Risk of cardiovascular death in patients with hepatocellular carcinoma based on the Fine-Gray model.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of cancers worldwide, ranking fifth among men and seventh among women, resulting in more than 7 million deaths annually. With the development of medical technology, the 5-year survival rate of HCC patients can be increased to 70%. However, HCC patients are often at increased risk of cardiovascular disease (CVD) death due to exposure to potentially cardiotoxic treatments compared with non-HCC patients. Moreover, CVD and cancer have become major disease burdens worldwide. Thus, further research is needed to lessen the risk of CVD death in HCC patient survivors. AIM: To determine the independent risk factors for CVD death in HCC patients and predict cardiovascular mortality (CVM) in HCC patients. METHODS: This study was conducted on the basis of the Surveillance, Epidemiology, and End Results database and included HCC patients with a diagnosis period from 2010 to 2015. The independent risk factors were identified using the Fine-Gray model. A nomograph was constructed to predict the CVM in HCC patients. The nomograph performance was measured using Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and area under the ROC curve (AUC) value. Moreover, the net benefit was estimated via decision curve analysis (DCA). RESULTS: The study included 21545 HCC patients, of whom 619 died of CVD. Age (< 60) [1.981 (1.573-2.496), P < 0.001], marital status (married) [unmarried: 1.370 (1.076-1.745), P = 0.011], alpha fetoprotein (normal) [0.778 (0.640-0.946), P = 0.012], tumor size (≤ 2 cm) [(2, 5] cm: 1.420 (1.060-1.903), P = 0.019; > 5 cm: 2.090 (1.543-2.830), P < 0.001], surgery (no) [0.376 (0.297-0.476), P < 0.001], and chemotherapy(none/unknown) [0.578 (0.472-0.709), P < 0.001] were independent risk factors for CVD death in HCC patients. The discrimination and calibration of the nomograph were better. The C-index values for the training and validation sets were 0.736 and 0.665, respectively. The AUC values of the ROC curves at 2, 4, and 6 years were 0.702, 0.725, 0.740 in the training set and 0.697, 0.710, 0.744 in the validation set, respectively. The calibration curves showed that the predicted probabilities of the CVM prediction model in the training set vs the validation set were largely consistent with the actual probabilities. DCA demonstrated that the prediction model has a high net benefit. CONCLUSION: Risk factors for CVD death in HCC patients were investigated for the first time. The nomograph served as an important reference tool for relevant clinical management decisions.

ESCO2's oncogenic role in human tumors: a pan-cancer analysis and experimental validation.

PURPOSE: Establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) is involved in the mitotic S-phase adhesins acetylation and is responsible for bridging two sister chromatids. However, present ESCO2 cancer research is limited to a few cancers. No systematic pan-cancer analysis has been conducted to investigate its role in diagnosis, prognosis, and effector function. METHODS: We thoroughly examined the ESCO2 carcinogenesis in pan-cancer by combining public databases such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), UALCAN and Tumor Immune Single-cell Hub (TISCH). The analysis includes differential expression analysis, survival analysis, cellular effector function, gene mutation, single cell analysis, and tumor immune cell infiltration. Furthermore, we confirmed ESCO2's impacts on clear cell renal cell carcinoma (ccRCC) cells' proliferative and invasive capacities in vitro. RESULTS: In our study, 30 of 33 cancer types exhibited considerably greater levels of ESCO2 expression in tumor tissue using TCGA and GTEx databases, whereas acute myeloid leukemia (LAML) exhibited significantly lower levels. Kaplan-Meier survival analyses in adrenocortical carcinoma (ACC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), mesothelioma (MESO), and pancreatic adenocarcinoma (PAAD) demonstrated that tumor patients with high ESCO2 expression have short survival periods. However, in thymoma (THYM), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ), ESCO2 was a favorable prognostic factor. Moreover, ESCO2 expression positively correlates with tumor stage and tumor size in several cancers, including LIHC, KIRC, KIRP and LUAD. Function analysis revealed that ESCO2 participates in mitosis, cell cycle, DNA damage repair, and other processes. CDK1 was identified as a downstream gene regulated by ESCO2. Furthermore, ESCO2 might also be implicated in immune cell infiltration. Finally, ESCO2'S knockdown significantly inhibited the A498 and T24 cells' proliferation, invasion, and migration. CONCLUSIONS: In conclusion, ESCO2 is a possible pan-cancer biomarker and oncogene that can reliably predict the prognosis of cancer patients. ESCO2 was also implicated in the cell cycle and proliferation regulation. In a nutshell, ESCO2 is a therapeutically viable and dependable target.

Liver injury and prolonged hospitalization as indicators of severity in patients with adenovirus infections.

BACKGROUND: Adenovirus (ADV) is a prevalent infective virus in children, accounting for around 5-10% of all cases of acute respiratory illnesses and 4-15% of pneumonia cases in children younger than five years old. Without treatment, severe ADV pneumonia could result in fatality rates of over 50% in cases of emerging strains or disseminated disease. This study aims to uncover the relationship of clinical indicators with primary ADV infection severity, regarding duration of hospitalization and liver injury. METHODS: In this retrospective study, we collected and analyzed the medical records of 1151 in-patients who met the inclusion and exclusion criteria. According to duration of hospitalization, all patients were divided into three groups. Then the difference and correlation of clinical indicators with ADV infection were analyzed, and the relationship among liver injury, immune cells and cytokines was evaluated. RESULTS: The study revealed that patients with a duration of hospitalization exceeding 14 days had the highest percentage of abnormalities across most indicators. This was in contrast to the patients with a hospitalization duration of either less than or equal to 7 days or between 7 and 14 days. Furthermore, correlation analysis indicated that a longer duration of body temperature of ≥ 39°C, bilateral lung lobes infiltration detected by X ray, abnormal levels of AST, PaO2, and SPO2, and a lower age were all predictive of longer hospital stays. Furthermore, an elevated AST level and reduced liver synthesis capacity were related with a longer hospital stay and higher ADV copy number. Additionally, AST/ALT was correlated positively with IFN-γ level and IFN-γ level was only correlated positively with CD4+ T cells. CONCLUSIONS: The study provided a set of predicting indicators for longer duration of hospitalization, which responded for primary severe ADV infection, and elucidated the possible reason for prolonged duration of hospitalization attributing to liver injury via higher ADV copy number, IFN-γ and CD4+ T cells, which suggested the importance of IFN-γ level and liver function monitoring for the patients with primary severe ADV infection.

Predictive effect of triglyceride-glucose index on No-Reflow Phenomenon in patients with type 2 diabetes mellitus and acute myocardial infarction undergoing primary percutaneous coronary intervention.

OBJECTIVE: Triglyceride glucose (TyG) index is considered as a new alternative marker of insulin resistance and a clinical predictor of type 2 diabetes mellitus (T2DM) combined with coronary artery disease. However, the prognostic value of TyG index on No-Reflow (NR) Phenomenon in T2DM patients with acute myocardial infarction (AMI) remains unclear. METHODS: In this retrospective study, 1683 patients with T2DM and AMI underwent primary percutaneous coronary intervention (PCI) were consecutively included between January 2014 and December 2019. The study population was divided into two groups as follows: Reflow (n = 1277) and No-reflow (n = 406) group. The TyG index was calculated as the ln [fasting triglycerides (mg/dL)×fasting plasma glucose (mg/dL)/2].Multivariable logistic regression models and receiver-operating characteristic curve analysis were conducted to predict the possible risk of no-reflow. Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) were calculated to determine the ability of the TyG index to contribute to the baseline risk model. RESULTS: Multivariable logistic regression models revealed that the TyG index was positively associated with NR[OR,95%CI:5.03,(2.72,9.28),p<0.001] in patients with T2DM and AMI. The area under the curve (AUC) of the TyG index predicting the occurrence of NR was 0.645 (95% CI 0.615-0.673; p < 0.001)], with the cut-off value of 8.98. The addition of TyG index to a baseline risk model had an incremental effect on the predictive value for NR [net reclassification improvement (NRI): 0.077(0.043to 0.111), integrated discrimination improvement (IDI): 0.070 (0.031to 0.108), all p < 0.001]. CONCLUSIONS: High TyG index was associated with an increased risk of no-reflow after PCI in AMI patients with T2DM. The TyG index may be a valid predictor of NR phenomenon of patients with T2DM and AMI. Early recognition of NR is critical to improve outcomes with AMI and T2DM patients.

Confined Transport Behavior of Biomolecules within Tilted Nanopores.

The transport behavior of biomolecules at the confined nanoscale is very different from that of the bulk state. Numerous disease diagnostics and targeted drug treatments are performed based on nanochannels in cells. The specific structure and shape of nanochannels play an important role in the behavior and efficiency of substance transport. In this paper, we fabricated nanopores with different tilt angles and the same diameters using focused ion beam. The capture frequency and the blocking current amplitude of λ-DNA within large-angle nanopores decrease obviously, suggesting an increase in the energy barrier of large-angle nanopores and the fact that they stretch biomolecules to thinness. Most importantly, large-angle nanopores slow down λ-DNA transport by 2-4 times. MD simulations find that the sloped electroosmotic flow inside the tilted nanopores is the main factor contributing to the transport phenomena. The increase in the capture time of biomolecules by nanopores assists in obtaining more biological information from the current trajectories. Our study provides a new understanding of substance transport in specially shaped nanopores, which can be instrumental in providing fresh inspiration and approaches to the biomedical field.

Development and Evaluation of Refreshable Braille Display and Active Touch-Reading System for Digital Reading of the Visually Impaired.

The traditional way of reading through Braille books is constraining the reading experience of blind or visually impaired (BVI) in the digital age. In order to improve the reading convenience of BVI, this paper proposes a low-cost and refreshable Braille display device, and solves the problems of high energy consumption and low latching force existing in existing devices. Further, the Braille display device was combined with the 3D Systems Touch device to develop an active Braille touch-reading system for digital reading of BVI with the help of the CHAI3D virtual environment. Firstly, according to the actual needs of BVI to touch and read the Braille dots, this paper utilizes the beam structure to provide a full latching function for the raised Braille dot without energy consumption. Through theoretical derivation and finite element analysis, the performance of the Braille dot actuator is optimized to provide sufficient feedback force and latching force for finger's touch-reading. Then, this paper designs a virtual Braille interactive environment based on the CHAI3D, and combines the sense of touch with audio to effectively improve the recognition accuracy and reading efficiency of BVI for Braille through the multi-modal presentation of Braille information. The performance test results of the device show that the average lifting force of the Braille dot actuator is 101.67 mN, the latching force is over 5 N, and the average refresh frequency is 17.1 Hz, which meets the touch-reading needs of BVI. User experiments show that the average accuracy rate of BVI subjects in identifying digitized Braille is 95.5%, and subjects have a high subjective evaluation of the system.

SERCA1 Overexpression in Skeletal Muscle Attenuates Muscle Atrophy and Improves Motor Function in a Mouse Model of ALS.

Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of muscle mass and muscle function. Previous work from our lab demonstrated that skeletal muscles from a mouse model of ALS show elevated intracellular calcium (Ca2+) levels and heightened endoplasmic reticulum (ER) stress. Objective: To investigate whether overexpression of sarcoplasmic reticulum (SR) Ca2+ ATPase 1 (SERCA1) in skeletal muscle would improve intracellular Ca2+ handling, attenuate ER stress, and improve motor function ALS transgenic mice. Methods: B6SJL-Tg (SOD1*G93A)1Gur/J (ALS-Tg) mice were bred with skeletal muscle α-actinin SERCA1 overexpressing mice to generate wild type (WT), SERCA1 overexpression (WT/+SERCA1), ALS-Tg, and SERCA1 overexpressing ALS-Tg (ALS-Tg/+SERCA1) mice. Motor function (grip test) was assessed weekly and skeletal muscles were harvested at 16 weeks of age to evaluate muscle mass, SR-Ca2+ ATPase activity, levels of SERCA1 and ER stress proteins - protein disulfide isomerase (PDI), Grp78/BiP, and C/EBP homologous protein (CHOP). Single muscle fibers were also isolated from the flexor digitorum brevis muscle to assess changes in resting and peak Fura-2 ratios. Results: ALS-Tg/+SERCA1 mice showed improved motor function, delayed onset of disease, and improved muscle mass compared to ALS-Tg. Further, ALS-Tg/+SERCA1 mice returned levels of SERCA1 protein and SR-Ca2+ ATPase activity back to levels in WT mice. Unexpectedly, SERCA-1 overexpression increased levels of the ER stress maker Grp78/BiP in both WT and ALS-Tg mice, while not altering protein levels of PDI or CHOP. Lastly, single muscle fibers from ALS-Tg/+SERCA1 had similar resting but lower peak Fura-2 levels (at 30 Hz and 100 Hz) compared to ALS-Tg mice. Conclusions: These data indicate that SERCA1 overexpression attenuates the progressive loss of muscle mass and maintains motor function in ALS-Tg mice while not lowering resting Ca2+ levels or ER stress.

Machine learning-coupled tactile recognition with high spatiotemporal resolution based on cross-striped nanocarbon piezoresistive sensor array.

Flexible pressure sensor arrays have been playing important roles in various applications of human-machine interface, including robotic tactile sensing, electronic skin, prosthetics, and human-machine interaction. However, it remains challenging to simultaneously achieve high spatial and temporal resolution in developing pressure sensor arrays for tactile sensing with robust function to achieve precise signal recognition. This work presents the development of a flexible high spatiotemporal piezoresistive sensor array (PRSA) by coupling with machine learning algorithms to enhance tactile recognition. The sensor employs cross-striped nanocarbon-polymer composite as an active layer, though screen printing manufacture processes. A miniaturized signal readout circuit and transmission board is developed to achieve high-speed acquisition of distributed pressure signals from the PRSA. Test results indicate that the developed PRSA platform simultaneously possesses the characteristics of high spatial resolution up to 1.5 mm, fast temporal resolution of about 5 ms, and long-term durability with a variation of less than 2%. The PRSA platform also exhibits excellent performance in real-time visualization of multi-point touch, mapping embossed shapes, and tracking motion trajectory. To test the performance of PRSA in recognizing different shapes, we acquired pressure images by pressing the finger-type device coated with PRSA film on different embossed shapes and implementing the T-distributed Stochastic Neighbor Embedding model to visualize the distinction between images of different shapes. Then we adopted a one-layer neural network to quantify the discernibility between images of different shapes. The analysis results show that the PRSA could capture the embossed shapes clearly by one contact with high discernibility up to 98.9%. Collectively, the PRSA as a promising platform demonstrates its promising potential for robotic tactile sensing.

Epitranscriptional regulation of TGF-ß pseudoreceptor BAMBI by m6A/YTHDF2 drives extrinsic radioresistance.

Activation of TGF-ß signaling serves as an extrinsic resistance mechanism that limits the potential for radiotherapy. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) antagonizes TGF-ß signaling and is implicated in cancer progression. However, the molecular mechanisms of BAMBI regulation in immune cells and its impact on antitumor immunity after radiation have not been established. Here, we show that ionizing radiation (IR) specifically reduces BAMBI expression in immunosuppressive myeloid-derived suppressor cells (MDSCs) in both murine models and humans. Mechanistically, YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) directly binds and degrades Bambi transcripts in an N6-methyladenosine-dependent (m6A-dependent) manner, and this relies on NF-κB signaling. BAMBI suppresses the tumor-infiltrating capacity and suppression function of MDSCs via inhibiting TGF-ß signaling. Adeno-associated viral delivery of Bambi (AAV-Bambi) to the tumor microenvironment boosts the antitumor effects of radiotherapy and radioimmunotherapy combinations. Intriguingly, combination of AAV-Bambi and IR not only improves local tumor control, but also suppresses distant metastasis, further supporting its clinical translation potential. Our findings uncover a surprising role of BAMBI in myeloid cells, unveiling a potential therapeutic strategy for overcoming extrinsic radioresistance.

Three-dimensional ultrashort echo time magnetic resonance imaging in pediatric patients with pneumonia: a comparative study.

BACKGROUND: UTE has been used to depict lung parenchyma. However, the insufficient discussion of its performance in pediatric pneumonia compared with conventional sequences is a gap in the existing literature. The objective of this study was to compare the diagnostic value of 3D-UTE with that of 3D T1-GRE and T2-FSE sequences in young children diagnosed with pneumonia. METHODS: Seventy-seven eligible pediatric patients diagnosed with pneumonia at our hospital, ranging in age from one day to thirty-five months, were enrolled in this study from March 2021 to August 2021. All patients underwent imaging using a 3 T pediatric MR scanner, which included three sequences: 3D-UTE, 3D-T1 GRE, and T2-FSE. Subjective analyses were performed by two experienced pediatric radiologists based on a 5-point scale according to six pathological findings (patchy shadows/ground-glass opacity (GGO), consolidation, nodule, bulla/cyst, linear opacity, and pleural effusion/thickening). Additionally, they assessed image quality, including the presence of artifacts, and evaluated the lung parenchyma. Interrater agreement was assessed using intraclass correlation coefficients (ICCs). Differences among the three sequences were evaluated using the Wilcoxon signed-rank test. RESULTS: The visualization of pathologies in most parameters (patchy shadows/GGO, consolidation, nodule, and bulla/cyst) was superior with UTE compared to T2-FSE and T1 GRE. The visualization scores for linear opacity were similar between UTE and T2-FSE, and both were better than T1-GRE. In the case of pleural effusion/thickening, T2-FSE outperformed the other sequences. However, statistically significant differences between UTE and other sequences were only observed for patchy shadows/GGO and consolidation. The overall image quality was superior or at least comparable with UTE compared to T2-FSE and T1-GRE. Interobserver agreements for all visual assessments were significant and rated "substantial" or "excellent." CONCLUSIONS: In conclusion, UTE MRI is a useful and promising method for evaluating pediatric pneumonia, as it provided better or similar visualization of most imaging findings compared with T2-FSE and T1-GRE. We suggest that the UTE MRI is well-suited for pediatric population, especially in younger children with pneumonia who require longitudinal and repeated imaging for clinical care or research and are susceptible to ionizing radiation.

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial.

Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600-1,600 mg and after 14 daily doses of ≥95% at 50-200 mg. In patients, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885 .

A nomogram to predict postoperative nausea and vomiting in the ward following laparoscopic bariatric surgery.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common and distressing complication of laparoscopic bariatric surgery (LBS). However, there is a lack of effective integrated prediction models for preventing and treating PONV in patients after LBS. METHODS: Based on a randomized controlled trial conducted between November 1, 2021, and May 13, 2022, we included 334 participants who underwent LBS according to the inclusion criteria. The database was divided randomly into training and validation cohorts in a ratio of 7:3. Least absolute shrinkage and selection operator plus multivariable logistic regression were used to identify independent predictors and construct a nomogram. The performance of the nomogram was assessed and validated by the area under the receiver operating characteristic curve (AUC), the concordance index (C-index), calibration plots, and a decision curve analysis (DCA). We also explored specific risk factors for PONV in patients with diabetes. RESULTS: The subjects were divided randomly into training (n = 234) and validation (n = 100) cohorts. Age, history of diabetes, type of surgery, and sugammadex use were incorporated to construct a nomogram prediction model. In the training cohort, the AUC and the optimism-corrected C-index were 0.850 [95% confidence interval (CI) 0.801-0.899] and 0.848, while in the validation cohort they were 0.847 (95% CI 0.768-0.925) and 0.844, respectively. The calibration plots showed good agreement between the predicted and actual observations. The DCA results demonstrated that the nomogram was clinically useful. The type of surgery, sugammadex use, and insulin level at 120 min were predictors of PONV in patients with diabetes with an AUC of 0.802 (95% CI 0.705-0.898). CONCLUSIONS: We developed and validated a prediction model for PONV in patients after LBS. A risk factor analysis of PONV in patients with diabetes provides clinicians with a more precise prophylactic protocol.

Single-cell analysis reveals the immune heterogeneity and interactions in lungs undergoing hepatic ischemia-reperfusion.

Hepatic ischemia-reperfusion IR (HIR) is an unavoidable pathophysiological process during liver transplantation, resulting in systematic sterile inflammation and remote organ injury. Acute lung injury (ALI) is a serious complication after liver transplantation with high postoperative morbidity and mortality. However, the underlying mechanism is still unclear. To assess the phenotype and plasticity of various cell types in the lung tissue microenvironment after HIR at the single-cell level, single-cell RNA sequencing (scRNA-seq) was performed using the lungs from HIR-induced mice. In our results, we identified 23 cell types in the lungs after HIR and found that this highly complex ecosystem was formed by subpopulations of bone marrow-derived cells that signaled each other and mediated inflammatory responses in different states and different intervals. We described the unique transcriptional profiles of lung cell clusters and discovered two novel cell subtypes (Tspo+Endothelial cells and Vcan+ monocytes), as well as the endothelial cell-immune cell and immune cell-T cell clusters interactome. In addition, we found that S100 calcium binding protein (S100a8/a9), specifically and highly expressed in immune cell clusters of lung tissues and exhibited detrimental effects. Finally, the cellular landscape of the lung tissues after HIR was established, highlighting the heterogeneity and cellular interactions between major immune cells in HIR-induced lungs. Our findings provided new insights into the mechanisms of HIR-induced ALI and offered potential therapeutic target to prevent ALI after liver transplantation.

A Breath-Based In Vitro Diagnostics for Lower Respiratory Tract Infection.

Lower Respiratory Tract Infections (LRTIs) represent the leading cause of death due to infectious diseases. Current diagnostic modalities primarily depend on clinical symptoms and lack specificity, especially in light of common colonization without overt infection. To address this, we developed a noninvasive diagnostic approach that employs BreathBiomics™, an advanced human breath sampling system, to detect protease activities induced by bacterial infection in the lower respiratory tract. Specifically, we engineered a high-sensitivity and high-specificity molecular sensor for human neutrophil elastase (HNE). The sensor undergoes cleavage in the presence of HNE, an event that is subsequently detected via Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS). Application of this methodology to clinical samples, breath specimens collected from intubated patients with LRTIs, demonstrated the detection of the cleaved sensor by MALDI-TOF MS. Our findings indicate that this novel approach offers a noninvasive and specific diagnostic strategy for people with LRTIs.

Space and Bond Synergistic Conjugation Controlling Multiple-Aniline NIR-II Absorption for Photoacoustic Imaging Guided Photothermal Therapy.

Currently, clinical photothermal therapy (PTT) is greatly limited by the poor tissue penetration of the excitation light sources in visible (390-780 nm) and first near-infrared (NIR-I, 780-900 nm) window. Herein, based on space and bond synergistic conjugation, a multiple-aniline organic small molecule (TPD), is synthesized for high-efficiency second near-infrared (NIR-II, 900-1700 nm) photoacoustic imaging guided PTT. With the heterogeneity of six nitrogen atoms in TPD, the lone electrons on the nitrogen atom and the π bond orbital on the benzene ring form multielectron conjugations with highly delocalized state, which endowed TPD with strong NIR-II absorption (maximum peak at 925 nm). Besides, according to the single molecular reorganization, the alkyl side chains on TPD make more free space for intramolecular motion to enhance the photothermal conversion ability. Forming TPD nanoparticles (NPs) in J-aggregation, they show a further bathochromic-shifted absorbance (maximum peak at 976 nm) as well as a high photothermal conversion efficiency (66.7%) under NIR-II laser irradiation. In vitro and in vivo experiments demonstrate that TPD NPs can effectively inhibit the growth of tumors without palpable side effects. The study provides a novel NIR-II multiple-aniline structure based on multielectron hyperconjugation, and opens a new design thought for photothermal agents.

Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer.

Targeted therapies in cancer treatment can improve in vivo efficacy and reduce adverse effects by altering the tissue exposure of specific biomolecules. However, there are still large number of target proteins in cancer are still undruggable, owing to the following factors including (1) lack of ligand-binding pockets, (2) function based on protein-protein interactions (PPIs), (3) the highly specific conserved active sites among protein family members, and (4) the variability of tertiary docking structures. The current status of undruggable targets proteins such as KRAS, TP53, C-MYC, PTP, are carefully introduced in this review. Some novel techniques and drug designing strategies have been applicated for overcoming these undruggable proteins, and the most classic and well-known technology is proteolysis targeting chimeras (PROTACs). In this review, the novel drug development strategies including targeting protein degradation, targeting PPI, targeting intrinsically disordered regions, as well as targeting protein-DNA binding are described, and we also discuss the potential of these strategies for overcoming the undruggable targets. Besides, intelligence-assisted technologies like Alpha-Fold help us a lot to predict the protein structure, which is beneficial for drug development. The discovery of new targets and the development of drugs targeting them, especially those undruggable targets, remain a huge challenge. New drug development strategies, better extraction processes that do not disrupt protein-protein interactions, and more precise artificial intelligence technologies may provide significant assistance in overcoming these undruggable targets.

A novel biodegradable polymer-coated sirolimus-eluting stent: 1-year results of the HELIOS registry.

BACKGROUND: The HELIOS stent is a sirolimus-eluting stent with a biodegradable polymer and titanium oxide film as the tie-layer. The study aimed to evaluate the safety and efficacy of HELIOS stent in a real-world setting. METHODS: The HELIOS registry is a prospective, multicenter, cohort study conducted at 38 centers across China between November 2018 and December 2019. A total of 3060 consecutive patients were enrolled after application of minimal inclusion and exclusion criteria. The primary endpoint was target lesion failure (TLF), defined as a composite of cardiac death, non-fatal target vessel myocardial infarction (MI), and clinically indicated target lesion revascularization (TLR) at 1-year follow-up. Kaplan-Meier methods were used to estimate the cumulative incidence of clinical events and construct survival curves. RESULTS: A total of 2998 (98.0%) patients completed the 1-year follow-up. The 1-year incidence of TLF was 3.10% (94/2998, 95% closed interval: 2.54-3.78%). The rates of cardiac death, non-fatal target vessel MI and clinically indicated TLR were 2.33% (70/2998), 0.20% (6/2998), and 0.70% (21/2998), respectively. The rate of stent thrombosis was 0.33% (10/2998). Age ≥60 years, diabetes mellitus, family history of coronary artery disease, acute myocardial infarction at admission, and device success were independent predictors of TLF at 1 year. CONCLUSION: The 1-year incidence rates of TLF and stent thrombosis were 3.10% and 0.33%, respectively, in patients treated with HELIOS stents. Our results provide clinical evidence for interventional cardiologists and policymakers to evaluate HELIOS stent. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03916432.

HepaClear, a blood-based panel combining novel methylated CpG sites and protein markers, for the detection of early-stage hepatocellular carcinoma.

BACKGROUND: Early screening and detection of hepatocellular carcinoma (HCC) can efficiently improve patient prognosis. We aimed to identify a series of hypermethylated DNA markers and develop a blood-based HCC diagnosis panel containing DNA methylation sites and protein markers with improved sensitivity for early-stage HCC detection. RESULTS: Overall, 850K methylation arrays were performed using paired tissue DNA samples from 60 HCC patients. Ten candidate hypermethylated CpG sites were selected for further evaluation by quantitative methylation-specific PCR with 60 pairs of tissue samples. Six methylated CpG sites, along with α-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP), were assayed in 150 plasma samples. Finally, an HCC diagnosis panel, named HepaClear, was developed in a cohort consisting of 296 plasma samples and validated in an independent cohort consisting of 198 plasma samples. The HepaClear panel, containing 3 hypermethylated CpG sites (cg14263942, cg12701184, and cg14570307) and 2 protein markers (AFP and DCP), yielded a sensitivity of 82.6% and a specificity of 96.2% in the training set and a sensitivity of 84.7% and a specificity of 92.0% in the validation set. The HepaClear panel had higher sensitivity (72.0%) for early-stage HCC than AFP (≥ 20 ng/mL, 48.0%) and DCP (≥ 40 mAU/mL, 62.0%) and detected 67.5% of AFP-negative HCC patients (AFP ≤ 20 ng/mL). CONCLUSIONS: We developed a multimarker HCC detection panel (HepaClear) that shows high sensitivity for early-stage HCC. The HepaClear panel exhibits high potential for HCC screening and diagnosis from an at-risk population.