Posttranscriptional regulation of de novo lipogenesis by glucose-induced O-GlcNAcylation.

O-linked ß-N-acetyl glucosamine (O-GlcNAc) is attached to proteins under glucose-replete conditions; this posttranslational modification results in molecular and physiological changes that affect cell fate. Here we show that posttranslational modification of serine/arginine-rich protein kinase 2 (SRPK2) by O-GlcNAc regulates de novo lipogenesis by regulating pre-mRNA splicing. We found that O-GlcNAc transferase O-GlcNAcylated SRPK2 at a nuclear localization signal (NLS), which triggers binding of SRPK2 to importin α. Consequently, O-GlcNAcylated SRPK2 was imported into the nucleus, where it phosphorylated serine/arginine-rich proteins and promoted splicing of lipogenic pre-mRNAs. We determined that protein nuclear import by O-GlcNAcylation-dependent binding of cargo protein to importin α might be a general mechanism in cells. This work reveals a role of O-GlcNAc in posttranscriptional regulation of de novo lipogenesis, and our findings indicate that importin α is a "reader" of an O-GlcNAcylated NLS.

BGL3 lncRNA mediates retention of the BRCA1/BARD1 complex at DNA damage sites.

Long non-coding RNAs (lncRNAs) are emerging regulators of genomic stability and human disease. However, the molecular mechanisms by which nuclear lncRNAs directly contribute to DNA damage responses remain largely unknown. Using RNA antisense purification coupled with quantitative mass spectrometry (RAP-qMS), we found that the lncRNA BGL3 binds to PARP1 and BARD1, exhibiting unexpected roles in homologous recombination. Mechanistically, BGL3 is recruited to DNA double-strand breaks (DSBs) by PARP1 at an early time point, which requires its interaction with the DNA-binding domain of PARP1. BGL3 also binds the C-terminal BRCT domain and an internal region (amino acids 127-424) of BARD1, which mediates interaction of the BRCA1/BARD1 complex with its binding partners such as HP1γ and RAD51, resulting in BRCA1/BARD1 retention at DSBs. Cells depleted for BGL3 displayed genomic instability and were sensitive to DNA-damaging reagents. Overall, our findings underscore the biochemical versatility of RNA as a mediator molecule in the DNA damage response pathway, which affects the accumulation of BRCA1/BARD1 at DSBs.

Study on Gesture Recognition Method with Two-Stream Residual Network Fusing sEMG Signals and Acceleration Signals.

Currently, surface EMG signals have a wide range of applications in human-computer interaction systems. However, selecting features for gesture recognition models based on traditional machine learning can be challenging and may not yield satisfactory results. Considering the strong nonlinear generalization ability of neural networks, this paper proposes a two-stream residual network model with an attention mechanism for gesture recognition. One branch processes surface EMG signals, while the other processes hand acceleration signals. Segmented networks are utilized to fully extract the physiological and kinematic features of the hand. To enhance the model's capacity to learn crucial information, we introduce an attention mechanism after global average pooling. This mechanism strengthens relevant features and weakens irrelevant ones. Finally, the deep features obtained from the two branches of learning are fused to further improve the accuracy of multi-gesture recognition. The experiments conducted on the NinaPro DB2 public dataset resulted in a recognition accuracy of 88.25% for 49 gestures. This demonstrates that our network model can effectively capture gesture features, enhancing accuracy and robustness across various gestures. This approach to multi-source information fusion is expected to provide more accurate and real-time commands for exoskeleton robots and myoelectric prosthetic control systems, thereby enhancing the user experience and the naturalness of robot operation.

Patient's Healthy-Limb Motion Characteristic-Based Assist-As-Needed Control Strategy for Upper-Limb Rehabilitation Robots.

The implementation of a progressive rehabilitation training model to promote patients' motivation efforts can greatly restore damaged central nervous system function in patients. Patients' active engagement can be effectively stimulated by assist-as-needed (AAN) robot rehabilitation training. However, its application in robotic therapy has been hindered by a simple determination method of robot-assisted torque which focuses on the evaluation of only the affected limb's movement ability. Moreover, the expected effect of assistance depends on the designer and deviates from the patient's expectations, and its applicability to different patients is deficient. In this study, we propose a control method with personalized treatment features based on the idea of estimating and mapping the stiffness of the patient's healthy limb. This control method comprises an interactive control module in the task-oriented space based on the quantitative evaluation of motion needs and an inner-loop position control module for the pneumatic swing cylinder in the joint space. An upper-limb endpoint stiffness estimation model was constructed, and a parameter identification algorithm was designed. The upper limb endpoint stiffness which characterizes the patient's ability to complete training movements was obtained by collecting surface electromyographic (sEMG) signals and human-robot interaction forces during patient movement. Then, the motor needs of the affected limb when completing the same movement were quantified based on the performance of the healthy limb. A stiffness-mapping algorithm was designed to dynamically adjust the rehabilitation training trajectory and auxiliary force of the robot based on the actual movement ability of the affected limb, achieving AAN control. Experimental studies were conducted on a self-developed pneumatic upper limb rehabilitation robot, and the results showed that the proposed AAN control method could effectively estimate the patient's movement needs and achieve progressive rehabilitation training. This rehabilitation training robot that simulates the movement characteristics of the patient's healthy limb drives the affected limb, making the intensity of the rehabilitation training task more in line with the patient's pre-morbid limb-use habits and also beneficial for the consistency of bilateral limb movements.

Radiotherapy Improves Survival of Patients With Lymphovascular Invasion in pT1b Esophageal Squamous Cell Cancer After Endoscopic Submucosal Dissection.

INTRODUCTION: Adjuvant radiotherapy is recommended for pT1b esophageal squamous cell cancer (ESCC) after endoscopic submucosal dissection (ESD). However, it is unclear whether additional radiotherapy can improve patient survival. This study aimed to evaluate the efficacy of adjuvant radiotherapy after ESD for pT1b ESCC. METHODS: This was a multicenter, cross-sectional study involving 11 hospitals in China. Between January 2010 and December 2019, patients with T1bN0M0 ESCC treated with or without adjuvant radiotherapy after ESD were included. Survival between groups was compared. RESULTS: Overall, 774 patients were screened, and 161 patients were included. Forty-seven patients (29.2%) received adjuvant radiotherapy after ESD (RT group) and 114 (70.8%) underwent ESD alone (non-RT group). There were no significant differences in overall survival (OS) and disease-free survival (DFS) between the RT and non-RT groups. Lymphovascular invasion (LVI) was the only prognostic factor. In the LVI+ group, adjuvant radiotherapy significantly improved survival (5-year OS: 91.7% vs 59.5%, P = 0.050; 5-year DFS: 92.9% vs 42.6%, P = 0.010). In the LVI- group, adjuvant radiotherapy did not improve survival (5-year OS: 83.5% vs 93.9%, P = 0.148; 5-year DFS: 84.2% vs 84.7%, P = 0.907). The standardized mortality ratios were 1.52 (95% confidence interval 0.04-8.45) in the LVI+ group with radiotherapy and 0.55 (95% confidence interval 0.15-1.42) in the LVI- group without radiotherapy. DISCUSSION: Adjuvant radiotherapy could improve survival in pT1b ESCC with LVI+ other than LVI- after ESD. Selective adjuvant radiotherapy based on LVI status achieved survival rates similar to those of the general population.

Co-profiling reveals distinct patterns of genomic chromatin accessibility and gene expression in pulmonary hypertension caused by chronic hypoxia.

INTRODUCTION: Aberrant gene expression is a key mechanism underlying pulmonary hypertension (PH) development. The alterations of genomic chromatin accessibility and their relationship with the aberrant gene expressions in PH are poorly understood. We used bulk Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing (RNA-seq) in pulmonary artery smooth muscle cells (PASMCs) of chronic hypoxia-exposed rats mimicking group 3 human PH. METHODS: Adult Sprague Dawley rats were commercially obtained from Hunan SJA (Hunan SJA Laboratory Animal Co., Changsha, China) and randomizedly allocated into four groups exposing to nomobaric hypoxia or normoxia for 1 or 28 days respectively. After the assessment of pulmonary hemodynamics, smooth muscle cells were isolated from intralobular arteries and simultaneously subjected to bulk Assay of ATAC-seq and RNA-seq. RESULTS: Hypoxic exposure for continuous 28-days, but not for 1-day, induced established PH phenotypes in rats. ATAC-seq revealed a major distribution of differential accessibility regions (DARs) annotated to the genome in out-of-promoter regions, following 1-day or 28-days hypoxia. 1188 DAR-associated genes and 378 differentially expressed genes (DEGs) were identified in rats after exposure to 1-day hypoxia, while 238 DAR-associated genes and 452 DEGs for 28-days hypoxia. Most of the DAR-associated genes or DEGs in 1-day did not overlap with that of 28-days hypoxia. A Pearson correlation analysis indicated no significant correlation between ATAC-seq and RNA-seq. CONCLUSIONS: The alterations in genomic chromatin accessibility and genes expression of PASMCs in the initial stage of hypoxia are distinct from the established stage of hypoxia-induced PH. The genomic differential accessibility regions may not be the main mechanisms directly underlying the differentially expressed genes observed either in the initial or established stages of PH. Thus the time-course alterations of gene expression and their possible indirect link with genomic chromatin accessibility warrant more attention in mechanistic study of pulmonary hypertension.

Dosimetric impact of hollow intraoral stents for head and neck cancer radiotherapy: A phantom study.

PURPOSE: To investigate the dosimetric impact of the calculation boundaries and dose calculation algorithms of radiotherapy in head and neck cancer patients with an opened oral cavity connected to the exterior by a hollow intraoral positioning stent. METHODS AND MATERIALS: A homemade silicone phantom with an opened oral cavity was placed in a CIRS head phantom to model head and neck cancer patients with a hollow intraoral positioning stent. 3D-CRT plans were designed on CT images of the phantom in Monaco and Pinnacle3 treatment planning systems (TPSs) with the same beam parameters. The default boundary and manually extrapolated boundary were both adopted in these two TPSs to explore the dosimetric impact on treatment plans. The nanoDot™ optically stimulated luminescence dosimeters (OSLDs) were chosen to measure the planned dose surrounding the oral cavity of the head phantom after calibration. RESULT: The doses in the air cavity and two measuring points at the joint area were dramatically changed from 0.0, 92.4 and 148.8 cGy to 177.8, 244.2 and 244.1 cGy in Monaco after adopting the extrapolated boundary. While the calculated doses at the same place were changed from 61.2, 143.7 and 198.3 cGy to 175.4, 234.7 and 233.2 cGy in Pinnacle3 with a similar calculation boundary. For the Monaco TPS, the relative errors compared to the OSLD measured doses were 2.94 ± 1.93%, 0.53 ± 8.64%, 2.65 ± 1.87% and 3.93 ± 1.69% at 4 measuring positions. In contrast, the relative errors 4.03 ± 1.93%, 4.85 ± 8.64%, 7.61 ± 1.87% and 5.61 ± 1.69% were observed in Pinnacle3 . CONCLUSION: The boundary setting of an opened oral cavity in TPSs has a significant dosimetric impact on head and neck cancer radiotherapy. An extrapolated boundary should be manually set up to include the whole oral cavity in the dose calculation domain to avoid major dose deviations.

Customized Trajectory Optimization and Compliant Tracking Control for Passive Upper Limb Rehabilitation.

Passive rehabilitation training in the early poststroke period can promote the reshaping of the nervous system. The trajectory should integrate the physicians' experience and the patient's characteristics. And the training should have high accuracy on the premise of safety. Therefore, trajectory customization, optimization, and tracking control algorithms are conducted based on a new upper limb rehabilitation robot. First, joint friction and initial load were identified and compensated. The admittance algorithm was used to realize the trajectory customization. Second, the improved butterfly optimization algorithm (BOA) was used to optimize the nonuniform rational B-spline fitting curve (NURBS). Then, a variable gain control strategy is designed, which enables the robot to track the trajectory well with small human-robot interaction (HRI) forces and to comply with a large HRI force to ensure safety. Regarding the return motion, an error subdivision method is designed to slow the return movement. The results showed that the customization force is less than 6 N. The trajectory tracking error is within 12 mm without a large HRI force. The control gain starts to decrease in 0.5 s periods while there is a large HRI force, thereby improving safety. With the decrease in HRI force, the real position can return to the desired trajectory slowly, which makes the patient feel comfortable.

Synthesis of novel 4,7-disubstituted quinoline derivatives as autophagy inducing agents via targeting stabilization of ATG5.

A series of new 4,7-disubstituted quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 10c, 10g, 10i, 10j and 10k displayed potent antiproliferative activity with IC50 value of lower than 5.0 µM against human tumor cell lines, and N-(3-nitrophenyl)-7-((3,4,5-trimethoxybenzyl)oxy)quinoline - 4-amine 10k was found to be the most potent antiproliferative agent against HCT-116, HepG2, BCG-823, A549 and A2780 cell lines with IC50 values of 0.35, 1.98, 0.60, 0.39 and 0.67 µM, respectively. The antitumor efficacy of the representative compound 10k in mice was also evaluated, and the results showed that compound 10k effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 10k could inhibit colorectal cancer growth through inducing autophagy via excessively targeting stabilization of ATG5. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.

Silencing of lncRNA SNHG20 delays the progression of nonalcoholic fatty liver disease to hepatocellular carcinoma via regulating liver Kupffer cells polarization.

This study aims to investigate the role of long noncoding RNA SNHG20 in the progression of nonalcoholic fatty liver disease (NALFD) to hepatocellular carcinoma (HCC), and to elucidate whether polarization of Kupffer cells (KCs, liver macrophages) was involved in this process. Mouse NALFD was induced by 16 weeks of high-fat diet (HFD) feeding. Mouse NALFD-HCC was induced by 36 weeks of HFD feeding (from 1 week to 36 weeks) and 20 weeks of diethyl nitrosamine (DEN) administration (from 17 weeks to 36 weeks). The LV-shRNA- and LV-sh-SNHG20-infected RAW264.7 cells were injected into the NALFD mice followed by DEN treatment to evaluate the role of SNHG20 in regulating the progression of NALFD to HCC in mice. The proportion of M1 and M2 macrophages was determined by flow cytometry. The levels of M1-related inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α and M2-related Arg-1 and interleukin (IL)-10 were also examined. SNHG20 expression was decreased in NALFD but increased in NALFD-HCC, both in human and experimental mouse livers. Furthermore, human and mouse NALFD-HCC KCs displayed decreased M1/M2 ratio compared with NALFD KCs. Moreover, SNHG20 overexpression induced M2 polarization through activating STAT6, whereas SNHG20 silencing suppressed M1 polarization in RAW264.7 macrophages and delayed the progression of NALFD to HCC in mice. SNHG20 may facilitate the progression of NALFD to HCC via inducing liver KCs M2 polarization via STAT6 activation.

Different trends of gastric cancer in China, Japan, Republic of Korea and United States of America.

Gastric cancer exerts a significant healthcare burden worldwide and is highly geographically heterogeneous. This study investigates the burden of gastric cancer in China from 1990 to 2019 and compares it with Japan, South Korea, and the United States. The results indicated a declining trend in ASIR and ASDR in four countries. However, the incidence and death rates in China remain disproportionately high. Significant gender disparities exist in the incidence and death rates, with males experiencing significantly higher rates than females. Incidence and death rates were found to increase with age in all studied countries. In China, a transient upward trend was observed in the period effect, whereas the cohort effect has been declining. In contrast, the remaining countries showed decreasing patterns in both period and cohort effects. The burden of disease remains high in China, therefore, broaden the scope of gastroscopy screening and concentrate on high-risk groups is vital.

Partial response to trastuzumab deruxtecan (DS8201) following progression in HER2-amplified breast cancer with pulmonary metastases managed with disitamab vedotin (RC48): a comprehensive case report and literature review.

Breast cancer remains one of the predominant malignancies worldwide. In the context of inoperable advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, systemic management primarily relies on HER2-targeting monoclonal antibodies. With the successful development of anti-HER2 antibody-drug conjugates (ADCs), these agents have been increasingly integrated into therapeutic regimens for metastatic breast cancer. Here, we present the case of a 42-year-old female patient with HER2-positive pulmonary metastatic breast cancer who underwent an extensive treatment protocol. This protocol included chemotherapy, radiation therapy, hormonal therapy, surgical intervention on the breast, and anti-HER2 therapies. The anti-HER2 therapies involved both singular and dual targeting strategies using trastuzumab and the ADC disitamab vedotin (RC48) over an 8-year period. After experiencing disease progression following HER2-targeted therapy with RC48, the patient achieved noticeable partial remission through a therapeutic regimen that combined trastuzumab deruxtecan (DS8201) and tislelizumab. The data suggest a promising role for DS8201 in managing advanced stages of HER2-amplified metastatic breast cancer, especially in cases that demonstrate progression after initial HER2-directed therapies using ADCs. Furthermore, its combination with anti-PD-1 agents enhances therapeutic efficacy by augmenting the anti-tumoral immune response.

Targeting O-GlcNAcylation in cancer therapeutic resistance: The sugar Saga continues.

O-linked-N-acetylglucosaminylation (O-GlcNAcylation), a dynamic post-translational modification (PTM), holds profound implications in controlling various cellular processes such as cell signaling, metabolism, and epigenetic regulation that influence cancer progression and therapeutic resistance. From the therapeutic perspective, O-GlcNAc modulates drug efflux, targeting and metabolism. By integrating signals from glucose, lipid, amino acid, and nucleotide metabolic pathways, O-GlcNAc acts as a nutrient sensor and transmits signals to exerts its function on genome stability, epithelial-mesenchymal transition (EMT), cell stemness, cell apoptosis, autophagy, cell cycle. O-GlcNAc also attends to tumor microenvironment (TME) and the immune response. At present, several strategies aiming at targeting O-GlcNAcylation are under mostly preclinical evaluation, where the newly developed O-GlcNAcylation inhibitors markedly enhance therapeutic efficacy. Here we systematically outline the mechanisms through which O-GlcNAcylation influences therapy resistance and deliberate on the prospects and challenges associated with targeting O-GlcNAcylation in future cancer treatments.

Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks.

Genome-wide association studies (GWASs) have identified over 140 colorectal cancer (CRC)-associated loci; however, target genes at the majority of loci and underlying molecular mechanisms are poorly understood. Here, we utilized a Bayesian approach, integrative risk gene selector (iRIGS), to prioritize risk genes at CRC GWAS loci by integrating multi-omics data. As a result, a total of 105 high-confidence risk genes (HRGs) were identified, which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC. Among the 105 HRGs, CEBPB, located at the 20q13.13 locus, acted as a transcription factor playing critical roles in cancer. Our subsequent assays indicated the tumor promoter function of CEBPB that facilitated CRC cell proliferation by regulating multiple oncogenic pathways such as MAPK, PI3K-Akt, and Ras signaling. Next, by integrating a fine-mapping analysis and three independent case-control studies in Chinese populations consisting of 8,039 cases and 12,775 controls, we elucidated that rs1810503, a putative functional variant regulating CEBPB, was associated with CRC risk (OR=0.90, 95%CI=0.86-0.93, P=1.07×10-7). The association between rs1810503 and CRC risk was further validated in three additional multi-ancestry populations consisting of 24,254 cases and 58,741 controls. Mechanistically, the rs1810503 A to T allele change weakened the enhancer activity in an allele-specific manner to decrease CEBPB expression via long-range promoter-enhancer interactions, mediated by the transcription factor, REST, and thus decreased CRC risk. In summary, our study provides a genetic resource and a generalizable strategy for CRC etiology investigation, and highlights the biological implications of CEBPB in CRC tumorigenesis, shedding new light on the etiology of CRC.

Developing an optimal stratification model for colorectal cancer screening and reducing racial disparities in multi-center population-based studies.

BACKGROUND: Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population. METHODS: To develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants. RESULTS: Three trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose-response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32). CONCLUSIONS: Our comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity.

Effect of radiotherapy interruption on nasopharyngeal cancer.

Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the epithelial cells of the nasopharynx with a unique geographic distribution, and is particularly prevalent in East and Southeast Asia. Due to its anatomical location, the surgery is difficult to access and the high sensitivity of nasopharyngeal cancer to radiotherapy (RT) makes it the main treatment modality. Radical radiotherapy is the first-line treatment for early-stage nasopharyngeal carcinoma and the cornerstone of multidisciplinary treatment for patients with locally advanced nasopharyngeal carcinoma. Nevertheless, radiotherapy interruption is inevitable as a consequence of unavoidable factors such as public holidays, machine malfunction, patient compliance, and adverse response to treatment, which in turn leads to a reduction in bioactivity and causes sublethal loss of tumor cells to repair. Unirradiated tumor cells are more likely to repopulate at or near their original fastest growth rate during this interval. If no measures are taken after the radiotherapy interruption, such as increasing the dose of radiotherapy and systemic therapy, the tumor is most likely to go uncontrolled and then progress. This review describes the effects of radiotherapy interruption on nasopharyngeal carcinoma, the mechanism of the effect, and explores the measures that can be taken in response to such interruption.

Design, synthesis and pharmacological evaluation of ß-carboline derivatives as potential antitumor agent via targeting autophagy.

A series of novel ß-carboline derivatives was designed, synthesized and evaluated as potential anticancer agents. Among them, compound 6g showed the most potent antiproliferative activity against the 786-0, HT-29 and 22RV1 cell lines with IC50 values of 2.71, 2.02, and 3.86 µM, respectively. The antitumor efficiency of compound 6gin vivo was also evaluated, and the results revealed that compound 6g significantly suppressed tumor development and reduced tumor weight in a mouse colorectal cancer homograft model. Further investigation on mechanisms of action demonstrated that compound 6g inhibited HCT116 cell growth by stimulating the ATG5/ATG7-dependent autophagic pathway. These molecules might be served as candidates for further development of colorectal cancer therapy agent.

New treatment insights into pancreatic acinar cell carcinoma: case report and literature review.

Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic malignancy with unique clinical, molecular, and morphologic features. The long-term survival of patients with PACC is substantially better than that of patients with ductal adenocarcinoma of the pancreas. Surgical resection is considered the first choice for treatment; however, there is no standard treatment option for patients with inoperable disease. The patient with metastatic PACC reported herein survived for more than 5 years with various treatments including chemotherapy, radiotherapy, antiangiogenic therapy and combined immunotherapy.

Redox-associated messenger RNAs identify novel prognostic values and influence the tumor immune microenvironment of lung adenocarcinoma.

Background: An imbalance of redox homeostasis participates in tumorigenesis, proliferation, and metastasis, which results from the production of reactive oxygen species (ROS). However, the biological mechanism and prognostic significance of redox-associated messenger RNAs (ramRNAs) in lung adenocarcinoma (LUAD) still remain unclear. Methods: Transcriptional profiles and clinicopathological information were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) of LUAD patients. A total of 31 overlapped ramRNAs were determined, and patients were separated into three subtypes by unsupervised consensus clustering. Biological functions and tumor immune-infiltrating levels were analyzed, and then, differentially expressed genes (DEGs) were identified. The TCGA cohort was divided into a training set and an internal validation set at a ratio of 6:4. Least absolute shrinkage and selection operator regression were used to compute the risk score and determine the risk cutoff in the training set. Both TCGA and GEO cohort were distinguished into a high-risk or low-risk group at the median cutoff, and then, relationships of mutation characteristics, tumor stemness, immune differences, and drug sensitivity were investigated. Results: Five optimal signatures (ANLN, HLA-DQA1, RHOV, TLR2, and TYMS) were selected. Patients in the high-risk group had poorer prognosis, higher tumor mutational burden, overexpression of PD-L1, and lower immune dysfunction and exclusion score compared with the low-risk group. Cisplatin, docetaxel, and gemcitabine had significantly lower IC50 in the high-risk group. Conclusion: This study constructed a novel predictive signature of LUAD based on redox-associated genes. Risk score based on ramRNAs served as a promising biomarker for prognosis, TME, and anti-cancer therapies of LUAD.

Biophysical cues to improve the immunomodulatory capacity of mesenchymal stem cells: The progress and mechanisms.

Mesenchymal stem cells (MSCs) can maintain immune homeostasis and many preclinical trials with MSCs have been carried out around the world. In vitro culture of MSCs has been found to result in the decline of immunomodulatory capacity, migration and proliferation. To address these problems, simulating the extracellular environment for preconditioning of MSCs is a promising and inexpensive method. Biophysical cues in the external environment that MSCs are exposed to have been shown to affect MSC migration, residency, differentiation, secretion, etc. We review the main ways in which MSCs exert their immunomodulatory ability, and summarize recent advances in mechanical preconditioning of MSCs to enhance immunomodulatory capacity and related mechanical signal sensing and transduction mechanisms.