Functional analysis of the CTNS gene exonic variants predicted to affect splicing.

Cystinosis is a severe, monogenic systemic disease caused by variants in CTNS gene. Currently, there is growing evidence that exonic variants in many diseases can affect pre-mRNA splicing. The impact of CTNS gene exonic variants on splicing regulation may be underestimated due to the lack of routine studies at the RNA level. Here, we analyzed 59 exonic variants in the CTNS gene using bioinformatics tools and identified candidate variants that may induce splicing alterations by minigene assays. We identified six exonic variants that induce splicing alterations by disrupting the ratio of exonic splicing enhancers/exonic splicing silencers (ESEs/ESSs) or by interfering with the recognition of classical splice sites, or both. Our results help in the correct molecular characterization of variants in cystinosis and inform emerging therapies. Furthermore, our work suggests that the combination of in silico and in vitro assays facilitates to assess the effects of DNA variants driving rare genetic diseases on splicing regulation and will enhance the clinical utility of variant functional annotation.

Identification of seven variants in the col4a1 gene that alter RNA splicing by minigene assay.

Type IV collagen is an integral component of basement membranes. Mutations in COL4A1, one of the key genes encoding Type IV collagen, can result in a variety of diseases. It is clear that a significant proportion of mutations that affect splicing can cause disease directly or contribute to the susceptibility or severity of disease. Here, we analyzed exonic mutations and intronic mutations described in the COL4A1 gene using bioinformatics programs and identified candidate mutations that may alter the normal splicing pattern through a minigene system. We identified seven variants that induce splicing alterations by disrupting normal splice sites, creating new ones, or altering splice regulatory elements. These mutations are predicted to impact protein function. Our results help in the correct molecular characterization of variants in COL4A1 and may help develop more personalized treatment options.

Analysis of the initial orbital MRI in aquaporin-4 antibody-positive optic neuritis (AQP4-ON): lesion location and lesion length can be predictive of visual prognosis.

PURPOSE: Despite mounting evidence indicating that aquaporin-4 antibody-positive optic neuritis (AQP4-ON) presents a less favorable prognosis than other types of optic neuritis, there exists substantial heterogeneity in the prognostic outcomes within the AQP4-ON cohort. Considering the persistent debate over the role of MRI in assessing the prognosis of optic neuritis, we aim to investigate the correlation between the MRI appearance and long-term visual prognosis in AQP4-ON patients. METHODS: We retrospectively reviewed the ophthalmological and imaging data of AQP4-ON patients admitted to our Neuro-ophthalmology Department from January 2015 to March 2018, with consecutive follow-up visits for a minimum of 3 years. RESULTS: A total of 51 AQP4-ON patients (59 eyes) meeting the criteria were enrolled in this research. After assessing the initial orbital MR images of each patient at the first onset, we observed the involvement of the canalicular segment (p < 0.001), intracranial segment (p = 0.004), optic chiasm (p = 0.009), and the presence of LEON (p = 0.002) were significantly different between recovery group and impairment group. For quantitative measurement, the length of the lesions is significantly higher in the impairment group (20.1 ± 9.3 mm) than in the recovery group (12.5 ± 5.3 mm) (p = 0.001). CONCLUSION: AQP4-ON patients with involvement of canalicular, intracranial segment and optic chiasm of the optic nerve, and the longer range of lesions threaten worse vision prognoses. Timely MR examination during the initial acute phase can not only exclude the intracranial or orbital mass lesions but also indicate visual prognosis in the long term.

'Fear, uncertain, tired ...' psychological distress among pulmonary hypertension patients: a qualitative interview study.

BACKGROUND: Patient-centered health care for patients with pulmonary hypertension (PH) is important and requires an understanding of patient experiences. However, there is a lack of approaches to examine what's the effects and how the disease impact patients' psychological well-beings. METHODS: We conducted qualitative interviews with PH patient representatives to understand patient psychological experiences and inform patient-centered research and care. Participants were chosen from a tertiary hospital located in northwest China. 20 patients with PH who be treated at the hospital (13 participants were women, aged 18-74 years) were strategically selected and individually interviewed. We used qualitative analysis to identify themes relating to existential psychological distress that would clarify the nature of such concerns. RESULTS: We found that patients experience tremendous psychological distress throughout the treatment process. Four categories that describe patients' psychological experiences emerged: burden of PH treatment, fear and uncertainty about the disease, frustration in social and family role, and lack of recognition of the condition. CONCLUSIONS: Existential concerns are salient in PH and involve the experience of loss and disruptions to the sense of self and relationships. Healthcare practitioners must work more in collaboration to detect patients' need for support and to develop the patient's own skills to manage daily life. The PH teams should tailor interventions to provide emotional, informational and instrumental support and guidance to patients.

A novel heterozygous variant of the SALL1 gene with atypical Townes-Brocks syndrome phenotypes in Chinese family.

Townes-Brocks syndrome (TBS) is an autosomal dominant disorder characterised by the triad of anorectal, thumb, and ear malformations. It may also be accompanied by defects in kidney, heart, eyes, hearing, and feet. TBS has been demonstrated to result from heterozygous variants in the SALL1 gene, which encodes zinc finger protein believed to function as a transcriptional repressor. The clinical characteristics of an atypical TBS phenotype patient from a Chinese family are described, with predominant manifestations including external ear dysplasia, unilateral renal hypoplasia with mild renal dysfunction, and hearing impairment. A novel heterozygous variant c.3060T>A (p.Tyr1020*) in exon 2 of the SALL1 gene was identified in this proband. Pyrosequencing of the complementary DNA of the proband revealed that the variant transcript accounted for 48% of the total transcripts in peripheral leukocytes, indicating that this variant transcript has not undergone nonsense-mediated mRNA decay. This variant c.3060T > A is located at the terminal end of exon 2, proximal to the 3' end of the SALL1 gene, and exerts a relatively minor impact on protein function. We suggest that the atypical TBS phenotype observed in the proband may be attributed to the truncated protein retaining partial SALL1 function.

Integrated multi-omics approach revealed cellular senescence landscape.

Cellular senescence is a complex multifactorial biological phenomenon that plays essential roles in aging, and aging-related diseases. During this process, the senescent cells undergo gene expression altering and chromatin structure remodeling. However, studies on the epigenetic landscape of senescence using integrated multi-omics approaches are limited. In this research, we performed ATAC-seq, RNA-seq and ChIP-seq on different senescent types to reveal the landscape of senescence and identify the prime regulatory elements. We also obtained 34 key genes and deduced that NAT1, PBX1 and RRM2, which interacted with each other, could be the potential markers of aging and aging-related diseases. In summary, our work provides the landscape to study accessibility dynamics and transcriptional regulations in cellular senescence. The application of this technique in different types of senescence allows us to identify the regulatory elements responsible for the substantial regulation of transcription, providing the insights into molecular mechanisms of senescence.

CRIP1 fosters MDSC trafficking and resets tumour microenvironment via facilitating NF-κB/p65 nuclear translocation in pancreatic ductal adenocarcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is among the most immunosuppressive tumour types. The tumour immune microenvironment (TIME) is largely driven by interactions between immune cells and heterogeneous tumour cells. Here, we aimed to investigate the mechanism of tumour cells in TIME formation and provide potential combination treatment strategies for PDAC patients based on genotypic heterogeneity. DESIGN: Highly multiplexed imaging mass cytometry, RNA sequencing, mass cytometry by time of flight and multiplex immunofluorescence staining were performed to identify the pro-oncogenic proteins associated with low immune activation in PDAC. An in vitro coculture system, an orthotopic PDAC allograft tumour model, flow cytometry and immunohistochemistry were used to explore the biological functions of cysteine-rich intestinal protein 1 (CRIP1) in tumour progression and TIME formation. RNA sequencing, mass spectrometry and chromatin immunoprecipitation were subsequently conducted to investigate the underlying mechanisms of CRIP1. RESULTS: Our results showed that CRIP1 was frequently upregulated in PDAC tissues with low immune activation. Elevated CRIP1 expression induced high levels of myeloid-derived suppressor cell (MDSC) infiltration and fostered an immunosuppressive tumour microenvironment. Mechanistically, we primarily showed that CRIP1 bound to nuclear factor kappa-B (NF-κB)/p65 and facilitated its nuclear translocation in an importin-dependent manner, leading to the transcriptional activation of CXCL1/5. PDAC-derived CXCL1/5 facilitated the chemotactic migration of MDSCs to drive immunosuppression. SX-682, an inhibitor of CXCR1/2, blocked tumour MDSC recruitment and enhanced T-cell activation. The combination of anti-PD-L1 therapy with SX-682 elicited increased CD8+T cell infiltration and potent antitumor activity in tumour-bearing mice with high CRIP1 expression. CONCLUSIONS: The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.

Identified eleven exon variants in PKD1 and PKD2 genes that altered RNA splicing by minigene assay.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic multisystem disease caused primarily by mutations in the PKD1 gene or PKD2 gene. There is increasing evidence that some of these variants, which are described as missense, synonymous or nonsense mutations in the literature or databases, may be deleterious by affecting the pre-mRNA splicing process. RESULTS: This study aimed to determine the effect of these PKD1 and PKD2 variants on exon splicing combined with predictive bioinformatics tools and minigene assay. As a result, among the 19 candidate single nucleotide alterations, 11 variants distributed in PKD1 (c.7866C > A, c.7960A > G, c.7979A > T, c.7987C > T, c.11248C > G, c.11251C > T, c.11257C > G, c.11257C > T, c.11346C > T, and c.11393C > G) and PKD2 (c.1480G > T) were identified to result in exon skipping. CONCLUSIONS: We confirmed that 11 variants in the gene of PKD1 and PKD2 affect normal splicing by interfering the recognition of classical splicing sites or by disrupting exon splicing enhancers and generating exon splicing silencers. This is the most comprehensive study to date on pre-mRNA splicing of exonic variants in ADPKD-associated disease-causing genes in consideration of the increasing number of identified variants in PKD1 and PKD2 gene in recent years. These results emphasize the significance of assessing the effect of exon single nucleotide variants in ADPKD at the mRNA level.

Identification of exosomal miR-484 role in reprogramming mitochondrial metabolism in pancreatic cancer through Wnt/MAPK axis control.

The microRNAs (miRNAs) are potent regulators of tumorigenesis in various cancers, especially pancreatic cancer. The abnormal expression of miRNAs can be observed in tumor cells. Noteworthy, miRNAs could be transferred by exosomes as small extracellular vesicles in regulation of carcinogenesis. This research focused on exploring the roles and mechanisms of exosomal miR-484, derived from human bone marrow mesenchymal stem cells (hBMSCs), in the context of molecular interactions and regulation of mitochondrial metabolism. Exosomes were isolated for the examination of miR-484 expression. The impacts of hBMSCs-derived exosomal miR-484 on pancreatic cancer cells were studied using various assays. Evaluation of mitochondrial function and metabolism was performed. Wnt/MAPK pathway-related protein expression was assessed, and an in vivo tumor xenograft model was utilized to examine the functions. Our findings demonstrated a decreased miR-484 expression in pancreatic cancer cells. However, hBMSCs-derived exosomal miR-484 inhibited the proliferation and migration of these cells, while inducing apoptosis. Moreover, miR-484 led to an upsurge in reactive oxygen species production, a decrease in ATP levels, and a disruption in mitochondrial metabolism. In vivo analyses showed that hBMSCs-derived exosomal miR-484 lessened tumor size and weight, while also suppressing the expression of mitochondrial biomarkers. Further, there was a decline in ß-catenin and p-p38 protein levels both in vitro and in vivo. The addition of LiCl restored the disrupted mitochondrial metabolism. Conclusively, our results suggest that hBMSCs-derived exosomal miR-484 mitigates the malignant transformation and mitochondrial metabolism of pancreatic cancer by deactivating the Wnt/MAPK pathway.

Differentiation of Sinonasal NKT From Diffuse Large B-Cell Lymphoma Using Machine Learning and MRI-Based Radiomics.

PURPOSE: The aim of this study was to construct and validate a noninvasive radiomics method based on magnetic resonance imaging to differentiate sinonasal extranodal natural killer/T-cell lymphoma from diffuse large B-cell lymphoma. METHODS: We collected magnetic resonance imaging scans, including contrast-enhanced T1-weighted imaging and T2-weighted imaging, from 133 patients with non-Hodgkin lymphoma (103 sinonasal extranodal natural killer/T-cell lymphoma and 30 diffuse large B-cell lymphoma) and randomly split them into training and testing cohorts at a ratio of 7:3. Clinical characteristics and image performance were analyzed to build a logistic regression clinical-image model. The radiomics features were extracted on contrast-enhanced T1-weighted imaging and T2-weighted imaging images. Maximum relevance minimum redundancy, selectKbest, and the least absolute shrinkage and selection operator algorithms (LASSO) were applied for feature selection after balancing the training set. Five machine learning classifiers were used to construct the single and combined sequences radiomics models. Sensitivity, specificity, accuracy, precision, F1score, the area under receiver operating characteristic curve, and the area under precision-recall curve were compared between the 15 models and the clinical-image model. The diagnostic results of the best model were compared with those of 2 radiologists. RESULTS: The combined sequence model using support vector machine proves to be the best, incorporating 7 features and providing the highest values of specificity (0.903), accuracy (0.900), precision (0.727), F1score (0.800), and area under precision-recall curve (0.919) with relatively high sensitivity (0.889) in the testing set, along with a minimum Brier score. The diagnostic results differed significantly ( P < 0.05) from those of radiology residents, but not significantly ( P > 0.05) from those of experienced radiologists. CONCLUSIONS: Magnetic resonance imaging based on machine learning and radiomics to identify the type of sinonasal non-Hodgkin lymphoma is effective and has the potential to help radiology residents for diagnosis and be a supplement for biopsy.

Expression Patterns and Prognostic Value of DNA Damage Repair Proteins in Resected Pancreatic Neuroendocrine Neoplasms.

OBJECTIVE: This study aimed to examine the expression profiles and prognostic value of multiple DDR proteins in resected PanNENs. BACKGROUND: DDR proteins play important roles in various cancers, including pancreatic ductal adenocarcinoma. However, the expression patterns and prognostic value of DDR proteins in PanNENs remain unclear. METHODS: This retrospective analysis included PanNEN patients who underwent resection at the Fudan University Shanghai Cancer Center from 2012 to 2018. Immunohistochemical staining was performed for 12 DDR proteins in tissue microarrays. The associations of DDR protein expression and clinicopathological features with recurrence-free survival (RFS) were examined via a Cox regression model and random survival forest. A recurrence signature was constructed using recursive partitioning analysis. RESULTS: In total, 131 PanNEN patients were included, with 32 (24.4%) cases of recurrence. Among the 12 DDR proteins, low checkpoint kinase 2 (CHK2) expression (P = 0.020) and loss of ataxia-telangiectasia-mutated (ATM) (P = 0.0007) significantly correlated with recurrence. Multivariable Cox regression analysis identified tumor size ≥3 cm, lymph node (LN) metastasis, high tumor grade, low CHK2 expression, and ATM loss as independent risk factors for recurrence. A recurrence signature was established based on the importance of recurrence-specific risk factors; patients with the LNnegTumorSize<3cm signature had a 5-year RFS rate of 96.8%, whereas patients with the LNposCHK2low signature had the worst 5-year RFS rate (0%). Discrimination (concordance index: 0.770) and calibration plots indicated that the recurrence signature had a good ability to identify patients at risk for recurrence. CONCLUSIONS: By analyzing large-scale tissue microarrays of PanNENs, we evaluated 12 DDR protein expression profiles. We developed a recurrence signature that can identify distinct subpopulations according to RFS, which may help refine individual follow-up.

Fe-Doped polydopamine nanoparticles with peroxidase-mimicking activity for the detection of hypoxanthine related to meat freshness.

Rapid and accurate monitoring of food freshness to provide consumers with high-quality meat continues to be of tremendous importance to the food industry. In this report, an efficient Fe-doped polydopamine (Fe-PDA) nanozyme with peroxidase-mimicking activity was synthesized by a high-temperature hydrothermal method, and was applied to a spectrophotometric sensing system, which successfully reports the concentration of hypoxanthine (Hx) related to meat freshness. The Fe-PDA nanozyme showed excellent peroxidase simulation activity, which was primarily verified by steady-state kinetics experiments. In the presence of xanthine oxidase (XOD), Hx can react quantitatively with dissolved O2 to generate H2O2, which can be further catalyzed and produce hydroxyl radicals (•OH) under acidic conditions via the Fe-PDA nanozyme and oxidize colorless TMB to blue oxTMB with absorbance at 653 nm. The absorbance at 653 nm expressed a clear linear relationship with hypoxanthine concentration in the range of 5.13-200 µM, and the detection limit was 1.54 µM. This method was further assessed by measuring the recovery of Hx added to meat samples, which showed promising accuracy. Overall, the developed Fe-PDA nanozyme with excellent peroxidase-mimicking activity is cost-effective, high-performance and easy to produce, offering an efficient and low-cost sensing system based on spectrophotometry for meat freshness determination as an alternative to conventional methods.

Cell membrane-coated human hair nanoparticles for precise disease therapies.

Precision medicine is the ultimate goal for current disease therapies, including tumor and infection. The lack of specific targeted drugs for liver cancer and the lack of specific anti-infective drugs in the treatment of diabetic foot ulcer with infection (DFI) are the representative obstacles in those 2 major diseases currently plaguing human beings. Inventing natural biocompatible polymers derived from natural materials is one of the main development directions of current bio-medical materials. Though previous studies have demonstrated the potential application values of human black hair-derived nanoparticles (HNP) in cancer, methicillin-resistant Staphylococcus aureus (MRSA) infection, and thrombosis scenarios treatments, it still has not solved the problem of low local therapeutic concentration and general targeting ability. Here, we firstly modified the HNP with membrane encapsulations, which endowed these dual-pure natural bio-fabricated materials with better targeting ability at the disease sites with no reduction in photothermal therapy (PTT) effect. HNP coated by red blood cell membrane loaded with DSPE-PEG-cRGD peptide for the therapeutic application of liver cancer greatly prolonged in vivo circulation time and enhanced local targeting efficacy as well as low toxicity; HNP coated by the murine macrophage cell membrane (RAWM) for the DFIs treatment greatly promoted the adhesive ability of HNP on the bacteria and thereby improved the killing effect. Briefly, the appropriate cell membranes camouflaged HNP nanomedicine has the characteristics of excellent photothermal effect, an all-natural source with excellent biocompatibility and easy access, which is expected to have huge potential in both benign and malignant diseases.

Population genetics reveal multiple independent invasions of Spodoptera frugiperda (Lepidoptera: Noctuidae) in China.

The fall armyworm (Spodoptera frugiperda), a destructive pest that originated in South and North America, spread to China in early 2019. Controlling this invasive pest requires an understanding of its population structure and migration patterns, yet the invasion genetics of Chinese S. frugiperda is not clear. Here, using the mitochondrial cytochrome oxidase subunit I (COI) gene, triose phosphate isomerase (Tpi) gene and eight microsatellite loci, we investigated genetic structure and genetic diversity of 16 S. frugiperda populations in China. The Tpi locus identified most S. frugiperda populations as the corn-strains, and a few were heterozygous strains. The microsatellite loci revealed that the genetic diversity of this pest in China was lower than that in South America. Furthermore, we found moderate differentiation among the populations, distinct genetic structures between adjacent populations and abundant genetic resources in the S. frugiperda populations from China sampled across 2 years. The survival rate of S. frugiperda was significantly higher when it was fed on corn leaves than on rice leaves, and the larval stage mortality rate was the highest under both treatments. Our results showed that S. frugiperda probably invaded China via multiple independent introductions and careful pesticide control, continuous monitoring and further studies will be needed to minimize its potential future outbreak.

PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications.

Pancreatic cancer is a highly lethal disease with a poor prognosis, and existing therapies offer only limited effectiveness. Mutation gene sequencing has shown several gene associations that may account for its carcinogenesis, revealing a promising research direction. Poly (ADP-ribose) polymerase (PARP) inhibitors target tumor cells with a homologous recombination repair (HRR) deficiency based on the concept of synthetic lethality. The most prominent target gene is BRCA, in which mutations were first identified in breast cancer and ovarian cancer. PARP inhibitors can trap the PARP-1 protein at a single-stranded break/DNA lesion and disrupt its catalytic cycle, ultimately leading to replication fork progression and consequent double-strand breaks. For tumor cells with BRCA mutations, HRR loss would result in cell death. Pancreatic cancer has also been reported to have a strong relationship with BRCA gene mutations, which indicates that pancreatic cancer patients may benefit from PARP inhibitors. Several clinical trials are being conducted and have begun to yield results. For example, the POLO (Pancreatic Cancer Olaparib Ongoing) trial has demonstrated that the median progression-free survival was observably longer in the olaparib group than in the placebo group. However, PARP inhibitor resistance has partially precluded their use in clinical applications, and the major mechanism underlying this resistance is the restoration of HRR. Therefore, determining how to use PARP inhibitors in more clinical applications and how to avoid adverse effects, as well as prognosis and treatment response biomarkers, require additional research. This review elaborates on future prospects for the application of PARP inhibitors in pancreatic cancer.

Engineering of a Dual-Recognition Ratiometric Fluorescent Nanosensor with a Remarkably Large Stokes Shift for Accurate Tracking of Pathogenic Bacteria at the Single-Cell Level.

Rapid, accurate, reliable, and risk-free tracking of pathogenic microorganisms at the single-cell level is critical to achieve efficient source control and prevent outbreaks of microbial infectious diseases. For the first time, we report a promising approach for integrating the concepts of a remarkably large Stokes shift and dual-recognition into a single matrix to develop a pathogenic microorganism stimuli-responsive ratiometric fluorescent nanoprobe with speed, cost efficiency, stability, ultrahigh specificity, and sensitivity. As a proof-of-concept, we selected the Gram-positive bacterium Staphylococcus aureus (S. aureus) as the target analyte model, which easily bound to its recognition aptamer and the broad-spectrum glycopeptide antibiotic vancomycin (Van). To improve the specificity and short sample-to-answer time, we employed classic noncovalent π-π stacking interactions as a driving force to trigger the binding of Van and aptamer dual-functionalized near-infrared (NIR) fluorescent Apt-Van-QDs to the surface of an unreported blue fluorescent π-rich electronic carbon nanoparticles (CNPs), achieving S. aureus stimuli-responsive ratiometric nanoprobe Apt-Van-QDs@CNPs. In the assembly of Apt-Van-QDs@CNPs, the blue CNPs (energy donor) and NIR Apt-Van-QDs (energy acceptor) became close to allow the fluorescence resonance energy transfer (FRET) process, leading to a remarkable blue fluorescence quenching for the CNPs at ∼465 nm and a clear NIR fluorescence enhancement for Apt-Van-QDs at ∼725 nm. In the presence of S. aureus, the FRET process from CNPs to Apt-Van-QDs was disrupted, causing the nanoprobe Apt-Van-QDs@CNPs to display a ratiometric fluorescent response to S. aureus, which exhibited a large Stokes shift of ∼260 nm and rapid sample-to-answer detection time (∼30.0 min). As expected, the nanoprobe Apt-Van-QDs@CNPs showed an ultrahigh specificity for ratiometric fluorescence detection of S. aureus with a good detection limit of 1.0 CFU/mL, allowing the assay at single-cell level. Moreover, we also carried out the precise analysis of S. aureus in actual samples with acceptable results. We believe that this work offers new insight into the rational design of efficient ratiometric nanoprobes for rapid on-site accurate screening of pathogenic microorganisms at the single-cell level in the early stages, especially during the worldwide spread of COVID-19 today.

The microbiota and microbiome in pancreatic cancer: more influential than expected.

Microbiota is just beginning to be recognized as an important player in carcinogenesis and the interplay among microbes is greater than expected. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for which mortality closely parallels incidence. Early detection would provide the best opportunity to increase survival rates. Specific well-studied oral, gastrointestinal, and intrapancreatic microbes and some kinds of hepatotropic viruses and bactibilia may have potential etiological roles in pancreatic carcinogenesis, or modulating individual responses to oncotherapy. Concrete mechanisms mainly involve perpetuating inflammation, regulating the immune system-microbe-tumor axis, affecting metabolism, and altering the tumor microenvironment. The revolutionary technology of omics has generated insight into cancer microbiomes. A better understanding of the microbiota in PDAC might lead to the establishment of screening or early-stage diagnosis methods, implementation of cancer bacteriotherapy, adjustment of therapeutic efficacy even alleviating the adverse effects, creating new opportunities and fostering hope for desperate PDAC patients.

Prognostic Value of the Expression of DNA Repair-Related Biomarkers Mediated by Alcohol in Gastric Cancer Patients.

Alcohol consumption likely induces gastric carcinogenesis through deregulation of RNA polymerase (Pol) III genes and oxidative damage. Transcription factor IIB-related factor 1 (BRF1) overexpression alleviates RNA Pol III transcription inhibition through breast cancer susceptibility gene 1 (BRCA1). Myeloperoxidase (MPO) involvement in cancer is induced by alcohol-mediated oxidative damage. BRCA1/2 and MPO play key roles in DNA repair. BRCA1 and BRCA2 exert different roles in homologous recombination repair. By using human gastric cancer (GC) biopsies, we investigated the prognostic value of these proteins upon alcohol induction. In total, high expression of BRF1 (P = 0.010) and positive cell infiltration of MPO (P = 0.004) in tumor tissues as well as positive expression of BRCA1 (P < 0.001) in para-tumor tissues were more frequent in GC patients with hazardous or harmful alcohol consumption habits. BRF1 (P = 0.021), BRCA2 (P < 0.001), and MPO (P = 0.039) were independent prognostic factors for disease-free survival. BRCA1 (P = 0.005) and BRCA2 (P < 0.001) also were identified as independent prognostic factors for overall survival. Furthermore, BRCA2 was an independent unfavorable prognostic factor for disease-free survival and overall survival (P < 0.001) in GC patients who underwent platinum-based adjuvant chemotherapy. BRF1, BRCA1/2, and MPO are DNA repair-related biomarkers, induced by alcohol with prognostic value in GC patients.

Prognostic and diagnostic significance of galectins in pancreatic cancer: a systematic review and meta-analysis.

BACKGROUND: Galectins constitute a family of ß-galactoside-binding proteins, which influence various hallmarks of pancreatic cancer, including cell proliferation, invasion and migration; immune escape; and angiogenesis. Although many studies have concentrated on the role of galectins in pancreatic cancer, the results remain controversial. Hence, we performed a comprehensive meta-analysis to clarify the precise diagnostic and prognostic value of galectins in pancreatic cancer. METHODS: PubMed/MEDLINE, EMBASE and Web of Science were used to search related published literature up to July 2019. Pooled hazard ratios (HRs), diagnostic accuracy variables and related 95% confidence intervals (CIs) were calculated using STATA 14.0 software. RESULTS: Eleven studies including 1227 participants met our inclusion criteria. High expression of galectin family was not correlated with overall survival (OS) in pancreatic cancer (HR, 1.19; 95% CI 0.67-2.11). According to subgroup analysis, high levels of galectin-1 were significantly correlated with worse OS in pancreatic cancer (HR, 4.77; 95% CI 2.47-9.21), while high levels of tandem-repeat galectins (galectin-4 or galectin-9) predicted both better OS (HR, 0.63; 95% CI 0.46-0.86) and disease-free survival (DFS) (HR, 0.63; 95% CI 0.48-0.83). The expression levels of galectin-3 did not directly correlate with prognosis (HR, 0.99; 95% CI 0.40-2.46). The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratios of galectin-3 were 0.64 (95% CI 0.41-0.82), 0.76 (95% CI 0.59-0.88), 2.70 (95% CI 1.21-6.1), and 0.47 (95% CI 0.23-0.98), respectively. The area under the curve (AUC) of galectin-3 was 0.77. CONCLUSION: Taken together, our results suggest that high expression of galectin-1 and low levels of galectin-4 or galectin-9 are predictors of worse prognosis in pancreatic cancer patients. The expression of galectin-3 was not directly related to OS and other clinical characteristics. Although galectin-3 exhibited some diagnostic value in patients with pancreatic cancer in this meta-analysis, clinical application prospects remain to be validated. Further studies are warranted to confirm and strengthen these findings.

Robotic Versus Video-assisted Lobectomy/Segmentectomy for Lung Cancer: A Meta-analysis.

: Objective: To compare the safety/efficacy of the robotic-assisted lobectomy/segmentectomy (RAL/S) with the video-assisted lobectomy/segmentectomy (VAL/S) for radical lung cancer resection. BACKGROUND: It remains uncertain whether the newly developed RAL/S is comparable with the VAL/S. METHODS: A comprehensive search of online databases was performed. Perioperative outcomes were synthesized. Cumulative meta-analysis was performed to evaluate the temporal trend of pooled outcomes. Specific subgroups (propensity score matching studies, pure lobectomy studies) were examined. RESULTS: Analysis of 14 studies including a total of 7438 patients was performed. RAL/S was performed on 3239 patients, whereas the other 4199 patients underwent VAL/S. The 30-day mortality [0.7% vs 1.1%; odds ratio (OR) 0.53, P = 0.045] and conversion rate to open surgery (10.3% vs 11.9%; OR 0.57, P < 0.001) were significantly lower in patients who underwent RAL/S than VAL/S. Meanwhile, the postoperative complications (27.5% vs 28.2%; OR 0.95, P = 0.431), operation time [176.63 vs 162.74 min; standardized mean difference (SMD) 0.30, P = 0.086], duration of hospitalization (4.90 vs 5.23 days; SMD -0.08, P = 0.292), days to tube removal (4.10 vs 3.53 days; SMD 0.25, P = 0.120), retrieved lymph node (11.96 vs 10.67; SMD 0.46, P = 0.381), and retrieved lymph node station (4.98 vs 4.32; SMD 0.83, P = 0.261) were similar between the 2 groups. The cumulative meta-analyses suggested that the relative effects between 2 groups have already stabilized. All outcomes of subgroup and overall analyses were similar. CONCLUSIONS: This up-to-date meta-analysis confirms that RAL/S is a feasible and safe alternative to VAL/S for radical resection of lung cancer. Future studies should focus on the long-term benefits and cost effectiveness of RAL/S compared with VAL/S.