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Background Cervical cancer (CC) is the leading cause of cancer-related death in women. A limited number of studies have investigated whether immune-prognostic features can be used to predict the prognosis of CC. This study aimed to develop an improved prognostic risk scoring model (PRSM) for CC based on immune-related genes (IRGs) to predict survival and determine the key prognostic IRGs. Methods We downloaded the gene expression profiles and clinical data of CC patients from the TCGA and GEO databases. The ESTIMATE algorithm was used to calculate the score for both immune and stromal cells. Differentially expressed genes (DEGs) in different subpopulations were analyzed by “Limma”. A weighted gene co-expression network analysis (WGCNA) was used to establish a DEG co-expression module related to the immune score. Immune-related gene pairs (IRGPs) were constructed, and univariate- and Lasso-Cox regression analyses were used to analyze prognosis and establish a PRSM. A log-rank test was used to verify the accuracy and consistency of the scoring model. Identification of the predicted key IRG was ensured by the application of functional enrichment, DisNor, protein–protein interactions (PPIs) and heatmap. Finally, we extracted the key prognostic immune-related genes from the gene expression data, validated the key genes by immunohistochemistry and analyzed the correlation between their expression and drug sensitivity. Results A new PRSM was developed based on 22 IRGPs. The prognosis of the low-risk group in the model group (P P = 0.039) was significantly better than that in the high-risk group. Furthermore, M1 and M2 macrophages were highly expressed in the low-risk group. Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway were significantly enriched in the low-risk group. Three representative genes (CD80, CD28, and LCP2) were markers of CC prognosis. CD80 and CD28 may more prominent represent important indicators to improve patient prognosis. These key genes was positively correlated with drug sensitivity. Finally, we found that differences in the sensitivity to JNK inhibitors could be distinguished based on the use and risk grouping of this PRSM. Conclusions The prognostic model based on the IRGs and key genes have potential clinical significance for predicting the prognosis of CC patients, providing a foundation for clinical prognosis judgment and individualized treatment.

Human gastrointestinal malignancies are highly heterogeneous cancers. Clinically, heterogeneity largely contributes to tumor progression and resistance to therapy. Heterogeneity within gastrointestinal cancers is defined by molecular subtypes in genomic and transcriptomic analyses. Cancer stem cells (CSCs) have been demonstrated to be a major source of tumor heterogeneity; therefore, assessing tumor heterogeneity by CSC trait-guided classification of gastrointestinal cancers is essential for the development of effective therapies. CSCs share critical features with embryonic stem cells (ESCs). Molecular investigations have revealed that embryonic genes and developmental signaling pathways regulating the properties of ESCs or cell lineage differentiation are abnormally active and might be oncofetal drivers in certain tumor subtypes. Currently, multiple strategies allow comprehensive identification of tumor subtype-specific oncofetal signatures and evaluation of subtype-specific therapies. In this review, we summarize current knowledge concerning the molecular classification of gastrointestinal malignancies based on CSC features and elucidate their clinical relevance. We also outline strategies for molecular subtype identification and subtype-based therapies. Finally, we explore how clinical implementation of tumor classification by CSC subtype might facilitate the development of more effective personalized therapies for gastrointestinal cancers.

Histopathological examination (biopsy) is the “gold standard” for the diagnosis of colorectal cancer (CRC). However, biopsy is an invasive method, and due to the temporal and spatial heterogeneity of the tumor, a single biopsy cannot reveal the comprehensive biological characteristics and dynamic changes of the tumor. Therefore, there is a need for new biomarkers to improve CRC diagnosis and to monitor and treat CRC patients. Numerous studies have shown that “liquid biopsy” is a promising minimally invasive method for early CRC detection. A liquid biopsy mainly samples circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), microRNA (miRNA) and extracellular vesicles (EVs). CTCs are malignant cells that are shed from the primary tumors and/or metastases into the peripheral circulation. CTCs carry information on both primary tumors and metastases that can reflect dynamic changes in tumors in a timely manner. As a promising biomarker, CTCs can be used for early disease detection, treatment response and disease progression evaluation, disease mechanism elucidation, and therapeutic target identification for drug development. This review will discuss currently available technologies for plasma CTC isolation and detection, their utility in the management of CRC patients and future research directions.

Background Little attention has been paid to chest high resolution computed tomography (HRCT) findings in idiopathic pulmonary arterial hypertension (IPAH) patients so far, while a couple of small studies suggested that presence of centrilobular ground-glass opacifications (GGO) on lung scans could have a significant negative prognostic value. Therefore, the aims of the present study were: to assess frequency and clinical significance of GGO in IPAH, and to verify if it carries an add-on prognostic value in reference to multidimensional risk assessment tool recommended by the 2015 European pulmonary hypertension guidelines. Methods Chest HRCT scans of 110 IPAH patients were retrospectively analysed. Patients were divided into three groups: with panlobular (p)GGO, centrilobular (c)GGO, and normal lung pattern. Association of different GGO patterns with demographic, functional, haemodynamic, and biochemical parameters was tested. Survival analysis was also performed. Results GGO were found in 46% of the IPAH patients: pGGO in 24% and cGGO in 22%. Independent predictors of pGGO were: positive history of haemoptysis, higher number of low-risk factors, and lower cardiac output. Independent predictors of cGGO were: positive history of haemoptysis, younger age, higher right atrial pressure, and higher mixed venous blood oxygen saturation. CGGO had a negative prognostic value for outcome in a 2-year perspective. This effect was not seen in the longer term, probably due to short survival of cGGO patients. Conclusions Lung HRCT carries a significant independent prognostic information in IPAH, and in patients with cGGO present on the scans an early referral to lung transplantation centres should be considered.

Highlights CD40 expression correlates with the type I anti-tumor response and better survival. Pan-cancer bioinformatics characterization reveals reduced CD40 expression in 11 cancer types, including RASmut melanoma compared to nevi. RAS mutation correlates with reduced CD40 expression in malignant melanoma. CD40 expression is associated with better response to immune checkpoint blockade therapy in melanoma.

Background Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common types of cancer that cause a substantial number of cancer-related deaths. Our previous study has revealed that makorin ring finger protein 3 (MKRN3) may act as a key regulator of the SCCHN tumorigenesis; however, its specific role in SCCHN progression has not been reported. Methods The Cancer Genome Atlas (TCGA) data analysis and quantitative polymerase chain reaction (qPCR) were used to quantify the MKRN3 mRNA expression levels in SCCHN; immunohistochemical staining or immunoblotting analyses were performed to detect MKRN3 protein expression. Kaplan–Meier plotter was used to assess the prognostic values of MKRN3 in terms of overall survival and disease-free survival. The expression differences based on various clinicopathological features were evaluated using subgroup analysis and forest map analysis. The regulatory mechanism of MKRN3 was further investigated using gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Subsequently, STRING was used to perform a co-expression and enrichment analysis for MKRN3. Homologous modeling, molecular docking, and western blot analyses were performed to investigate the relationship between MKRN3 and its potential target gene P53. Results MKRN3 was ectopically expressed between cancerous and noncancerous SCCHN tissues, and its expression level was tightly associated with high T classifications as well as advanced clinical stages. qPCR analysis revealed that MKRN3 was upregulated in the SCCHN cell line. Moreover, Kaplan–Meier and Cox regression analyses indicated that SCCHN patients with high MKRN3 expression had poorer prognosis and that MKRN3 was a potential prognostic marker for SCCHN. Using gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses, we determined that MKRN3 may be involved in the regulation of synthesis and metabolism and cell growth, death and motility, as well as cancer pathways associated with SCCHN progression. Mechanism investigation further revealed that P53, a potential target of MKRN3, may be involved in the SCCHN tumorigenesis mediated by MKRN3. Conclusions We performed a comprehensive evaluation of the clinical significance of MKRN3 and explored its underlying mechanisms. We concluded that MKRN3 represents a valuable predictive biomarker and potential therapeutic target in SCCHN.

Background The incidence of colorectal cancer (CRC) has increased during recent years in Iran and other developing countries. Clinical studies suggest that essential folate dietary intake and moderate deficiency of methylenetetrahydrofolate reductase (MTHFR) may protect and reduce the risk of CRC. The present study aimed to investigate the clinical significance of C677T polymorphism within the MTHFR gene and its correlation with the serum folate and Vit B12 in the Iranian population suffering from CRC. Methods Blood samples were taken from 1017 Iranian individuals (517 cases and 500 controls) who were referred for colonoscopy. TaqMan probe assay was performed for C677T MTHFR polymorphism. Sera were fractionated from the blood samples of 43 patients and controls and folate and Vit B12 concentrations were measured by a monobind kit. The correlation of MTHFR polymorphisms and folate/vitamin-B12 with CRC risk was analyzed. Results In the current study, we found the frequency of three different genotypes of MTHFR polymorphism in the Iranian population i.e., CC, CT, and TT, to be 51.31, 26.73, 21.96 and 61, 32.2, 6.8 in case and control groups, respectively. The homozygote genotype of MTHFR rs1801133 polymorphism is associated with an increased risk of CRC by 3.68, 1.42, and 3.74-fold in codominant, dominant, and recessive models respectively (p value 0.05). Conclusions This study revealed that there was no significant difference between the amount of folate and Vit B12 in the case and control groups. Furthermore, our results demonstrated a higher risk association for 677TT and 677TT + C677T genotypes of MTHFR compared with 677CC carriers among CRC patients.

Background Up to 30% of all scrotal masses are sarcomas. Leiomyosarcoma of the scrotal wall is rare, and its clinical significance and prognosis have not been well defined, since the most reported cases have little or no follow-up. Case presentation We report a 45-year-old Caucasian man who was admitted with a firm, nontender, mobile scrotal wall mass from 15 months ago. Laboratory data including testicular tumor markers were within normal range, and transscrotal ultrasonography revealed an oval-shaped, hypoechogenic, solid mass with blood flow and well-defined border. Histopathologic examination and immunohistochemistry staining, following surgical excision, were in favor of malignant leiomyosarcoma. Conclusion Here we describe the morphological features and immunohistochemical presentations of the tumor and the patient’s relatively long-term follow-up.

This chapter underlines the potential clinical relevance and practical difficulties of the currently available measurement of vitamin C. In recent years, there has been increasing interest in the effects of intravenous vitamin C in critically ill patients, but results of multiple clinical trials are not consistent. A possible explanation is the heterogeneity in study designs and included patients. Patients with vitamin C deficiency may benefit more from vitamin C therapy than non-deficient patients. Rapid plasma vitamin C measurements could help identify this subgroup, but the ready oxidation of vitamin C ex-vivo leads to several practical difficulties. Vitamin C measurement is therefore cumbersome, time consuming and not available for routine care. To obtain correct samples for vitamin C analysis it is recommended that heparin-anticoagulated tubes be used, that samples be processed within less than 1 h at low temperature, and that the sample be stabilized by acidification and deproteinization with metaphosphoric acid. A potential surrogate marker is the point-of-care static oxidation-reduction potential (sORP), which can estimate vitamin C status within 20 min using unprocessed plasma samples. sORP could be used to screen for low vitamin C status for research and maybe eventually also for clinical purposes.

Background The prenatal test of cell-free fetal DNA (cffDNA) is also known as noninvasive prenatal testing (NIPT) with high sensitivity and specificity. This study is to evaluate the performance of NIPT and its clinical relevance with various clinical indications. Methods A retrospective analysis was conducted on 14,316 pregnant women with prenatal indications, including advanced maternal age (≥35 years), maternal serum screening abnormalities, the thickened nuchal translucency (≥2.5 mm) and other ultrasound abnormalities, twin pregnancy/IVF-ET pregnancy, etc. The whole-genome sequencing (WGS) of maternal plasma cffDNA was employed in this study. Results A total of 189 (1.32%) positive NIPT cases were identified, and 113/189 (59.79%)cases were confirmed by invasive prenatal testing. Abnormal serological screening (53.14%) was the most common indication, followed by elderly pregnancy (23.02%). The positive prediction value for T21, T18, T13, sex chromosome abnormalities, other autosomal aneuploidy abnormalities, and CNV abnormalities were 91.84, 68.75,37.50, 66.67, 14.29, and 6.45%, respectively. The positive rate and the true positive rate of nuchal translucency (NT) thickening were the highest (4.17 and 3.33%), followed by the voluntary requirement group (3.49 and 1.90%) in the various prenatal screening indications. The cffDNA concentration was linearly correlated with gestational age (≥10 weeks) and the positive NIPT group’s Z-score values. Conclusions whole-genome sequencing of cffDNA has extremely high sensitivity and specificity for T21, high sensitivity for T18, sex chromosome abnormalities, and T13. It also provides evidence for other abnormal chromosomal karyotypes (CNV and non-21/18/13 autosomal aneuploidy abnormalities). The cffDNA concentration is closely related to the gestational age and determines the specificity of NIPT. Our results highlight NIPT’s clinical significance, which is an effective prenatal screening tool for high-quality care of pregnancy., Highlights The whole-genome sequencing of cell-free fetal DNA from maternal plasma is an effective prenatal screening tool for pregnancies with various prenatal indications.The concentration of cffDNA was linear with gestational age and the Z-score values of the positive NIPT group.NIPT has a significant positive predictive value for pregnancies with prenatal indications.

Background The novel coronavirus disease 2019 (COVID-19) spreads rapidly among people and causes a pandemic. It is of great clinical significance to identify COVID-19 patients with high risk of death. Methods A total of 2169 adult COVID-19 patients were enrolled from Wuhan, China, from February 10th to April 15th, 2020. Difference analyses of medical records were performed between severe and non-severe groups, as well as between survivors and non-survivors. In addition, we developed a decision tree model to predict death outcome in severe patients. Results Of the 2169 COVID-19 patients, the median age was 61 years and male patients accounted for 48%. A total of 646 patients were diagnosed as severe illness, and 75 patients died. An older median age and a higher proportion of male patients were found in severe group or non-survivors compared to their counterparts. Significant differences in clinical characteristics and laboratory examinations were found between severe and non-severe groups, as well as between survivors and non-survivors. A decision tree, including three biomarkers, neutrophil-to-lymphocyte ratio, C-reactive protein and lactic dehydrogenase, was developed to predict death outcome in severe patients. This model performed well both in training and test datasets. The accuracy of this model were 0.98 in both datasets. Conclusion We performed a comprehensive analysis of COVID-19 patients from the outbreak in Wuhan, China, and proposed a simple and clinically operable decision tree to help clinicians rapidly identify COVID-19 patients at high risk of death, to whom priority treatment and intensive care should be given.

Preeclampsia (PE) is an idiopathic disease that occurs during pregnancy. It comprises multiple organ and system damage, and can seriously threaten the safety of the mother and infant throughout the perinatal period. As the pathogenesis of PE is unclear, there are few specific remedies. Currently, the only way to eliminate the clinical symptoms is to terminate the pregnancy. Although noncoding RNA (ncRNA) was once thought to be the “junk” of gene transcription, it is now known to be widely involved in pathological and physiological processes, including pregnancy-related disorders. Moreover, there is growing evidence that the unbalanced expression of specific ncRNA is involved in the pathogenesis of PE. In the present review, we summarize the expression patterns of ncRNAs, i.e., microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), and the functional mechanisms by which they affect the development of PE, and examine the clinical significance of ncRNAs as biomarkers for the diagnosis of PE. We also discuss the contributions made by genetic polymorphisms and epigenetic ncRNA regulation to PE. In the present review, we wish to explore and reinforce the clinical value of ncRNAs as noninvasive biomarkers of PE.

Isolated systolic hypertension typically occurs in young males; however, its clinical significance is unknown. Given the prevalence of the hypertension and its contribution to global morbidity and mortality, a synthesis of the most recent available evidence around isolated systolic hypertension is warranted. This review aims firstly to review the haemodynamic and physical characteristics indicative of cardiovascular risk in young males (aged 18 to 30 years) with isolated systolic hypertension, and secondly to synthesize the associated clinical management recommendations reported in the literature. Six databases were systematically searched for all relevant peer-reviewed literature examining isolated systolic hypertension in young males. Search results were screened and examined for validity, those that did not meet the inclusion criteria were removed. A total of 20 articles were appropriate for inclusion. Key factors indicative of cardiovascular risk in isolated systolic hypertension were characterized by several distinctive haemodynamic parameters and physical characteristics. After the literature was synthesized based around these key factors, two distinct cohorts (healthy and unhealthy) were highlighted. The healthy cohort of younger males with isolated systolic hypertension was associated with a decreased cardiovascular risk and therefore no medical interventions were recommended. The second (unhealthy) cohort was, however, associated with an increased cardiovascular risk and may therefore, benefit from antihypertensive therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s40885-021-00169-z.

Background Since inflammation and the immune system contribute to the development and progression of malignancies, parameters that reflect a host’s immune-inflammatory status may be useful prognostic indicators of gastric cancer (GC). The present study examined the clinical significance of a preoperative systemic immune-inflammation index (SII) for predicting postoperative survival outcomes in GC. Methods A total of 447 patients who underwent curative gastrectomy for GC were included in the present study. SII was calculated as platelet count × neutrophil count/lymphocyte count. The prognostic impact of preoperative SII was examined using univariate and multivariate analyses. Results Preoperative SII ranged between 105 and 4455 (median 474), and the optimal cutoff value for predicting overall survival (OS) was 395 based on a receiver operating characteristic curve. The 5-year OS rate of the SII ≥ 395 group was 80.0%, which was significantly worse than that (92.7%) of the SII < 395 group (p < 0.001). The multivariate analysis identified SII ≥ 395 (hazard ratio [HR] 2.95; 95% confidence interval [CI] 1.49–6.39; p = 0.001), heart disease (HR 2.14, 95% CI 1.07–4.07), C-reactive protein ≥ 0.5 (HR 2.45, 95% CI 1.15–4.94), pT4 (HR 4.46, 95% CI 2.44–8.14), and pN+ (HR 4.02, 95% CI 2.10–7.93) as independent predictors of worse OS. Peritoneal recurrence was more frequent in the high SII group than in the low SII group (p = 0.028). Conclusion Preoperative SII may be a useful predictor of postoperative survival outcomes in GC. The meticulous surveillance of GC relapse, particularly peritoneal dissemination, is necessary for patients with SII ≥ 395 even after curative gastrectomy.

Background Cancer cachexia worsens the treatment outcomes of patients with small-cell lung cancer (SCLC). However, no reliable biomarker of cancer cachexia is yet known. Methods We retrospectively evaluated male SCLC patients who received induction chemotherapy or concurrent chemoradiotherapy. The cachexia index (CXI) was calculated as skeletal muscle index × serum albumin level (g/dL)/neutrophil-to-lymphocyte ratio. The CXI cutoff according to tumor stage was determined based on a time-dependent receiver operating characteristic curve, and all patients were divided into low- and high-CXI groups. Results Of 267 patients, 83 and 24 patients with limited-stage disease (LD) and 123 and 37 patients with extensive-stage disease (ED) were assigned to the high- and low-CXI groups, respectively. Only one of 24 patients (4.2%) with LD in the low-CXI group achieved a complete response (CR), whereas 30 of 83 patients (36.1%) with LD in the high-CXI group achieved CRs (p = 0.004). More low-CXI patients required early discontinuation of treatment because of treatment-related toxicity compared to the high-CXI patients (37.5% vs. 16.9%, respectively, p = 0.030, for LD patients; 27.0% vs. 11.4%, respectively, p = 0.019, for ED patients). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in the low-CXI group than the high-CXI group (6.3 vs. 11.1 months and 7.5 vs. 20.6 months, respectively, both p p Conclusion A low CXI was associated with treatment intolerance, poor treatment response rate, and poor prognosis in SCLC.

BackgroundThe objective of the study was to report the incidence and risk factors associated with positive urine bacterial cultures as well as long-term outcome in cats with subcutaneous ureteral bypass (SUB) devices.ResultsMedical records of cats that underwent SUB device placement were retrospectively reviewed. Signalment of the cat, laterality of the ureteral obstruction, surgery, anesthesia and hospitalization duration, bacterial culture results and follow-up data were retrieved.Thirty-two cats met the inclusion criteria. Four cats (12.5%) had a positive intraoperative culture, with two of them being treated successfully. Ten cats out of 28 (35.7%) were documented with a positive urine culture during follow-up period, with a median time between discharge and identification of the first positive urine culture of 159 days (range 8–703 days). Bacteriuria resolved in 60% of cats (6/10).Escherichia coliwas the most common organism, isolated in 4 out of 10 postoperative urine cultures. Overall, subclinical bacteriura was documented for 6 of 32 (18.8%) cats and 5 of 32 (15.6%) cats displayed clinicals signs suggestive of persistent UTI. One cat had subclinical bacteriuria. Three cats died during the follow-up period.There was a significant difference between negative and positive urine bacterial culture groups in median hospitalization duration (5 days versus 6 days,P = 0.022) and in median body condition score (5/9 versus 4/9,P = 0.03). Cats with a longer hospital stay and with a lower body condition score were more likely to have a positive urine culture during follow-up period.ConclusionsSUB device placement surgery is associated with complications such as chronic bacteriuria. Bacteriuria in our study resolved with appropriate antibiotic treatment in more than half of cats. Risk factors identified for positive urine culture were a longer hospitalization duration and a decreased body condition score.

Background The utility of bronchoscopy for patients with suspected immune checkpoint inhibitor (ICI)-related pneumonitis is currently debatable. The purpose of this study was to examine the findings of bronchoalveolar lavage (BAL) analysis and transbronchial lung biopsy (TBLB) in non-small cell lung cancer (NSCLC) patients with ICI-related pneumonitis, and to elucidate the clinical significance of bronchoscopy for this health condition. Patients and methods Consecutive NSCLC patients treated with ICIs, diagnosed with ICI-related pneumonitis after undergoing bronchoscopy between October 2015 and March 2019 were retrospectively screened. Findings of BAL fluid analysis and/or TBLB specimen histology were reviewed. Results Twelve patients underwent bronchoscopy for the diagnosis of ICI-related pneumonitis, ten of whom underwent BAL. An increase in the proportion of lymphocytes higher than 20% was observed in all ten patients. An increase in the proportion of neutrophils (> 10%) and eosinophils (> 10%) was observed in two and one patient, respectively. TBLB specimens were analyzed for eight patients. Major histologic findings included alveolitis in seven (87.5%) and organizing pneumonia (OP) in five (62.5%) patients. Other findings included acute lung injury and fibrosis. All twelve patients demonstrated favorable outcomes. Conclusion A major characteristic of BAL analysis in ICI-related pneumonitis with NSCLC was an increased proportion of lymphocytes. The histologic features of lung tissue included alveolitis and/or OP. Acute lung injury and fibrosis were observed. Although the necessity of bronchoscopy should be determined on a case-by-case basis, it is necessary to assess these parameters when proper differential diagnosis is needed.

Background and objectives Each individual studies is limited to multi-factors and potentially lead to a significant difference of results among them. The present study aim to explore the critical genes related to the development of Esophageal squamous cell carcinoma (ESCC) by integrated transcriptomics and to investigate the clinical significance by experimental validation. Methods Datasets of protein-coding genes expression which involved in ESCC were downloaded from Gene Expression Omnibus (GEO) database. The “Robustrankaggreg” package in language was used for data integration, and the different expression genes (DEGs) were identified based the cut-off criteria as follows: adjust p-value x2 test. The P value of less than 0.05 was considered statistically significant. Results A total of 244 DEGs were identified by comparing gene expression patterns between ESCC patients and the controls based on integrating dataset of GSE77861, GSE77861, GSE100942, GSE26886, GSE17351, GSE38129, GSE33426, GSE20347 and GSE23400; The Cyclin-dependent kinase inhibitor 3 (CDKN3) were identified the top 1 seed gene of top cluster by use of protein-protein Interaction network and plug-in Molecular Complex Detection; The level of CDKN3 mRNA was significantly increased in ESCC patients compared to controls; The positive expression rate of CDKN3 protein in ESCC tissue samples was 32 and 61.4% in control, respectively. The correlations between the expression level of CDKN3 and lymph node metastasis or clinical staging of ESCC patients are statistically significant. Conclusion Integrated transcriptomics is an efficient approach to system biology. By this procedure, our study improved the understanding of the transcriptome status of ESCC.

Purpose The role of HHLA2, a new immune checkpoint ligand, is gradually being elucidated in various solid tumours. However, its role in ovarian cancer remains unclear; thus, its expression profile and clinical significance in ovarian cancer must be examined. Methods We performed immunohistochemistry to examine HHLA2 expression in 64 ovarian cancer tissues and 16 normal ovarian tissues. The relationships between HHLA2 expression and clinicopathological features, prognosis, and CD8+ tumour-infiltrating lymphocytes (TILs) in patients were analysed. Additionally, the Cancer Cell Line Encyclopedia database was used to analyse the correlation between HHLA2 expression and PD-L1 or B7x expression. Furthermore, the biological function of HHLA2 in ovarian cancer cells was initially explored. Results Only 17.2% of ovarian cancer patients showed HHLA2 expression, which was significantly associated with the differentiation of ovarian cancer cells (p = 0.027), and well-differentiated tumours expressed higher levels of HHLA2. The density of CD8+ TIL was associated with increased HHLA2 expression (p = 0.017), and the CD8+ TIL count was higher in the HHLA2-positive group than that in the HHLA2-negative group (p = 0.023). Moreover, multivariate analysis identified HHLA2 expression as an independent prognostic factor that predicted improved survival (p = 0.049; HR = 0.156; 95% CI = 0.025–0.992). Additionally, we also found that overexpressing HHLA2 inhibited the proliferation of ovarian cancer cells. Conclusion HHLA2 is associated with tumour differentiation and high CD8+ TIL levels; and predicts improved survival in ovarian cancer. Along with previously reported findings that HHLA2 behaves as a co-stimulatory ligand, our study suggests that the loss of HHLA2 may contribute to the immunosuppressive microenvironment and progression of ovarian cancer.

Background The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is widely considered as a pivotal immune checkpoint molecule to suppress antitumor immunity. However, the significance of soluble CTLA-4 (sCTLA-4) remains unclear in the patients with brain glioma. Here we aimed to investigate the significance of serum sCTLA-4 levels as a noninvasive biomarker for diagnosis and evaluation of the prognosis in glioma patients. Methods In this study, the levels of sCTLA-4 in serum from 50 patients diagnosed with different grade gliomas including preoperative and postoperative, and 50 healthy individuals were measured by an enzyme-linked immunosorbent assay (ELISA). And then ROC curve analysis and survival analyses were performed to explore the clinical significance of sCTLA-4. Results Serum sCTLA-4 levels were significantly increased in patients with glioma compared to that of healthy individuals, and which was also positively correlated with the tumor grade. ROC curve analysis showed that the best cutoff value for sCTLA-4 for glioma is 112.1 pg/ml, as well as the sensitivity and specificity with 82.0 and 78.0%, respectively, and a cut-off value of 220.43 pg/ml was best distinguished in patients between low-grade glioma group and high-grade glioma group with sensitivity 73.1% and specificity 79.2%. Survival analysis revealed that the patients with high sCTLA-4 levels (> 189.64 pg/ml) had shorter progression-free survival (PFS) compared to those with low sCTLA-4 levels (≤189.64 pg/ml). In the univariate analysis, elder, high-grade tumor, high sCTLA-4 levels and high Ki-67 index were significantly associated with shorter PFS. In the multivariate analysis, sCTLA-4 levels and tumor grade remained an independent prognostic factor. Conclusion These findings indicated that serum sCTLA-4 levels play a critical role in the pathogenesis and development of glioma, which might become a valuable predictive biomarker for supplementary diagnosis and evaluation of the progress and prognosis in glioma.

Background Due to the technical limitations of coronary artery angiography (CAG), ramus intermedius (RI) is sometimes difficult to distinguish from a high-origin obtuse marginal branch or a high-origin diagonal branch. This study sought to investigate the role of intravascular ultrasonography (IVUS) in the rectification of angiographically judged RI. Methods This study retrospectively analyzed 165 patients who were reported to have an RI based on CAG and underwent IVUS implementation from 02/01/2009 to 31/12/2019 in Zhongshan Hospital, Fudan University. Taking IVUS as the gold standard, we calculated the accuracy of RI identification by CAG and evaluated the impact of RI on revascularization strategy. Results Among the 165 patients, 89 patients (54%) were demonstrated to have an RI on IVUS (IVUS-RI), 32 patients (19%) were identified to have a high-origin diagonal branch on IVUS (IVUS-h-D), and 44 patients (27%) had an actual high-origin obtuse marginal artery on IVUS (IVUS-h-OM). Among 84 patients who underwent one-stent crossover stenting because of left main furcation lesions (48 patients in the IVUS-RI group, 12 patients in the IVUS-h-D group, and 24 in the IVUS-h-OM group), 14.6% of patients in the IVUS-RI group, 33.3% in the IVUS-h-D group and 0% in the IVUS-h-OM group had CAG-RI compromise (P = 0.02), which was defined as severe stenosis of the RI ostium (> 75%) or significant RI flow impairment (TIMI Conclusions Only 54% of CAG-RIs were confirmed by IVUS, which indicates the necessity of preintervention IVUS to distinguish real RIs from other branches in LM furcation lesions.

Circular RNAs (circRNAs) are a new class of endogenous regulatory RNAs characterized by covalently closed cyclic structure lacking poly-adenylated tails, and are capable of regulating gene expression at transcription or post-transcription levels. Recently, plentiful circRNAs have been discovered in breast cancer and some circRNAs expression profiles are specifically involved in the triple-negative breast cancer (TNBC). TNBC is a type of malignant tumor defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Considering its clinical characteristics of high invasion, metastasis, poor prognosis, and lack of effective response to conventional chemotherapies or targeted therapies, it could be a promosing option to discover specific circRNAs as new targets for TNBC treatment. Meanwhile, accumulating evidence has demonstrated that circRNAs are dysregulated in TNBC tissues and are correlated with clinicopathological features and prognosis of TNBC patients. Furthermore, looking for circRNAs with high specificity and sensitivity will provide a new opportunity for the early diagnosis, clinical treatment, and prognosis monitoring of TNBC. Herein, we reviewed the biogenesis, regulatory mechanisms, and biological functions of circRNAs in TNBC and summarized the relationship between circRNAs expression and the clinicopathology, diagnosis, and prognosis of patients with TNBC. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-021-01052-y.

Background Pazopanib, a multitargeted tyrosine kinase inhibitor, is recommended as the standard treatment for refractory soft tissue sarcoma (STS). However, there are comparatively few molecular determinants for predicting pazopanib efficacy. Based on correlative studies regarding the predictive impact of PD-L1, we investigated the clinical relevance of PD-L1 expression and evaluated its value for predicting pazopanib efficacy. Methods Tumour tissues from patients with advanced STS who went on to receive pazopanib were assessed for PD-L1 expression. Immunohistochemistry was performed using an anti-PD-L1 antibody, and the PD-L1 tumour proportion score (TPS) was calculated as the percentage of at least 100 viable cells with positive expression, defined as TPS ≥ 1%. Results Among the 67 patients, 8 (11.9%) achieved partial response and a median progression-free survival (PFS) of 4.8 months (95% CI 3.8–5.7). PD-L1 expression in tumour cells was detected in 13 (19.4%) cases and the TPS scores ranged from 1 to 100%, as follows: 0 (n = 54, 80.6%), 1–9% (n = 3, 4.5%), 10–49% (n = 9, 13.4%), and ≥ 50% (n = 1, 1.5%). PD-L1 positive tumours exhibited a poorer response to pazopanib treatment than the PD-L1 negative tumours (0% vs 14.8%, P = 0.07). PD-L1-positive tumours had significantly shorter PFS than the PD-L1-negative tumours (median PFS 2.8 vs 5.1 months, P = 0.003), and PD-L1 positivity was an independent predictor of poor response to pazopanib treatment (HR 2.77, 95% CI; 1.45–5.56, P = 0.006). Conclusion We identified that PD-L1 expression can help predict the clinical outcome of patients with advanced STS treated with pazopanib. Based on our study, stratification should be actively considered in order to identify patients who will benefit from pazopanib or further therapeutic strategies for future clinical trials.

Background The search for new Alzheimer’s disease (AD) cerebrospinal fluid (CSF) and blood biomarkers with potential pathophysiological and clinical relevance continues, as new biomarkers might lead to improved early and differential diagnosis, monitoring of disease progression and might even identify new druggable targets. Melatonin might be an interesting biomarker as an inverse correlation between CSF melatonin levels, and severity of the neuropathology as measured by Braak stages has been described. Melatonin can be measured in different body fluids, such as CSF, blood, saliva and urine. Objectives The aim of this systematic review was to review all available studies regarding melatonin levels in different body fluids in the AD continuum and give an extensive overview of reported outcomes. Methods We included papers comparing melatonin levels between healthy controls and human patients belonging to the AD continuum. A systematic search of PubMed and Web of Science led to inclusion of 20 full-length English papers following exclusion of duplicates. Results This systematic literature search showed that disruptions in melatonin levels occur with age, but also in AD when compared to age-matched controls. Night-time melatonin levels were found to be lower in CSF and blood of AD patients as compared to controls. Literature was not conclusive regarding alterations in blood daytime melatonin levels or regarding saliva melatonin in AD patients. Decreased total and night-time melatonin production has been described in urine of AD patients. Conclusion Our systematic review shows evidence for disruptions in (night-time) melatonin levels in AD as compared to age-matched controls. Although more studies are needed to understand the contribution of disruption of the melatonergic system to the pathophysiology of AD, the potential anti-AD effects that have been attributed to melatonin, renders research on this topic relevant for the discovery of potential future treatment effects of melatonin for AD. The use of melatonin as potential blood biomarker for disease progression should also be further investigated.

Background Non-invasive diagnosis of IDH1 mutation for gliomas has great clinical significance, and PET has natural advantage to detect metabolism, as IDH mutated gliomas share lower glucose consumption. Methods Clinical data of patients with gliomas and 18F-FDG PET were retrospectively reviewed. Receiver operating characteristic curve (ROC) analysis was conducted, and standard uptake value (SUV) was estimated in combination with grades or IDH1 mutation. The glucose consumption was investigated with U251 cells expressing wild-type or mutated IDH1 by glucose assay. Quantification of glucose was determined by HPLC in clinical tissues. Meanwhile, bioinformatics and western blot were applied to analyze the expression level of metabolic enzymes (e.g. HK1, PKM2, PC) in gliomas. Results Seventy-one glioma cases were enrolled, including 30 carrying IDH1 mutation. The sensitivity and specificity dependent on SUVmax (3.85) predicting IDH1 mutation reached 73.2 and 86.7%, respectively. The sensitivity and specificity of differentiating grades by SUVmax (3.1) were 92.3 and 64.4%, respectively. Glucose consumption of U251 IDH1 mutant cells (0.209 ± 0.0472 mg/ml) was obviously lower than IDH1wild-type cells (0.978 ± 0.0773 mg/ml, P = 0.0001) and astrocyte controls (0.335 ± 0.0592 mg/ml, P = 0.0451). Meanwhile, the glucose quantity in IDH1mutant glioma samples were significantly lower than those in IDH1 wild-type tissues (1.033 ± 1.19608 vs 6.361 ± 4.3909 mg/g, P = 0.0051). Silico analysis and western blot confirmed that HK1 and PKM2 in IDH1 wild-type gliomas were significantly higher than in IDH1 mutant group, while PC was significantly higher in IDH1 mutant gliomas. Conclusion SUVmax on PET can predict IDH1 mutation with adequate sensitivity and specificity, as is supported by reduced glucose consumption in IDH1 mutant gliomas.

BackgroundPneumonitis (Pn) is one of the main immune-related adverse effects, having a special importance in lung cancer, since they share affected tissue. Despite its clinical relevance, Pn development remains an unpredictable treatment adverse effect, whose mechanisms are mainly unknown, being even more obscure when it is associated to chemoimmunotherapy.MethodsIn order to identify parameters associated to treatment related Pn, we analyzed clinical variables and molecular parameters from 46 patients with potentially resectable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoimmunotherapy included in the NADIM clinical trial (NCT03081689). Pn was defined as clinical or radiographic evidence of lung inflammation without alternative diagnoses, from treatment initiation to 180 days.ResultsAmong 46 patients, 12 developed Pn (26.1%). Sex, age, smoking status, packs-year, histological subtype, clinical or pathological response, progression-free survival, overall survival and number of nivolumab cycles, were not associated to Pn development. Regarding molecular parameters at diagnosis, Pn development was not associated to programmed death ligand 1, TPS, T cell receptor repertoire parameters, or tumor mutational burden. However, patients who developed Pn had statistically significant lower blood median levels of platelet to monocyte ratio (p=0.012) and teratocarcinoma-derived growth factor 1 (p=0.013; area under the curve (AUC) 0.801), but higher median percentages of natural killers (NKs) (p=0.019; AUC 0.786), monocytes (p=0.017; AUC 0.791), MSP (p=0.006; AUC 0.838), PARN (p=0.017; AUC 0.790), and E-Cadherin (p=0.022; AUC 0.788). In addition, the immune scenario of Pn after neoadjuvant treatment involves: high levels of neutrophils and NK cells, but low levels of B and T cells in peripheral blood; increased clonality of intratumoral T cells; and elevated plasma levels of several growth factors (EGF, HGF, VEGF, ANG-1, PDGF, NGF, and NT4) and inflammatory cytokines (MIF, CCL16, neutrophil gelatinase-associated lipocalin, BMP-4, and u-PAR).ConclusionsAlthough statistically underpowered, our results shed light on the possible mechanisms behind Pn development, involving innate and adaptative immunity, and open the possibility to predict patients at high risk. If confirmed, this may allow the personalization of both, the surveillance strategy and the therapeutic approaches to manage Pn in patients receiving chemoimmunotherapy.