Tumor mutation load better predicts the prognosis of patients treated with immune checkpoint inhibitors in upper gastrointestinal cancers: A systematic review and meta-analysis.

BACKGROUND: Tumor mutational load (TML) has emerged as a potential biomarker for multiple solid tumors. However, data on its prognostic impact on upper gastrointestinal (UGI) cancer are limited. Therefore, the aim of this systematic review and meta-analysis was to assess the prognostic value of TML for the survival of patients with UGI cancer. METHOD: A comprehensive search of the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted up to February 13, 2023. Eleven studies met our inclusion criteria. Hazard ratios (HRs) for progression-free survival and overall survival and their 95% confidence intervals (CIs) were calculated. Subsequently, the combined HR and its 95% CI were calculated for UGI tract cancers in the high and low TML groups. I2 statistics and p-values were used to evaluate heterogeneity. Publication bias, sensitivity, and subgroup analyses were performed to determine sources of heterogeneity. RESULTS: In total, 932 patients with UGI tract cancer from 11 publications were included. The high TML group treated with immunotherapy showed significantly improved overall survival (HR = 0.68; 95% CI: 0.53, 0.86; p = .001) and progression-free survival (HR = 0.74; 95% CI: 0.58, 0.95; p = .020) compared with the low TML group. CONCLUSION: Our study demonstrated that patients with UGI tumors and higher TML have a better prognosis with immunotherapy, suggesting that TML is a promising predictive biomarker for immunotherapy. REGISTRATION: The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO Registration No: CRD42023405596).

Pan-cancer analysis of the tumorigenic role of Fanconi anemia complementation group D2 (FANCD2) in human tumors.

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors.

Identification of a ferroptosis-related gene signature predicting recurrence in stage II/III colorectal cancer based on machine learning algorithms.

Background: Colorectal cancer (CRC) is one of the most prevalent cancer types globally. A survival paradox exists due to the inherent heterogeneity in stage II/III CRC tumor biology. Ferroptosis is closely related to the progression of tumors, and ferroptosis-related genes can be used as a novel biomarker in predicting cancer prognosis. Methods: Ferroptosis-related genes were retrieved from the FerrDb and KEGG databases. A total of 1,397 samples were enrolled in our study from nine independent datasets, four of which were integrated as the training dataset to train and construct the model, and validated in the remaining datasets. We developed a machine learning framework with 83 combinations of 10 algorithms based on 10-fold cross-validation (CV) or bootstrap resampling algorithm to identify the most robust and stable model. C-indice and ROC analysis were performed to gauge its predictive accuracy and discrimination capabilities. Survival analysis was conducted followed by univariate and multivariate Cox regression analyses to evaluate the performance of identified signature. Results: The ferroptosis-related gene (FRG) signature was identified by the combination of Lasso and plsRcox and composed of 23 genes. The FRG signature presented better performance than common clinicopathological features (e.g., age and stage), molecular characteristics (e.g., BRAF mutation and microsatellite instability) and several published signatures in predicting the prognosis of the CRC. The signature was further stratified into a high-risk group and low-risk subgroup, where a high FRG signature indicated poor prognosis among all collected datasets. Sensitivity analysis showed the FRG signature remained a significant prognostic factor. Finally, we have developed a nomogram and a decision tree to enhance prognosis evaluation. Conclusion: The FRG signature enabled the accurate selection of high-risk stage II/III CRC population and helped optimize precision treatment to improve their clinical outcomes.

Shaping focal field by grafted polarization.

In this paper, we propose a novel (to our knowledge) vector beam by combining the radially polarized beams with the different polarization orders, which is called the grafted polarization vector beam (GPVB). Compared with the tight focusing of traditional cylindrical vector beams, GPVB can present more flexible focal field patterns by adjusting the polarization order of two (or more) grafted parts. Moreover, because the GPVB possesses the non-axisymmetrical polarization state distribution, which will lead to the spin-orbit coupling in its tight focusing, it can obtain the spatial separation of spin angular momentum (SAM) and orbital angular momentum (OAM) in the focal plane. The SAM and the OAM are well modulated by adjusting the polarization order of two (or more) grafted parts. Furthermore, we also find the on-axis energy flow in the tight focusing of the GPVB can be changed from positive to negative by adjusting its polarization order. Our results provide more modulation freedom and potential applications in optical tweezers and particles trapping.

PeGRF6-PeGIF1 complex regulates cell proliferation in the leaf of Phalaenopsis equestris.

Phalaenopsis equestris is an ornamental plant with very large leaves. In this study, we identified genes related to the regulation of leaf development in Phalaenopsis and explored their mechanism of action. Sequence alignment and phylogenetic analyses revealed that PeGRF6 in the PeGRF family of P. equestris has similarities with the Arabidopsis genes AtGRF1 and AtGRF2, which are known to be involved in the regulation of leaf development. Among the PeGRFs, PeGRF6 was continuously and stably expressed at various stages of leaf development. The functions of PeGRF6 and of its complex formed with PeGIF1 in leaf development were verified by virus-induced gene silencing (VIGS) technology. The results show that the PeGRF6-PeGIF1 complex forms in the nucleus and positively regulates leaf cell proliferation via influencing cell size. Interestingly, VIGS suppression of PeGRF6 resulted in anthocyanin accumulation in Phalaenopsis leaves. Analyses of the regulatory mechanism of the miR396-PeGRF6 model based on the P. equestris small RNA library constructed here suggested that PeGRF6 transcripts are cleaved by Peq-miR396. These results show that, compared with PeGRF6 or PeGIF1 alone, the PeGRF6-PeGIF1 complex plays a more important role in the leaf development of Phalaenopsis, possibly by regulating the expression of cell cycle-related genes.

Machine learning-based identification of a novel prognosis-related long noncoding RNA signature for gastric cancer.

Gastric cancer (GC) is one of the most common malignancies with a poor prognosis. Immunotherapy has attracted much attention as a treatment for a wide range of cancers, including GC. However, not all patients respond to immunotherapy. New models are urgently needed to accurately predict the prognosis and the efficacy of immunotherapy in patients with GC. Long noncoding RNAs (lncRNAs) play crucial roles in the occurrence and progression of cancers. Recent studies have identified a variety of prognosis-related lncRNA signatures in multiple cancers. However, these studies have some limitations. In the present study, we developed an integrative analysis to screen risk prediction models using various feature selection methods, such as univariate and multivariate Cox regression, least absolute shrinkage and selection operator (LASSO), stepwise selection techniques, subset selection, and a combination of the aforementioned methods. We constructed a 9-lncRNA signature for predicting the prognosis of GC patients in The Cancer Genome Atlas (TCGA) cohort using a machine learning algorithm. After obtaining a risk model from the training cohort, we further validated the model for predicting the prognosis in the test cohort, the entire dataset and two external GEO datasets. Then we explored the roles of the risk model in predicting immune cell infiltration, immunotherapeutic responses and genomic mutations. The results revealed that this risk model held promise for predicting the prognostic outcomes and immunotherapeutic responses of GC patients. Our findings provide ideas for integrating multiple screening methods for risk modeling through machine learning algorithms.

Kinematic and biomechanical responses of the spine to distraction surgery in children with early onset scoliosis: A 3-D finite element analysis.

Periodical and consecutive distraction is an effective treatment for severe early onset scoliosis (EOS), which enables the spinal coronal and sagittal plane deformity correction. However, the rate of rod fractures and postoperative complications was still high mainly related to the distraction process. Previous studies have primarily investigated the maximum safe distraction force without a rod broken, neglecting the spinal re-imbalance and distraction energy consumption, which is equally vital to evaluate the operative value. This study aimed to reveal the kinematic and biomechanical responses occurring after spinal distraction surgery, which were affected by traditional bilateral fixation. The spinal models (C6-S1) before four distractions were reconstructed based on CT images and the growing rods were applied with the upward displacement load of 0-25 mm at an interval of 5 mm. Relationships between the distraction distance, the distraction force and the thoracic and lumbar Cobb angle were revealed, and the spinal displacement and rotation in three-dimensional directions were measured. The spinal overall imbalance would also happen during the distraction process even under the safe force, which was characterized by unexpected cervical lordosis and lateral displacement. Additionally, the law of diminishing return has been confirmed by comparing the distraction energy consumption in different distraction distances, which suggests that more attention paid to the spinal kinematic and biomechanical changes is better than to the distraction force. Notably, the selection of fixed segments significantly impacts the distraction force at the same distraction distance. Accordingly, some results could provide a better understanding of spinal distraction surgery.

Biomechanical responses of human lumbar spine and pelvis according to the Roussouly classification.

BACKGROUND: Few studies have analyzed the different biomechanical properties of the lumbar with various morphological parameters, which play an important role in injury and degeneration. This study aims to preliminarily investigate biomechanical characteristics of the spine with different sagittal alignment morphotypes by using finite element (FE) simulation and in-vitro testing. METHODS: According to the lumbar-pelvic radiographic parameters of the Chinese population, the parametric FE models (L1-S1-pelvis) of Roussouly's type (1-4) were validated and developed based on the in-vitro biomechanical testing. A pure moment of 7.5 Nm was applied in the three anatomical planes to simulate the physiological activities of flexion, extension, left-right lateral bending and left-right axial rotation. RESULTS: The sagittal configuration of four Roussouly's type models had a strong effect on the biomechanical responses in flexion and extension. The apex of the lumbar lordosis is a critical position where the segment has the lowest range of motion among all the models. In flexion-extension, type 3 and 4 models with a good lordosis shape had a more uniform rotation distribution at each motor function segment, however, type 1 and 2 models with a straighter spine had a larger proportion of rotation at the L5-S1 level. In addition, type 1 and 2 models had higher intradiscal pressures (IDPs) at the L4-5 segment in flexion, while type 4 model had larger matrix and fiber stresses at the L5-S1 segment in extension. CONCLUSION: The well-marched lordotic type 3 lumbar had greater stability, however, a straighter spine (type 1 and 2) had poor balance and load-bearing capacity. The hypolordotic type 4 model showed larger annulus fiber stress. Therefore, the sagittal alignment of Roussouly's type models had different kinetic and biomechanical responses under various loading conditions, leading to different clinical manifestations of the lumbar disease.

Effects of Growing Rod Technique with Different Surgical Modes and Growth Phases on the Treatment Outcome of Early Onset Scoliosis: A 3-D Finite Element Analysis.

Early onset scoliosis (EOS) is emerging as a serious threat to children's health and is the third largest threat to their health after myopia and obesity. At present, the growing rod technique (GRT), which allows patients to regain a well-balanced sagittal profile, is commonly considered as an invasive surgical procedure for the treatment of EOS. However, the risk of postoperative complications and instrumentation breakage remains high, which is mainly related to the choice of fixed mode. Several authors have studied primary stability and instrumentation loads, neglecting the mechanical transmission of the spinal long-segment model in different growth phases, which is fundamental to building a complete biomechanical environment. The present study aimed to investigate the kinematic and biomechanical properties that occur after GRT, across the long spinal structure and the posterior instrumentation, which are affected by unilateral or bilateral fixation. Accordingly, spinal segments (C6-S1) were loaded under flexion (Flex), extension (Ext), left lateral bending (LB), right lateral bending (RB), left torsion (LT), and right torsion (RT) using 11 established spinal models, which were from three growth phases. The stress distribution, spinal and intervertebral range of motion (ROM), counter torque of the vertebra, and bracing force on the rods were measured. The results showed that bilateral posterior fixation (BPF) is more stable than unilateral posterior fixation (UPF), at the expense of more compensations for the superior adjacent segment (SAS), especially when the superior fixed segment is closer to the head. Additionally, the bracing force of the instrumentation on the spine increases as the Cobb angle decreases. Accordingly, this biomechanical analysis provides theoretical suggestions for the selection of BPF or UPF and fixed segments in different growing phases.

Spin-orbit Hall effect in the tight focusing of a radially polarized vortex beam.

When the first-order radially polarized vortex beam propagates in an uniaxial crystal, the spin and the orbital angular momentum parts can be separated. It is called the optical spin-orbit Hall effect. In this study, we investigate the tight focusing of the radially polarized vortex beam theoretically and find the spatial separation of the spin and the orbital angular momentum parts occurs in the focal plane when the polarization order equals 1 and the vortex charge equals 1 (or -1). Moreover, when the initial phase of the polarization state takes π/2, the spatial separation of intensity in the focal plane corresponds to the spatial separation of the spin and the orbital angular momentum parts. This phenomenon can be considered as a manifestation of the optical spin-orbit Hall effect in the tight focusing of radially polarized vortex beam. Also, we show that, when the polarization order is greater than 1, the initial phase change of polarization state just leads to the rotation of the focal field and the spin and the orbital angular momentum density in the focal plane. Our results provide the potential application in the field of optical micro-manipulation.

Opposing and Operated Side Electroacupuncture Generates Similar Analgesic Effects on Pain after Knee Surgery.

The purpose of this study was to investigate whether opposing electroacupuncture (EA) could produce similar analgesic effects as operated side EA after knee surgery in rats. Sprague Dawley rats were randomly divided into the sham surgery group, and three surgery groups: opposing EA, operated side EA, and model. After surgery, compared with the sham surgery group, three kinds of pain behavior test methods (mechanical withdrawal threshold (MWT), cumulative pain score [CPS], and mechanical hypersensitivity of knee) were used to assess the pain behavior of the rats in the surgery groups. After knee surgery, the three surgery groups were intervened for three consecutive days: EA on the nonoperated side in the opposing EA group, EA on the operated side in the operated side EA group, and no intervention in the model group. It was shown that MWT was higher and CPS was lower in the two EA groups than in the model group on the first and second days after surgery. On the third day after surgery, MWT in the two EA groups was the highest among the 3 days, CPS was the lowest among the 3 days, and the number of nonvocalizations in rats also increased compared with the model group. Moreover, the MWT of the nonoperated side increased more in the opposing EA group than in the model and operated side EA groups. This indicated that both opposing EA and operated side EA methods can be used to relieve pain after knee joint surgery.

Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis.

Anti-PD-1/PD-L1 inhibitors provide a survival advantage over conventional therapies for treatment of advanced or metastatic cancer. However, the factors determining which patients benefit the most from anti-PD-1/PD-L1 inhibitors are unknown, making treatment-related decisions difficult. We performed a systematic review and meta-analysis of acquired data to assess the efficacy and toxicity of anti-PD-1/PD-L1 inhibitors in advanced and metastatic cancer. A thorough search strategy was applied to identify randomised controlled trials (RCTs) in Pubmed, Embase, Cochrane, and major conferences. Studies meeting predefined selection criteria were selected, and two independent investigators performed data extraction; overall survival (OS), progression-free survival (PFS), and overall response rate were compared between anti-PD-1/PD-L1 inhibitors and control therapies. We calculated the pooled response rate and 95% CIs of all-grade and high-grade (≥3) adverse effects and evaluated the within-study heterogeneity using subgroup, sensitivity, and meta-regression analyses. In final, we included eligible 35 RCTs (21047 patients). The main estimated hazard ratios (HRs) for OS and PFS were 0.76 (0.71-0.82) and 0.81 (0.73-0.89) in a random-effects model. The anti-PD-1/PD-L1 inhibitor group had a significantly high risk for all-grade immune-related adverse events. Anti-PD-1/PD-L1 inhibitors were identified as a preferable treatment option for advanced or metastatic cancer patients who are male, aged < 65 years, current or former smokers, had no CNS or liver metastasis, had not EGFR mutation, and had high PD-L1 expression.

Comparison of Immune Checkpoint Inhibitors between Older and Younger Patients with Advanced or Metastatic Lung Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVES: Despite the fact that it is widely acknowledged that immune checkpoint inhibitors (ICIs) rely on the presence of immune response to take their antitumor effect, little is known whether there is an influence exerted on the efficacy of ICIs based on patients' age. We performed a systematic review and meta-analysis to explore the efficacy of ICIs between younger and older patients. MATERIALS AND METHODS: We searched online database and major conference proceedings for randomized controlled trials (RCTs) published of ICIs and included RCTs that conducted subgroup comparisons of age with available combination of hazard ratios (HRs) and 95% confidence interval (95%CI). Subsequently, we figured out the pooled HR and 95%CI in younger and older patients with a random-effects model and evaluated the within-study heterogeneity by using subgroup, sensitivity, and meta-regression analysis. RESULTS AND CONCLUSION: A total of 12 eligible RCTs included in our study, which reported OS according to patients' age. The overall estimated random-effects for HR was 0.75 with 95% CI of 0.65-0.87 in younger arm versus 0.81 with 95% CI of 0.72-0.92 in older arm. ICIs can improve OS for patients with advanced or metastatic lung cancer when compared to controls, especially for those patients with NSCLC, anti-PD-1/PD-L1 inhibitors, non-squamous, Pembrolizumab or Atezolizumab used as well as subsequent-line setting, and the magnitude of benefit in OS had comparable efficacy in both younger and older arms using a cut-off of 65 yr. Conversely, we also drew a statically significant conclusion that older patients failed to acquire benefit from ICIs when subdivided with a further cut-off of 75 yr.