An individualized protein-based prognostic model to stratify pediatric patients with papillary thyroid carcinoma.

Pediatric papillary thyroid carcinomas (PPTCs) exhibit high inter-tumor heterogeneity and currently lack widely adopted recurrence risk stratification criteria. Hence, we propose a machine learning-based objective method to individually predict their recurrence risk. We retrospectively collect and evaluate the clinical factors and proteomes of 83 pediatric benign (PB), 85 pediatric malignant (PM) and 66 adult malignant (AM) nodules, and quantify 10,426 proteins by mass spectrometry. We find 243 and 121 significantly dysregulated proteins from PM vs. PB and PM vs. AM, respectively. Function and pathway analyses show the enhanced activation of the inflammatory and immune system in PM patients compared with the others. Nineteen proteins are selected to predict recurrence using a machine learning model with an accuracy of 88.24%. Our study generates a protein-based personalized prognostic prediction model that can stratify PPTC patients into high- or low-recurrence risk groups, providing a reference for clinical decision-making and individualized treatment.

Prognostic Value of ctDNA Detection in Patients With Locally Advanced Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy: A Systematic Review and Meta-analysis.

BACKGROUND: Circulating tumor DNA (ctDNA) is increasingly used as a biomarker for metastatic rectal cancer and has recently shown promising results in the early detection of recurrence risk. METHODS: We conducted a systematic review and meta-analysis to explore the prognostic value of ctDNA detection in LARC patients undergoing neoadjuvant chemoradiotherapy (nCRT). We systematically searched electronic databases for observational or interventional studies that included LARC patients undergoing nCRT. Study selection according to the PRISMA guidelines and quality assessment of the REMARK tool for biomarker studies. The primary endpoint was the impact of ctDNA detection at different time points (baseline, post-nCRT, post-surgery) on relapse-free survival (RFS) and overall survival (OS). The secondary endpoint was to study the association between ctDNA detection and pathological complete response(pCR) at different time points. RESULTS: After further review and analysis of the 625 articles initially retrieved, we finally included 10 eligible studies. We found no significant correlation between ctDNA detection at baseline and long-term survival outcomes or the probability of achieving a pCR. However, the presence of ctDNA at post-nCRT was associated with worse RFS (HR = 9.16, 95% CI, 5.48-15.32), worse OS (HR = 8.49, 95% CI, 2.20-32.72), and worse pCR results (OR = 0.40, 95%CI, 0.18-0.89). The correlation between the presence of ctDNA at post-surgery and worse RFS was more obvious (HR = 14.94; 95% CI, 7.48-9.83). CONCLUSIONS: Our results suggest that ctDNA detection is a promising biomarker for the evaluation of response and prognosis in LARC patients undergoing nCRT, which merits further evaluation in the following prospective trials.

Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection.

Although host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.

Tailoring Dirac Fermions by In-Situ Tunable High-Order Moiré Pattern in Graphene-Monolayer Xenon Heterostructure.

We report an experimental study of a high-order moiré pattern formed in graphene-monolayer xenon heterostructure. The moiré period is in situ tuned from few nanometers to +∞, by adjusting the lattice constant of the xenon monolayer through annealing. Using angle-resolved photoemission spectroscopy, we observe that Dirac node replicas move closer and finally overlap with a gap opening, as the moiré pattern expands to +∞ and evolves into a Kekulé distortion. A moiré Hamiltonian coupling Dirac fermions from different valleys explains experimental results and indicates narrow moiré band. Our Letter demonstrates a platform to study continuous evolution of the moiré pattern, and provides an unprecedented approach for tailoring Dirac fermions with tunable intervalley coupling.

High-throughput proteomic sample preparation using pressure cycling technology.

High-throughput lysis and proteolytic digestion of biopsy-level tissue specimens is a major bottleneck for clinical proteomics. Here we describe a detailed protocol of pressure cycling technology (PCT)-assisted sample preparation for proteomic analysis of biopsy tissues. A piece of fresh frozen or formalin-fixed paraffin-embedded tissue weighing ~0.1-2 mg is placed in a 150 µL pressure-resistant tube called a PCT-MicroTube with proper lysis buffer. After closing with a PCT-MicroPestle, a batch of 16 PCT-MicroTubes are placed in a Barocycler, which imposes oscillating pressure to the samples from one atmosphere to up to ~3,000 times atmospheric pressure. The pressure cycling schemes are optimized for tissue lysis and protein digestion, and can be programmed in the Barocycler to allow reproducible, robust and efficient protein extraction and proteolysis digestion for mass spectrometry-based proteomics. This method allows effective preparation of not only fresh frozen and formalin-fixed paraffin-embedded tissue, but also cells, feces and tear strips. It takes ~3 h to process 16 samples in one batch. The resulting peptides can be analyzed by various mass spectrometry-based proteomics methods. We demonstrate the applications of this protocol with mouse kidney tissue and eight types of human tumors.

Prognostic Effect of the Controlling Nutritional Status Score in Patients With Esophageal Cancer Treated With Immune Checkpoint Inhibitor.

In recent years, a growing number of clinical studies have shown that immune checkpoint inhibitor (ICI) can increase the remission rate and improve the prognosis of patients with esophageal cancer. The Controlling Nutritional Status (CONUT) score is a novel nutritional indicator that can predict the prognosis of certain malignancies. We retrospectively analyzed the clinical data of 69 patients with advanced esophageal cancer treated with ICI and assessed the relationship between clinicopathological factors including CONUT score, systemic immune-inflammatory index (SII), and neutrophil-to-lymphocyte ratio and the prognosis. We found the CONUT score and SII, neutrophil-to-lymphocyte ratio were an independent prognostic factor for overall survival ( P <0.05). Furthermore, among patients treated with ICI, a high CONUT score was associated with a significantly worse progression-free survival (PFS) and overall survival compared with a low CONUT group. In conclusion, the CONUT can be used to predict the efficacy and prognosis of ICI therapy in patients with esophageal cancer. Our studies have shown that the CONUT score can be used as an effective indicator for the prognosis of patients with esophageal cancer receiving ICI.

Conceptual Modeling of Extended Collision Warning System from the Perspective of Smart Product-Service System.

While Product-Service Systems (PSS) have a potential sustainability impact by increasing a product's life and reducing resource consumption, the lack of ownership might lead to less responsible user behavior. Smart PSS can overcome this obstacle and guarantee correct and safe PSS use. In this context, intelligent connected vehicles (ICVs) with PSS can effectively reduce traffic accidents and ensure the safety of vehicles and pedestrians by guaranteeing optimal and safe vehicle operation. A core subsystem to support that is the collision-warning system (CWS). Existing CWSs are, however, limited to in-car warning; users have less access to the warning information, so the result of CWS for collision avoidance is insufficient. Therefore, CWS needs to be extended to include more elements and stakeholders in the collision scenario. This paper aims to provide a novel understanding of extended CWS (ECWS), outline the conceptual framework of ECWS, and contribute a conceptual modeling approach of ECWS from the smart PSS perspective at the functional level. It defines an integrated solution of intelligent products and warning services. The function is modeled based on the Theory of Inventive Problem Solving (TRIZ). Functions of an ECWS from the perspective of smart PSS can be comprehensively expressed to form an overall solution of integrated intelligent products, electronic services, and stakeholders. Based on the case illustration, the proposed method can effectively help function modeling and development of the ECWS at a conceptual level. This can effectively avoid delays due to traffic accidents and ensure the safety of vehicles and pedestrians.

5-Hydroxymethylcytosine signature in circulating cell-free DNA as a potential diagnostic factor for early-stage colorectal cancer and precancerous adenoma.

Approximately 85% colorectal cancers (CRCs) are thought to evolve through the adenoma-to-carcinoma sequence associated with specific molecular alterations, including the 5-hydroxymethylcytosine (5hmC) signature in circulating cell-free DNA (cfDNA). To explore colorectal disease progression and evaluate the use of cfDNA as a potential diagnostic factor for CRC screening, here, we performed genome-wide 5hmC profiling in plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 plasma and 38 tissues), collected from 21 early-stage CRC patients, 21 AD patients, and 21 healthy controls (HC). The gDNA and cfDNA 5hmC signatures identified in gene bodies and promoter regions in CRC and AD groups were compared with those in HC group. All the differential 5hmC-modified regions (DhMRs) were gathered into four clusters: Disease-enriched, AD-enriched, Disease-lost, and AD-lost, with no overlap. AD-related clusters, AD-enriched and AD-lost, displayed the unique 5hmC signals in AD patients. Disease-enriched and Disease-lost clusters indicated the general 5hmC changes when colorectal lesions occurred. Cancer patients with a confirmable adenoma history segmentally gathered in AD-enriched clusters. KEGG functional enrichment and GO analyses determined distinct differential 5hmC-modified profiles in cfDNA of HC individuals, AD, and CRC patients. All patients had comprehensive 5hmC signatures where Disease-enriched and Disease-lost DhMR clusters demonstrated similar epigenetic modifications, while AD-enriched and AD-lost DhMR clusters indicated complicated subpopulations in adenoma. Analysis of CRC patients with adenoma history showed exclusive 5hmC-gain characteristics, consistent with the 'parallel' evolution hypothesis in adenoma, either developed through the adenoma-to-carcinoma sequence or not. These findings deepen our understanding of colorectal disease and suggest that the 5hmC modifications of different pathological subtypes (cancer patients with or without adenoma history) could be used to screen early-stage CRC and assess adenoma malignancy with large-scale follow-up studies in the future.

Prognostic value of combined preoperative fibrinogen-albumin ratio and platelet-lymphocyte ratio score in patients with breast cancer: A prognostic nomogram study.

OBJECTIVE: The purpose of this study was to evaluate the prognostic value of combined preoperative fibrinogen-albumin ratio and platelet-lymphocyte ratio score (FAR-PLR score) in breast cancer, and to establish a nomogram based on the score as well as clinicopathological factors to predict the prognosis of breast cancer. METHODS: The study cohort included 707 breast cancer patients who underwent curative resection in Taizhou Hospital of Zhejiang Province, China from January 2010 to April 2016. FAR and PLR increased by 2 at the same time, only one index increased by 1, and none increased by 0. The relationship of preoperative FAR-PLR score with overall survival time (OS) and disease free survival time (DFS) in breast cancer was analyzed by log-rank test and COX proportional risk regression model, and a nomogram was established based on the results of multivariate analysis. RESULTS: The average patient follow-up time was 61.2 months. The FAR-PLR score was conversely correlated with OS and DFS (P < 0.001). In the stage I-II group and III group, the FAR-PLR scores were significantly different among high, medium and low groups of OS and DFS (P < 0.01). FAR-PLR score was also found to be a powerful predictor of prognosis in Luminal B-like subtype, Her-2 overexpression subtype, and triple-negative subtype breast cancers; the higher the FAR-PLR score, the worse the prognosis. Forest charts and multivariate COX proportional risk regression model analysis showed that preoperative FAR-PLR score was an independent risk factor of OS (HR = 1.759, 95%CI = 1.410-2.210, P = 0.000) and DFS (HR = 1.729, 95%CI = 1.385-2.158, P = 0.000) in breast cancer. Based on the COX regression analysis of multiple factors, a nomogram prediction model for the survival of breast cancer was established. The calibration curve analysis indicated that the nomogram results were highly consistent between predicted and actual outcomes. Compared to stage (C-index of OS and DFS were 0.583 and 0.588 respectively), PR (C-index of OS and DFS were 0.592 and 0.592 respectively) and FAR-PLR score (C-index of OS and DFS were 0.592 and 0.591 respectively), the nomogram showed better predictive accuracy (C-index of OS and DFS were 0.652 and 0.651 respectively). CONCLUSIONS: The results of this study suggest that preoperative FAR-PLR score may be a potential new biomarker for predicting survival and prognosis of breast cancer. A prognostic nomogram model based on preoperative FAR-PLR score and clinicopathological factors may help doctors make better clinical decisions for breast cancer treatment.

Interaction of XRCC1 Arg399Gln Polymorphism and Alcohol Consumption Influences Susceptibility of Esophageal Cancer.

Background. To explore the correlation between the Arg399Gln polymorphism and susceptibility to esophageal cancer in Korean and Han Chinese individuals in Harbin, China, and its potential interaction with alcohol consumption. Methods. This prospective study included 203 patients with esophageal squamous cell carcinoma; 88 were of Korean descent and 115 were of Han Chinese descent. A group of healthy controls included 105 participants of Korean descent and 105 of Han Chinese descent. Genotyping of the Arg399Gln locus of XRCC1 was performed by PCR-RFLP. Results. The allelic and genotypic frequencies were not significantly different between individuals with esophageal cancer and controls or between individuals of Korean and Han Chinese descent (P > 0.05). However, when individuals with the wild-type Arg/Arg genotype also consumed alcohol, the risk of esophageal cancer was lower (OR = 3.539; 95% CI = 2.039-6.142; P < 0.05). Conclusions. The XRCC1 Arg399Gln polymorphism does not appear to be associated with esophageal cancer in individuals of Korean or Han Chinese descent in Harbin, China. However, alcohol consumption may decrease the risk of esophageal cancer in persons with the wild-type genotype.

Serum progranulin irrelated with Breg cell levels, but elevated in RA patients, reflecting high disease activity.

Soluble progranulin (PGRN) is known to directly regulate regulatory T cells; however, whether PGRN levels are elevated in patients with rheumatoid arthritis and affect the regulatory subsets of B cells remain unknown. In this study, a total of 80 RA patients and 60 healthy controls were studied. Serum progranulin levels were determined using enzyme-linked immune-sorbent assay. A receiver operating characteristic (ROC) curve was used to evaluate the feasibility of serum PGRN as a biomarker for distinguishing patients with RA. CD19(+)CD5(+)GrB(+) B cells were analyzed by flow cytometry in peripheral blood mononuclear cells (PBMCs). Serum progranulin levels in RA patients (median, 59.4 ng/mL) and in RA patients DAS28 > 5.1 (median, 71.98 ng/mL) were much higher than those in normal controls (median, 46.3 ng/mL; P < 0.001). The area under the ROC curve for progranulin levels was 0.705 for RA versus normal controls and the area under the ROC curve for progranulin levels in RA patients DAS28 > 5.1 was 0.977 versus normal controls (P < 0.001). Interestingly, serum progranulin and DAS28, CRP, ESR were all positively correlated in RA patients (P < 0.001). The number of CD19(+)CD5(+)GrB(+) B cells was significantly higher in RA patients (P < 0.05); however, the level of Breg cells was not related to PGRN (P > 0.05). Our findings indicated that induction of PGRN expression may play a role in RA immune reaction and PGRN levels could be a useful biomarker in RA inflammatory response, but irrelated with Breg cell levels.

Imaging guided photothermal therapy using iron oxide loaded poly(lactic acid) microcapsules coated with graphene oxide.

A novel multifunctional theranostic agent has been successfully fabricated by loading iron oxide nanoparticles into poly(lactic acid) (PLA) microcapsules followed by surface functionalization with graphene oxide. Both in vitro and in vivo experiments proved that the resulting microcapsules could serve as contrast agents to simultaneously enhance ultrasound, magnetic resonance and photoacoustic imaging. The composite microcapsules show good biocompatibility and rapid response to magnetic fields. Due to the strong absorption of the near-infrared light, the composite microcapsules could efficiently kill cancer cells upon NIR laser irradiation. In addition, it was found that such a photothermal effect could be obviously enhanced by applying an external magnetic field. In a nutshell, this multifunctional microcapsule can be developed as a promising platform that integrates multimodality imaging and therapy capabilities for effective cancer theranostics.

Initiation of apoptosis, cell cycle arrest and autophagy of esophageal cancer cells by dihydroartemisinin.

Dihydroartemisinin (DHA) has recently been shown anti-tumor activity in various cancer cells. However, its effect on esophageal cancer remains unclear. In this study, for the first time, we demonstrated that DHA reduced viability of esophageal cancer cells in a dose-dependent manner. The mechanism was at least partially due to DHA induced apoptosis by upregulating the expression of Bax, downregulating Bcl-2, Bcl-xL and Procaspase-3, and increasing caspase-9 activation, induced cell cycle arrest by downregulating cyclin E, CDK2 and CDK4. Furthermore, we firstly found that DHA induced autophagy in cancer cells. We concluded DHA might be a novel agent against esophageal cancer.