐13) expression are higher in prostate cancer patients than in healthy cancer‐free individuals. Mechanistic investigations revealed that melatonin inhibits MMP‐13 expression and the migratory and invasive capacities of prostate cancer cells via the MT1 receptor and the phospholipase C, p38, and c‐Jun signaling cascades. Importantly, tumor growth rate and metastasis to distant organs were suppressed by melatonin in an orthotopic prostate cancer model. This is the first demonstration showing that melatonin impedes metastasis of prostate cancer by suppressing MMP‐13 expression in both in vitro and in vivo models. Thus, melatonin is promising in the management of prostate cancer metastasis and deserves to undergo clinical investigations.
Melatonin acts on the MT1 receptor and inhibits phospholipase C (PLC) and p38 signal cascades, subsequently suppresses matrix metallopeptidase 13 (MMP‐13) expression through the c‐Jun‐dependent pathway, leading to the reduction of prostate cancer metastasis. This is the first indication that melatonin impedes metastasis via the targeting of MMP‐13 in prostate cancer cells, based on evidence from basic and clinical studies.
In severe respiratory virus infections, including influenza, an exaggerated host immune response has been linked to the severe disease and death. Control of the overwhelming immune response is thus ...essential. Efforts with broad‐spectrum immunosuppressive agents such as steroids are disappointing. A better understanding of host immune response using animal experimental system is required to avoid undesired outcome of experimental manipulation. Following severe influenza virus infection in influenza hemagglutinin antigen‐specific transgenic mouse experimental model, step‐wise evolving cells from a pool of naïve hemagglutinin‐specific CD4+ T cells were studied for phenotypic, genomic, and functional characterization in vivo. Naïve CD4+ T cells respond with Th1 commitment in the absolute majority. They first develop into LAG‐3MedIFN‐γ‐secreting Th1 effectors and then evolve into LAG‐3HighIFN‐γ‐not‐secreting regulators with increasing LAG‐3 expression upon continuous activation and cell division. The LAG‐3MedIFN‐γ‐secreting effectors contribute to inflammation, boost inflammatory response of cognate antigen‐specific CD8+ T cells, and aggravate the disease despite facilitated virus clearance. In contrast, LAG‐3High regulators do not contribute to inflammation, suppress CD8+ T cell inflammatory response, alleviate lung pathology, and ameliorate the disease with preserved virus clearance. Moderated CD8+ T cells retain proliferative capacity, and persist beyond virus clearance. Such moderation is distinct from Foxp‐3+ regulator‐mediated suppression, which suppresses proliferative and inflammatory responses of the CD8+ T cells and impairs virus clearance with inflammation alleviation. Origin of regulatory from the effector cells of LAG‐3‐marked Th1 immunity alleviates lung inflammation without impairment of virus eradication.
Naïve CD4+ T cells respond to influenza virus infection with the induction of T‐bet that directs Th1 lineage commitment. These cells first develop into IFN‐γ‐secreting Th1 effector cells, and this effector cell population contracts with virus eradication. LAG‐3 response appears earlier than the IFN‐γ response in these cells, and IFN‐γ‐secreting Th1 effector cells express moderate‐level LAG‐3. LAG‐3 expression level increases with continuous activation and cell division. The dividing cells lose IFN‐γ capacity and gain regulatory function with higher level LAG‐3 expression. These results demonstrate the origin of induced regulatory cells from the effector cells of Th1 immunity in severe influenza.
Tandem mass spectrometry allows biologists to identify and quantify protein samples in the form of digested peptide sequences. When performing peptide identification, spectral library search is more ...sensitive than traditional database search but is limited to peptides that have been previously identified. An accurate tandem mass spectrum prediction tool is thus crucial in expanding the peptide space and increasing the coverage of spectral library search.
We propose MS
CNN, a non-linear regression model based on deep convolutional neural networks, a deep learning algorithm. The features for our model are amino acid composition, predicted secondary structure, and physical-chemical features such as isoelectric point, aromaticity, helicity, hydrophobicity, and basicity. MS
CNN was trained with five-fold cross validation on a three-way data split on the large-scale human HCD MS
dataset of Orbitrap LC-MS/MS downloaded from the National Institute of Standards and Technology. It was then evaluated on a publicly available independent test dataset of human HeLa cell lysate from LC-MS experiments. On average, our model shows better cosine similarity and Pearson correlation coefficient (0.690 and 0.632) than MS
PIP (0.647 and 0.601) and is comparable with pDeep (0.692 and 0.642). Notably, for the more complex MS
spectra of 3+ peptides, MS
PIP is significantly better than both MS
PIP and pDeep.
We showed that MS
CNN outperforms MS
PIP for 2+ and 3+ peptides and pDeep for 3+ peptides. This implies that MS
CNN, the proposed convolutional neural network model, generates highly accurate MS
spectra for LC-MS/MS experiments using Orbitrap machines, which can be of great help in protein and peptide identifications. The results suggest that incorporating more data for deep learning model may improve performance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The widespread use of electronic health records in the clinical and biomedical fields makes the removal of protected health information (PHI) essential to maintain privacy. However, a significant ...portion of information is recorded in unstructured textual forms, posing a challenge for deidentification. In multilingual countries, medical records could be written in a mixture of more than one language, referred to as code mixing. Most current clinical natural language processing techniques are designed for monolingual text, and there is a need to address the deidentification of code-mixed text.
The aim of this study was to investigate the effectiveness and underlying mechanism of fine-tuned pretrained language models (PLMs) in identifying PHI in the code-mixed context. Additionally, we aimed to evaluate the potential of prompting large language models (LLMs) for recognizing PHI in a zero-shot manner.
We compiled the first clinical code-mixed deidentification data set consisting of text written in Chinese and English. We explored the effectiveness of fine-tuned PLMs for recognizing PHI in code-mixed content, with a focus on whether PLMs exploit naming regularity and mention coverage to achieve superior performance, by probing the developed models' outputs to examine their decision-making process. Furthermore, we investigated the potential of prompt-based in-context learning of LLMs for recognizing PHI in code-mixed text.
The developed methods were evaluated on a code-mixed deidentification corpus of 1700 discharge summaries. We observed that different PHI types had preferences in their occurrences within the different types of language-mixed sentences, and PLMs could effectively recognize PHI by exploiting the learned name regularity. However, the models may exhibit suboptimal results when regularity is weak or mentions contain unknown words that the representations cannot generate well. We also found that the availability of code-mixed training instances is essential for the model's performance. Furthermore, the LLM-based deidentification method was a feasible and appealing approach that can be controlled and enhanced through natural language prompts.
The study contributes to understanding the underlying mechanism of PLMs in addressing the deidentification process in the code-mixed context and highlights the significance of incorporating code-mixed training instances into the model training phase. To support the advancement of research, we created a manipulated subset of the resynthesized data set available for research purposes. Based on the compiled data set, we found that the LLM-based deidentification method is a feasible approach, but carefully crafted prompts are essential to avoid unwanted output. However, the use of such methods in the hospital setting requires careful consideration of data security and privacy concerns. Further research could explore the augmentation of PLMs and LLMs with external knowledge to improve their strength in recognizing rare PHI.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
The purpose of this study was to determine failure patterns and clinicopathologic prognostic factors in patients with locally advanced buccal cancer after postoperative intensity‐modulated ...radiotherapy (IMRT).
Methods
Eighty‐two patients with locally advanced (American Joint Committee on Cancer AJCC stage III/IV) buccal cancer who underwent surgery followed by postoperative IMRT between January 2007 and October 2012 were retrospectively analyzed.
Results
Eighteen patients had local recurrences as the first recurrent site and 11 had supramandibular notch recurrences; the majority of recurrences were classified as marginal failures. The median time from the first local or regional recurrence to death was 5.9 months. In multivariate analyses of survivals, the initial masticator space involvement was the most important prognostic factor. Masticator space involvement, N classification, and maxillectomy were the significant prognostic predictors for supramandibular notch recurrences.
Conclusion
Postoperative IMRT for buccal cancer should not include the surgical beds alone, rather, it should be based on the potential patterns of spread.
Introduction: The left atrium (LA) ablation in different regions, including LA appendage (LAA), LA roof, and LA septum, has recently been proposed to improve the success rate of treating patients ...with atrial fibrillation (AF). The purpose of this study was to investigate the anatomy of LAA, LA roof, and LA septum, using computed tomography (CT).
Methods and Results: Multidetector CT scan was used to depict the LA in 47 patients with drug‐refractory paroxysmal AF (39 males, age = 50 ± 12 years) and 49 control subjects (34 males, age = 54 ± 11 years). The area of LAA orifice, neck, and the length of roof line were greater in AF group than in control subjects. Three types of LAA locations and two types of LAA ridges were observed. Higher incidence of inferior LAA was noted in AF patients. The different morphologies of LA roof were described. Roof pouches were revealed in 15% of AF and 14% of controls. Moreover, we found septal ridge in 32% of AF and 23% of controls.
Conclusions: Considerable variations of LAA and LA roof morphologies were demonstrated. Peculiar structures, including roof pouches and septal ridges, were delineated by CT imaging. These findings were important for determining the strategy of AF ablation and avoiding the procedure‐related complications.
Epicardial adipose tissue (EAT) contains ganglionated plexuses and adipocytes that can affect the pathogenesis of atrial fibrillation (AF). The aim of this study was to quantify the EAT surrounding ...the left atrium (LA) and correlate it with occurrence of AF and outcome after catheter ablation. EAT was evaluated using 64-slice multidetector computed tomography in 68 patients with AF and 34 controls. EAT volume was acquired by semiautomatically tracing axial images from the pulmonary artery to the coronary sinus. Topographic distribution of EAT was assessed by dividing the periatrial space into 8 equal regions. EAT volume significantly increased in patients with AF than in controls (29.9 ± 12.1 vs 20.2 ± 6.5 cm3 , p <0.001). Most EAT was located in regions (1) within the superior vena cava, right pulmonary artery, and right-sided roof of the LA (29.8%), (2) within the aortic root, pulmonary trunk, and left atrial appendage (26.5%), and (3) between the left inferior pulmonary vein and left atrioventricular groove (18.1%). Baseline variables were analyzed in patients with (n = 24) and without (n = 44) AF recurrence after ablation. The recurrent group showed significantly increased EAT (35.2 ± 12.5 vs 26.8 ± 11.1 cm3 , p = 0.007). Multivariate analysis revealed that EAT was an independent predictor of AF recurrence after ablation (p = 0.038). In conclusion, EAT of LA was increased in patients with AF. Large clusters of EAT were observed adjacent to the anterior roof, left atrial appendage, and lateral mitral isthmus. Abundance of EAT was independently related to AF recurrence after ablation.
Background: The efficacy of ablation of complex fractionated atrial electrograms (CFEs) in the single ablation procedure for nonparoxysmal atrial fibrillation (AF) patients is not well demonstrated. ...The aim of this study was to compare the ablation strategies of pulmonary vein isolation (PVI) plus linear ablation with and without additional ablation of CFEs in these patients.
Methods: Consecutive 60 patients (49 ± 11 years old, 50 male, 10 female) with nonparoxysmal AF underwent catheter ablation guided by a NavX mapping system. A stepwise approach included a circumferential PVI and left atrial (LA) linear ablation followed by either the additional ablation of continuous CFEs in the LA/coronary sinus (the first 30 patients) or not (the second 30 patients), detected by an automatic algorithm.
Results: There was no difference in the baseline characteristics between the two groups. Complete PVI eliminated some continuous CFEs and altered the distribution of CFEs. Following PVI and linear ablation, the remaining continuous CFEs were identified in 7.9 ± 10% mapping sites of the LA and CS, and were ablated successfully with a procedural AF termination rate of 53%. With a follow‐up of 19 ± 11 months, a Kaplan–Meier analysis showed that the patients with additional ablation of the CFEs had a higher rate of sinus rhythm maintenance. Multivariate analysis showed the single procedure success could be predicted by the procedural AF termination and the additional ablation of continuous CFEs in the LA/CS.
Conclusions: Ablation of continuous CFEs after PVI and LA linear ablation had a better long‐term efficacy based on the results of single‐ablation procedure.
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