Differential long-term bivalent HPV vaccine cross-protection by variants in the Costa Rica HPV vaccine trial.

The AS04-adjuvanted human papillomavirus (HPV)16/18 vaccine, an L1-based vaccine, provides strong vaccine efficacy (VE) against vaccine-targeted type infections, and partial cross-protection to phylogenetically-related types, which may be affected by variant-level heterogeneity. We compared VE against incident HPV31, 33, 35, and 45 detections between lineages and SNPs in the L1 region among 2846 HPV-vaccinated and 5465 HPV-unvaccinated women through 11-years of follow-up in the Costa Rica HPV Vaccine Trial. VE was lower against HPV31-lineage-B (VE=60.7%;95%CI = 23.4%,82.8%) compared to HPV31-lineage-A (VE=94.3%;95%CI = 83.7%,100.0%) (VE-ratio = 0.64;95%CI = 0.25,0.90). Differential VE was observed at several lineage-associated HPV31-L1-SNPs, including a nonsynonymous substitution at position 6372 on the FG-loop, an important neutralization domain. For HPV35, the only SNP-level difference was at position 5939 on the DE-loop, with significant VE against nucleotide-G (VE=65.0%;95%CI = 28.0,87.8) but not for more the common nucleotide-A (VE=7.4%;95%CI = -34.1,36.7). Because of the known heterogeneity in precancer/cancer risk across cross-protected HPV genotype variants by race and region, our results of differential variant-level AS04-adjuvanted HPV16/18 vaccine efficacy has global health implications.

Prognostic value of EIF5A2 in solid tumors: A meta-analysis and bioinformatics analysis.

Aims: In cancer biology, the aberrant overexpression of eukaryotic translation initiation factor 5A2 (EIF5A2) has been correlative with an ominous prognosis, thereby underscoring its pivotal role in fostering metastatic progression. Consequently, EIF5A2 has garnered significant attention as a compelling prognostic biomarker for various malignancies. Our research endeavors were thus aimed at elucidating the utility and significance of EIF5A2 as a robust indicator of cancer outcome prediction. Method: An exhaustive search of the PubMed, EMBASE, and Web of Science databases found relevant studies. The link between EIF5A2 and survival prognosis was examined using hazard ratios and 95% confidence intervals. Subsequently, The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases were employed to validate EIF5A2 expression across various cancer types. Results: Through pooled analysis, we found that increased EIF5A2 expression was significantly associated with decreased overall survival (OS) and disease-free survival/progression-free survival/relapse-free survival (DFS/PFS/RFS). Moreover, TCGA analysis revealed that EIF5A2 was significantly upregulated in 27 types of cancer, with overexpression being linked to shorter OS in three, worse DFS in two, and worse PFS in six types of cancer. GEPIA showed that patients with EIF5A2 overexpression had reduced OS and DFS. Conclusions: In solid tumors, EIF5A2 emerges as a reliable prognostic marker. Our meta-analysis comprehensively analyzed the prognostic value of EIF5A2 in solid tumors and assessed its efficacy as a predictive marker.

Chimeric antigen receptor-based immunotherapy in breast cancer: Recent progress in China.

Breast cancer (BC) is the fourth most prevalent cancer in China. Despite conventional treatment strategies, BC patients often have poor therapeutic outcomes, leading to significant global cancer mortality rates. Chimeric antigen receptor (CAR)-based immunotherapy is a promising and innovative approach for cancer treatment that redirects immune cells to attack tumor cells expressing selected tumor antigens (TAs). T cells, natural killer (NK) cells, and macrophages, key components of the immune system, are used in CAR-based immunotherapies. Although remarkable progress has been made with CAR-T cells in hematologic malignancies, the application of CAR-based immunotherapy to BC has lagged. This is partly due to obstacles such as tumor heterogeneity, which is further associated with the TA and BC subtypes, and the immunosuppressive tumor microenvironment (TME). Several combinatorial approaches, including the use of immune checkpoint inhibitors, oncolytic viruses, and antitumor drugs, have been proposed to overcome these obstacles in BC treatment. Furthermore, several CAR-based immunotherapies for BC have been translated into clinical trials. This review provides an overview of the recent progress in CAR-based immunotherapy for BC treatment, including targeting of TAs, consideration of BC subtypes, assessment of the TME, and exploration of combinatorial therapies. The authors focused on preclinical studies and clinical trials of CAR-T cells, CAR-NK cells, and CAR-macrophages especially conducted in China, followed by an internal comparison and discussion of current limits. In conclusion, this review elucidates China's contribution to CAR-based immunotherapies for BC and provides inspiration for further research. PLAIN LANGUAGE SUMMARY: Despite conventional treatment strategies, breast cancer (BC) patients in China often have poor therapeutic outcomes. Chimeric antigen receptor (CAR)-based immunotherapy, a promising approach, can redirect immune cells to kill tumor cells expressing selected tumor antigens (TAs). However, obstacles such as TA selection, BC subtypes, and immunosuppressive tumor microenvironment still exist. Therefore, various combinatorial approaches have been proposed. This article elucidates several Chinese CAR-based preclinical and clinical studies in BC treatment with comparisons of foreign research, and CAR-immune cells are analyzed, providing inspiration for further research.

Circular RNAs in vascular diseases.

Vascular diseases are the leading cause of morbidity and mortality worldwide and are urgently in need of diagnostic biomarkers and therapeutic strategies. Circular RNAs (circRNAs) represent a unique class of RNAs characterized by a circular loop configuration and have recently been identified to possess a wide variety of biological functions. CircRNAs exhibit exceptional stability, tissue specificity, and are detectable in body fluids, thus holding promise as potential biomarkers. Their encoding function and stable gene expression also position circRNAs as an excellent alternative to gene therapy. Here, we briefly review the biogenesis, degradation, and functions of circRNAs. We summarize circRNAs discovered in major vascular diseases such as atherosclerosis and aneurysms, with a particular focus on molecular mechanisms of circRNAs identified in vascular endothelial cells and smooth muscle cells, in the hope to reveal new directions for mechanism, prognosis and therapeutic targets of vascular diseases.

Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: new insights and therapeutic implications.

The tumor microenvironment (TME) is a highly intricate milieu, comprising a multitude of components, including immune cells and stromal cells, that exert a profound influence on tumor initiation and progression. Within the TME, angiogenesis is predominantly orchestrated by endothelial cells (ECs), which foster the proliferation and metastasis of malignant cells. The interplay between tumor and immune cells with ECs is complex and can either bolster or hinder the immune system. Thus, a comprehensive understanding of the intricate crosstalk between ECs and immune cells is essential to advance the development of immunotherapeutic interventions. Despite recent progress, the underlying molecular mechanisms that govern the interplay between ECs and immune cells remain elusive. Nevertheless, the immunomodulatory function of ECs has emerged as a pivotal determinant of the immune response. In light of this, the study of the relationship between ECs and immune checkpoints has garnered considerable attention in the field of immunotherapy. By targeting specific molecular pathways and signaling molecules associated with ECs in the TME, novel immunotherapeutic strategies may be devised to enhance the efficacy of current treatments. In this vein, we sought to elucidate the relationship between ECs, immune cells, and immune checkpoints in the TME, with the ultimate goal of identifying novel therapeutic targets and charting new avenues for immunotherapy.

Predicting thermostability difference between cellular protein orthologs.

MOTIVATION: Protein thermostability is of great interest, both in theory and in practice. RESULTS: This study compared orthologous proteins with different cellular thermostability. A large number of physicochemical properties of protein were calculated and used to develop a series of machine learning models for predicting cellular thermostability differences between orthologous proteins. Most of the important features in these models are also highly correlated to relative cellular thermostability. A comparison between the present study with previous comparison of orthologous proteins from thermophilic and mesophilic organisms found that most highly correlated features are consistent in these studies, suggesting they may be important to protein thermostability. AVAILABILITY AND IMPLEMENTATION: Data freely available for download at https://github.com/fangj3/cellular-protein-thermostability-dataset.

The role of data imbalance bias in the prediction of protein stability change upon mutation.

There is a controversy over what causes the low robustness of some programs for predicting protein stability change upon mutation. Some researchers suggested that low-quality data and insufficiently informative features are the primary reasons, while others attributed the problem largely to a bias caused by data imbalance as there are more destabilizing mutations than stabilizing ones. In this study, a simple approach was developed to construct a balanced dataset that was then conjugated with a leave-one-protein-out approach to illustrate that the bias may not be the primary reason for poor performance. A balanced dataset with some seemly good conventional n-fold CV results should not be used as a proof that a model for predicting protein stability change upon mutations is robust. Thus, some of the existing algorithms need to be re-examined before any practical applications. Also, more emphasis should be put on obtaining high quality and quantity of data and features in future research.

Relations between anxiety sensitivity's cognitive concerns and anxiety severity: brooding and reflection as serial multiple mediators.

The outbreak of COVID-19 has caused a major impact on productivity and life functioning, and also led to adverse emotional reactions. In the face of this public health event, increased anxiety is one of the most common emotional reactions. Previous studies have shown that anxiety sensitivity, rumination and anxiety are closely related. Various dimensions of anxiety sensitivity have different effects on anxiety. Also, rumination can be divided into brooding and reflection. To explore the relationships among anxiety sensitivity's cognitive concerns, anxiety and different types of rumination, we conducted an online survey during the outbreak of coronavirus (February 17-25, 2020), using the Anxiety Sensitivity Scale-3 (ASI-3), Ruminative Responses Scale (RSS), and Depression Anxiety Stress Scale-21 (DASS-21). The results showed significant positive correlations among anxiety sensitivity's cognitive concerns, anxiety, brooding and reflection. Furthermore, brooding and reflection had a chain mediation effect between cognitive concerns and anxiety, and the mediation effect of reflection was even stronger. Results suggest that anxiety sensitivity's cognitive concerns may not only affect anxiety directly, but also affect anxiety through rumination, especially reflection.

Recent Advances in the Aging Microenvironment of Breast Cancer.

Aging is one of the risk factors for advanced breast cancer. With the increasing trend toward population aging, it is important to study the effects of aging on breast cancer in depth. Cellular senescence and changes in the aging microenvironment in vivo are the basis for body aging and death. In this review, we focus on the influence of the aging microenvironment on breast cancer. Increased breast extracellular matrix stiffness in the aging breast extracellular matrix can promote the invasion of breast cancer cells. The role of senescence-associated secretory phenotypes (SASPs) such as interleukin-6 (IL-6), IL-8, and matrix metalloproteases (MMPs), in breast cancer cell proliferation, invasion, and metastasis is worthy of exploration. Furthermore, the impact of senescent fibroblasts, adipocytes, and endothelial cells on the mammary matrix is discussed in detail. We also list potential targets for senotherapeutics and senescence-inducing agents in the aging microenvironment of breast cancer. In conclusion, this review offers an overview of the influence of the aging microenvironment on breast cancer initiation and progression, with the aim of providing some directions for future research on the aging microenvironment in breast cancer.

Neuron-Specific Enolase and Hemoglobin as Risk Factors of Intraocular Metastasis in Patients with Renal Cell Carcinoma.

Renal cell carcinoma (RCC) appears to be a high risk of spread. This research investigated the correlation between a different range of clinical features and intraocular metastasis (IOM) in RCC patients and attempted to determine potential risk factors of RCC patients with IOM. In the study, there are a total of 351 patients with RCC that were recruited between May 1994 and May 2016. The differences between RCC patients with IOM and RCC patients with non-IOM (NIOM) were evaluated by the chi-squared test and Student t test. Binary logistic regression analysis was applied to determine risk factors. Finally, the value of diagnosis for RCC patients with IOM was assessed by receiver operating characteristic (ROC) curve analysis. Eighteen individuals were identified with IOM. There were no significant differences that were detected in alkaline phosphatase (AFP), carcinoembryonic antigen (CEA), alkaline phosphatase (ALP), cancer antigen 125 (CA-125), cancer antigen 153 (CA-153), cancer antigen 199 (CA-199), calcium, age, primary tumor site, and histopathological subtypes between the two groups. But there was a difference in terms of gender (P < 0.05). The IOM group exhibited significantly higher neuron-specific enolase (NSE) and lower hemoglobin (Hb) values compared to the NIOM group (P < 0.05, respectively). Binary logistic regression identified NSE and Hb as significant risk factors of IOM for RCC patient (P < 0.05 and P < 0.001, respectively). The ROC curve analysis indicated that the area under the curve (AUC) values of NSE and Hb were 0.694 and 0.749, while cut-off values were 49.5 ng/mL and 102.5 g/L, respectively. The sensitivity and specificity of NSE were 72.2% and 66.4%, respectively, while those of Hb were 72.2% and 74.2%, respectively. The result reveals that NSE and Hb represent promising significant risk factors of IOM for RCC patients. Notably, Hb is more reliable than NSE in distinguishing case of IOM from NIOM in patients with RCC.

Identifying Epstein-Barr virus peptide sequences associated with differential IgG antibody response.

BACKGROUND: Epstein-Barr virus (EBV) infection contributes to cancers in a fraction of seropositive individuals, but much remains to be learned about variation in EBV-directed humoral immunity in cancer-free adults. METHODS: A protein microarray was used to probe serum from 175 Taiwanese and 141 Northern European adults for immunoglobulin G (IgG) antibody responses to 115 different peptide sequences, representing protein segments or protein variants, from 45 EBV proteins. It was posited that this antibody-based approach could identify EBV peptide sequences representing immunodominant regions relevant for B-cell immunity. RESULTS: Analyses of 45 EBV proteins with multiple protein segments or variants printed on the array identified eight EBV peptide sequences that appear to play a role in immunogenicity. This included: (1) three proteins with segments/regions associated with IgG reactivity (BALF5, LMP1, LMP2A); and (2) five proteins with sequence variants/amino acid changes associated with IgG reactivity (BDLF4, EBNA3A, EBNA3B, EBNA-LP, LF1). CONCLUSION: This examination of IgG antibody responses against 115 EBV peptide sequences in 316 cancer-free adults represents an important step toward identifying specific EBV protein sequences that play a role in generating B-cell immunity in humans.

Stress and Problematic Smartphone Use Severity: Smartphone Use Frequency and Fear of Missing Out as Mediators.

Problematic smartphone use (PSU) has been linked with stress. Higher levels of stress likely increased problematic smartphone use. We investigated relations between stress, fear of missing out, and problematic smartphone use. The aim of the current study was to analyze the mediating role of fear of missing out (FOMO) and smartphone use frequency (SUF) between stress and PSU. We surveyed a broad sample of 2,276 Chinese undergraduate students in July 2019, using the FOMO Scale, Smartphone Addiction Scale-Short Version, Smartphone Use Frequency Scale, and Depression Anxiety Stress Scale-21. The results showed that stress was associated with PSU severity. Gender differences were found in PSU severity. Furthermore, FOMO was positively associated with SUF and PSU severity. Structural equation modeling demonstrated that FOMO acted as a mediator between stress and PSU severity. FOMO and SUF acted as a chain of mediators between stress and PSU severity. SUF did not account for relations between stress and PSU severity. The study indicates that FOMO may be an important variable accounting for why some people with increased stress levels may overuse their smartphones.

Molecular genomic features associated with in vitro response of the NCI-60 cancer cell line panel to natural products.

Natural products remain a significant source of anticancer chemotherapeutics. The search for targeted drugs for cancer treatment includes consideration of natural products, which may provide new opportunities for antitumor cytotoxicity as single agents or in combination therapy. We examined the association of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 1302 small molecules which included natural products, semisynthetic natural product derivatives, and synthetic compounds based on a natural product pharmacophore from the Developmental Therapeutics Program of the US National Cancer Institute's database. These compounds were obtained from a variety of plant, marine, and microbial species. Molecular information utilized for the analysis included expression measures for 23059 annotated transcripts, lncRNAs, and miRNAs, and data on protein-changing single nucleotide variants in 211 cancer-related genes. We found associations of expression of multiple genes including SLFN11, CYP2J2, EPHX1, GPC1, ELF3, and MGMT involved in DNA damage repair, NOTCH family members, ABC and SLC transporters, and both mutations in tyrosine kinases and BRAF V600E with NCI-60 responses to specific categories of natural products. Hierarchical clustering identified groups of natural products, which correlated with a specific mechanism of action. Specifically, several natural product clusters were associated with SLFN11 gene expression, suggesting that potential action of these compounds may involve DNA damage. The associations between gene expression or genome alterations of functionally relevant genes with the response of cancer cells to natural products provide new information about potential mechanisms of action of these identified clusters of compounds with potentially similar biological effects. This information will assist in future drug discovery and in design of new targeted cancer chemotherapy agents.

Prognostic Value and Clinicopathological Features of MicroRNA-206 in Various Cancers: A Meta-Analysis.

It has been reported that microRNA-206(miR-206) plays an important role in cancers and could be used as a prognostic biomarker. However, the results are controversial. Therefore, we summarize all available evidence and present a meta-analysis to estimate the prognostic value of miR-206 in various cancers. The relevant studies were collected by searching PubMed, EMBASE, and Web of Science databases until August 21, 2020. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were applied to explore the association between miR-206 and survival results and clinicopathologic features. Sources of heterogeneity were investigated by subgroup analysis and sensitivity analysis. Publication bias was evaluated using Egger's test. Twenty articles involving 2095 patients were included in the meta-analysis. The pooled HR showed that low miR-206 expression was significantly associated with unfavourable overall survival (OS) (HR = 2.03, 95 CI%: 1.53-2.70, P < 0.01). In addition, we found that low miR-206 expression predicted significantly negative association with tumor stage (III-IV VS. I-II) (OR = 4.20, 95% CI: 2.17-8.13, P < 0.01), lymph node status (yes VS. no) (OR = 3.58, 95%: 1.51-8.44, P = 0.004), distant metastasis (yes VS. no) (OR = 3.19, 95%: 1.07-9.50, P = 0.038), and invasion depth (T3 + T4 vs. T2 + T1) (OR = 2.43, 95%: 1.70-3.49, P < 0.01). miR-206 can be used as an effective prognostic indicator in various cancers. Further investigations are warranted to validate the present results.

Abnormal Fractional Amplitude of Low-Frequency Fluctuation Changes in Patients with Monocular Blindness: A Functional Magnetic Resonance Imaging (MRI) Study.

BACKGROUND We used fractional amplitude of low-frequency fluctuation (fALFF) technology to investigate spontaneous cerebral activity in patients with monocular blindness (MB) and in healthy controls (HCs). MATERIAL AND METHODS Thirty MB patient and 15 HCs were included in this study. All subjects were scanned by resting-state functional magnetic resonance imaging (rs-fMRI). The independent sample t test and chi-squared test were applied to analyze demographics of MB patients and HCs. The 2-sample t test and receiver operating characteristic (ROC) curves were applied to identify the difference in average fALFF values between MB patients and HCs. Pearson's correlation analysis was applied to explore the relationship between the average fALFF values of brain areas and clinical behavior in the MB group. RESULTS MB patients had lower fALFF values in the left anterior cingulate and higher fALFF values in the left precuneus and right and left inferior parietal lobes than in HCs. Moreover, the mean fALFF values of MB patients in the left anterior cingulate had negative correlations with the anxiety scale score (r=-0.825, P<0.001) and the depression scale score (r=-0.871, P<0.001). CONCLUSIONS Our study found that MB patients had abnormal spontaneous activities in the visual and vision-related regions. The finding of abnormal neuronal activity helps to reveal the underlying neuropathologic mechanisms of vision loss.

Altered Intrinsic Functional Connectivity of the Primary Visual Cortex in Patients with Corneal Ulcer: A Resting-State fMRI Study.

PURPOSE: To investigate differences in the functional connectivity (FC) of the primary visual cortex between patients with corneal ulcer (CU) and healthy controls (HCs) using resting-state functional magnetic resonance imaging. PATIENTS AND METHODS: A total of 30 patients with CU and 30 HCs were closely matched in terms of sex, age, and level of education. Two-sample t-test, receiver operating characteristic curve, and Pearson's correlation coefficient analyses were used to determine the differences in FC between the two groups, the mean FC value of patients with CU and HCs, and the correlation between FC signal values and clinical manifestations in different brain regions of patients. RESULTS: The CU group showed significantly elevated FC in the left and right middle frontal gyri and lower FC with the right cuneus compared with the HC group. In addition, the FC of the right cingulate and left superior frontal gyri also increased in the CU group. The receiver operating characteristic curve revealed high diagnostic value in those brain regions. CONCLUSION: CU involves aberrant FC of the primary visual cortex in different brain areas, including visual-related and cognitive-related regions. This finding may unveil the underlying neural mechanisms of impaired visual function in CU.

13 J direct-liquid-cooled solid-state disk laser with an unstable cavity.

A 13 J direct-liquid-cooled solid-state disk laser with an unstable cavity is developed and demonstrated in this paper. The output energy of the resonant cavity is first analyzed according to the gain level in a stable cavity. At the optimum gain level, a magnification of 1.3 in the unstable cavity is achieved. Experimentally, a concave-convex mirror is used as the cavity mirror. At a magnification of 1.3, a repetition frequency of 100 Hz, and a pulse width of 350 µs, a single-pulse energy output of 13.2 J is obtained, corresponding to an optical-optical efficiency of 22% and a slope efficiency of 27.6%. The x-axis beam quality factor ß is 4.7, and the y-axis beam quality factorß is 16.6.

A critical review of five machine learning-based algorithms for predicting protein stability changes upon mutation.

A number of machine learning (ML)-based algorithms have been proposed for predicting mutation-induced stability changes in proteins. In this critical review, we used hypothetical reverse mutations to evaluate the performance of five representative algorithms and found all of them suffer from the problem of overfitting. This approach is based on the fact that if a wild-type protein is more stable than a mutant protein, then the same mutant is less stable than the wild-type protein. We analyzed the underlying issues and suggest that the main causes of the overfitting problem include that the numbers of training cases were too small, and the features used in the models were not sufficiently informative for the task. We make recommendations on how to avoid overfitting in this important research area and improve the reliability and robustness of ML-based algorithms in general.

Depression and anxiety symptoms are related to problematic smartphone use severity in Chinese young adults: Fear of missing out as a mediator.

INTRODUCTION: Recently studies examined mediating psychological constructs accounting for relations between both depression and anxiety with problematic smartphone use (PSU) severity. The aim of the current study was to analyze the fear of missing out (FOMO) as a possible mediator in these relationships. METHOD: We recruited 1034 Chinese undergraduate students via a web-based survey that measured smartphone use frequency, PSU, depression, anxiety and FOMO. RESULTS: Structural equation modeling demonstrated that FOMO was significantly related to smartphone use frequency and PSU severity. FOMO significantly mediated relations between anxiety and both smartphone use frequency and PSU severity. FOMO did not account for relations between depression and smartphone use/PSU. CONCLUSION: This is one of the first studies testing FOMO in relation to PSU severity among Asian participants. FOMO may be an important variable accounting for why some types of psychopathology (e.g., anxiety) are associated with PSU.