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The overlaps between segmental vitiligo (SV) and nonsegmental vitiligo (NSV) suggest the underlying features of SV, which may be helpful for treating SV. In this study, 379 vitiligo patients were recruited and divided into SV (33.2%), mild-to-moderate NSV (M-NSV, affected body affected area [BSA] ≤10%, 34.0%), and severe NSV (S-NSV, affected BSA >10%, 32.7%) groups. Demographics and clinical data were collected through in-person interviews. The disease activity, progression, and prognosis were assessed through 6 months' follow-up. Serum cytokines profile and tissue-infiltrating immune cells were measured by ELISA assay and immunofluorescence, respectively. The SV exhibited lower rates of autoimmune comorbidities and recurrence than the S-NSV, but performed similar to the M-NSV. Moreover, the disease activity, progression, serum cytokines profile, and tissue-infiltrating Th/c1 cells in the active SV and M-NSV were comparable, but differed significantly from those of the active S-NSV. The clinical and immunological similarities between SV and M-NSV presented a deeper autoimmune understanding of SV. Additionally, a classification of active vitiligo according to disease extent may be more clinically meaningful than subtypes for guiding immunomodulatory treatment.

Background This study aimed to describe the incidence, clinical characteristics, and prognosis of lung cancer patients with synchronous bone metastasis (SBM) and to analyze the prognostic factors of the lung cancer patients with SBM. Methods A total of 15,716 lung cancer patients who were diagnosed between 2009 to 2018 in the Tianjin Medical University Cancer Institute and Hospital were retrospectively reviewed. Among them, patients with SBM were checked. Both the demographic and clinical characteristics were included as follows: age, gender, marital status, history of smoking, alcohol consumption, family history of tumor, Karnofsky score, lymph node metastasis, histological type. Besides, laboratory data such as alkaline phosphatase, lactate dehydrogenase, carcinoembryonic antigen, squamous cell carcinoma antigen, cytokeratin-19 fragment, and neuron specific enolase were also included. The log-rank test and multivariate Cox regression analysis were employed to reveal the potential prognostic predictors. A further analysis using the Kaplan–Meier was employed to demonstrate the difference on the prognosis of LC patients between adenocarcinoma and non-adenocarcinoma. Results Among the included patients, 2738 patients (17.42%) were diagnosed with SBM. A total of 938 patients (34.3%) with SBM were successfully followed and the median survival was 11.53 months (95%CI: 10.57–12.49 months), and the 1-, 2-, and 5-year overall survival rate was 51, 17, and 8%, respectively. Multivariable Cox regression results showed history of smoking and high level of NSE were associated with the poor prognosis, while adenocarcinoma histological type was associated with better survival. Conclusion The prevalence of SBM in lung cancer is relatively high with poor survival. The lung cancer patients with SBM showed diverse prognosis. Among all the pathological types, the division of adenocarcinoma suggested different prognosis of the lung cancer patients with SBM. The present study emphasized the importance of pathological diagnosis on prognostic determinants in lung cancer patients with SBM.

This study aimed to develop a model that fused multiple features (multi-feature fusion model) for predicting metachronous distant metastasis (DM) in breast cancer (BC) based on clinicopathological characteristics and magnetic resonance imaging (MRI). A nomogram based on clinicopathological features (clinicopathological-feature model) and a nomogram based on the multi-feature fusion model were constructed based on BC patients with DM (n=67) and matched patients (n=134) without DM. DM was diagnosed on average (17.31±13.12) months after diagnosis. The clinicopathological-feature model included seven features: reproductive history, lymph node metastasis, estrogen receptor status, progesterone receptor status, CA153, CEA, and endocrine therapy. The multi-feature fusion model included the same features and an additional three MRI features (multiple masses, fat-saturated T2WI signal, and mass size). The multi-feature fusion model was relatively better at predicting DM. The sensitivity, specificity, diagnostic accuracy and AUC of the multi-feature fusion model were 0.746 (95% CI: 0.623-0.841), 0.806 (0.727-0.867), 0.786 (0.723-0.841), and 0.854 (0.798-0.911), respectively. Both internal and external validations suggested good generalizability of the multi-feature fusion model to the clinic. The incorporation of MRI factors significantly improved the specificity and sensitivity of the nomogram. The constructed multi-feature fusion nomogram may guide DM screening and the implementation of prophylactic treatment for BC.

We aimed to perform a pan-metastatic cancer analysis on survival and prognostic factors and to create a prognosis-based classification system. We selected distant metastasis patients from the Surveillance, Epidemiology, and End Results (SEER) database. The associations between the characteristics of the patients at admission and overall survival were determined. A prognosis-based metastatic cancer classification was established based on the identified prognostic factors. The differences in prognosis among these categories were tested. The survival rate and prognostic factors were not consistent across cancers. Three metastatic cancer categories were generated, each with different prognoses. The prognostic differences among the categories were satisfactorily validated. Different metastatic cancer types had homogeneous and heterogeneous survival rates and prognostic factors. A prognosis-based classification system for synchronous distant metastasis cancer patients at admission was created. This classification system reflects the grade of malignancy in metastatic cancers and may guide the prediction of survival and individualized treatment. Moreover, it may have important implications for the management of synchronous metastatic cancers and aid clinicians in properly allocating medical resources to metastatic patients.

ATP6L, the C subunit of the V‐ATPase V0 domain, is involved in regulating the acidic tumor micro‐environment and may promote tumor progression. However, the expression and functional role of ATP6L in tumors have not yet been well explored. In this study, we found that ATP6L protein overexpression was related to colorectal cancer histological differentiation (P, ATP6L is markedly overexpressed in the poorly differentiated colorectal cancer tissues evidently located in the invasive front and metastatic foci. More importantly, in vitro and in vivo data demonstrated that ATP6L can induce the EMT program in CRC cells. Ectopic ATP6L expression can promote microvessel density in animal xenograft tissue.

Background: Osteosarcoma is the most common primary malignant bone tumor. The current study was conducted to describe the general condition of patients with primary osteosarcoma in a single cancer center in Tianjin, China and to investigate the associated factors in osteosarcoma patients with lung metastasis. Methods: From February 2009 to October 2020, patients from Tianjin Medical University Cancer Institute and Hospital, China were retrospectively analyzed. The Kaplan–Meier method was used to evaluate the overall survival of osteosarcoma patients. Prognostic factors of patients with osteosarcoma were identified by the Cox proportional hazard regression analysis. Risk factor of lung metastasis in osteosarcoma were investigated by the logistic regression model. Results: A total of 203 patients were involved and 150 patients were successfully followed up for survival status. The 5-year survival rate of osteo-sarcoma patients was 70.0%. Surgery, bone and lung metastasis were the significant prognostic factors in multivariable Cox regression analysis. Twenty-one (10.3%) patients showed lung metastasis at the diagnosis of osteosarcoma and 67 (33%) lung metastases during the later course. T3 stage (OR=11.415, 95%CI 1.362-95.677, P=0.025) and synchronous bone metastasis (OR=6.437, 95%CI 1.69-24.51, P=0.006) were risk factors of synchronous lung metastasis occurrence. Good necrosis (≥90%, OR=0.097, 95%CI 0.028-0.332, P=0.000) and elevated Ki-67 (≥50%, OR=4.529, 95%CI 1.241-16.524, P=0.022) were proved to be significantly associated with metachronous lung metastasis occurrence. Conclusion: The overall survival, prognostic factors and risk factors for lung metastasis in this single center provided insight about osteosarcoma management.

BACKGROUND Esophageal cancer is a common cancer worldwide. We performed the present study to assess the homogeneous and heterogeneous risk and prognostic factors of bone metastasis (BM) in esophageal cancer patients using data extracted from the Surveillance, Epidemiology, and End Results (SEER) database. MATERIAL AND METHODS Data from patients with esophageal cancer in the SEER database from 2010 to 2016 were extracted to reveal the risk factors for BM through univariable and multivariable logistic regression. Cox hazard regression analysis was used to evaluate the prognostic factors in esophageal cancer patients with BM from 2010 to 2015. RESULTS A total of 2075 (8.0%) patients with initial bone metastasis were diagnosed from among 25 955 patients with esophageal cancer from 2010 to 2016. Male sex, T4 stage, brain metastasis, and liver metastasis were common risk factors for the occurrence and prognosis of BM. Patients with age younger than 67 years, grade III, higher N stage (N1, N2, and N3), histological subtype of esophageal adenocarcinoma or others, and lung metastasis were also more likely to experience bone metastasis, while unmarried patients were associated with shorter survival. CONCLUSIONS The prevalence of initial bone metastasis was approximately 8.0% in esophageal cancer patients. More attention should be paid to patients with revealed risk and prognostic factors because these factors can guide individualize bone metastasis screening and treatment of esophageal cancer patients.

To investigate whether quantitative radiomics features extracted from computed tomography (CT) can predict microsatellite instability (MSI) status in an Asian cohort of patients with stage Ⅱ colorectal cancer (CRC).This retrospective study was approved by our institutional review board, and the informed consent requirement was waived. From March 2016 to March 2018, 119 Chinese patients with pathologically confirmed stage Ⅱ CRC, available MSI status, and preoperative contrast-enhanced CT images were included in this study. Clinical and pathological information was obtained from the institutional database. The radiomics features were extracted from portal venous-phase CT images of segmented volumes of each entire primary tumor by using Matrix Laboratory (MATLAB), and radiomics signatures were generated using the least absolute shrinkage and selection operator logistic regression model. The minority group was balanced via synthetic minority over-sampling technique method. The association between the clinicopathologic characteristics and MSI status was assessed using Student's t test, Chi-square, or Fisher's exact test. The predictive efficacy of MSI status using radiomics features, clinical factors (including age, gender, CT-reported tumor location, differentiation degree of tumor, smoking history, hypertension history, family history of cancer, diabetes history, level of the Ki-67 expression, and laboratory analysis) and the combined models were evaluated, respectively. Predictive performance was evaluated by the area under receiver operating characteristic curve, accuracy, sensitivity, and specificity.MSI status was significantly associated with tumor location (p = 0.043); differentiation degree of tumor (p0.0001), hypertension history (p = 0.012), and the level of the Ki-67 expression (p = 0.015). Six radiomics features and 11 clinical characteristics were selected for predicting MSI status. The model that used the combination of clinical factors and radiomics features achieved the overall best performance than using either of the two features alone, yielding the area under the curve, sensitivity, and specificity of 0.752, 0.663, 0.841 for the combined model, 0.598, 0.371, 0.825 for clinical factors alone, and 0.688, 0.517, 0.858 for radiomics features alone, respectively.CT-based radiomic features of stage Ⅱ CRC are associated with MSI status. Combining analysis of clinical features and CT features could improve predictive efficacy and could potentially select the patients for individualized therapy noninvasively.

Chronic myeloid leukemia (CML) originates from normal hematopoietic stem cells acquiring BCR-ABL fusion gene, specific BCR-ABL inhibitors (e.g., imatinib mesylate, IM) have greatly improved patient management. However, some patients are still suffering from relapse and drug resistance, which urges better understanding of the growth/survival mechanisms of CML stem/progenitor cells. In the present study, the role and its underlying mechanism of heterogeneous nuclear ribonucleoprotein D-like (HNRPDL) in CML cells were investigated. Firstly, overexpression of HNRPDL promoted the growth of murine BaF3 cells in vitro and induced leukemia in vivo, which was enhanced by co-expression of BCR-ABL. Conversely, HNRPDL silencing inhibited colony-forming cell (CFC) production of CML CD34+ cells and attenuated BCR-ABL induced leukemia. In addition, HNRPDL modulated imatinib response of K562 cells and HNRPDL silencing sensitized CML CD34+ cells to imatinib treatment. Mechanistically, we found the stability of pre-B-cell leukemia homeobox 1 (PBX1) mRNA was sustained by HNRPDL through its binding to a specific motif (ACUAGC) in 3′-untranslated region (3′-UTR) of PBX1. The expression of PBX1 was significantly higher in CML CD34+ cells than that in control cells and PBX silencing inhibited the growth of CML cells and sensitized them to imatinib treatment. In contrast, overexpression of PBX1 elevated the CFC production of normal hematopoietic CD34+ cells and “rescued” HNRPDL silencing induced growth inhibition and imatinib sensitization. Taken together, our data have demonstrated that HNRPDL transforms hematopoietic cells and a novel HNRPDL/PBX1 axis plays an important role in human CML CD34+ cells.

Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix–loop–helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. Implications: Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.

Recently, a DNA tetrahedron has been reported to be a novel nanomedicine and promising drug vector because of its compactness, biocompatibility, biosafety, and editability. Here, we modified the DNA tetrahedron with a DNA aptamer (AS1411) as a DNA-based delivery system, which could bind to nucleolin for its cancer cell selectivity. Nucleolin is a specific biomarker protein overexpressed on membranes of malignant cancer cells and its deregulation is implicated in cell proliferation. The antimetabolite drug 5-fluorouracil (5-FU) is an extensively used anticancer agent; however, its major limitation is the lack of target specificity. Cyanine 5 (Cy5), a fluorescent probe, can be used to label DNA tetrahedron and enhance photostability with minimal effects on its basic functions. In this study, we additionally attached 5-FU to the DNA-based delivery system as a new tumor-targeting nanomedicine (AS1411-T-5-FU) to enhance the therapeutic efficacy and targeting of breast cancer. We examined the difference of the cellular uptake of AS1411-T-5-FU between breast cancer cells and normal breast cells and concluded that AS1411-T-5-FU had a better targeting ability to kill breast cancer cells than 5-FU. We further evaluated the expressions of cell apoptosis-related proteins and genes, which are associated with the mitochondrial apoptotic pathway. Ultimately, our results suggest the potential of DNA tetrahedron in cancer therapies, and we develop a novel approach to endow 5-FU with targeting property.

The purpose of this study was to show a systematic strategy for assessing the pharmacokinetics of indocyanine green (ICG)-loaded nanoparticles in the tumor tissue based on a dynamic diffuse fluorescence tomography (DFT) system. Twelve-seven-week-old male Balb/c nude mice bearing HepG2/ADR hepatocellular carcinoma were randomly divided into four groups (n = 3 per group). Four hundred microliters of three types of ICG-loaded nanoparticles (content of ICG: 50 μg/ml) and free ICG (50 μg/ml) was intravenously injected into the mice in each group, respectively. Afterwards, the real-time tomographic images on the spatial level were acquired at 2–11 min, 30 min, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h post-injection, and pharmacokinetic rates were derived for semi-quantitative assessment of the pharmacokinetics of nanoparticles at the tumor site using our proposed pharmacokinetic analysis method. The results obtained from our proposed dynamic DFT experiment demonstrated the distribution of different ICG formulations on the spatial level and enabled the semi-quantitative analysis of the pharmacokinetics of nanoparticles in the tumor tissue. The obtained pharmacokinetic rates effectively reflected the metabolic processes of nanoparticles in the tumor tissue, which proves to be beneficial for the development of tumor diagnosis and therapy.

Rationale and Objectives This study aimed to investigate whether quantitative radiomic features extracted from digital mammogram images are associated with molecular subtypes of breast cancer. Materials and Methods In this institutional review board–approved retrospective study, we collected 331 Chinese women who were diagnosed with invasive breast cancer in 2015. This cohort included 29 triple-negative, 45 human epidermal growth factor receptor 2 (HER2)-enriched, 36 luminal A, and 221 luminal B lesions. A set of 39 quantitative radiomic features, including morphologic, grayscale statistic, and texture features, were extracted from the segmented lesion area. Three binary classifications of the subtypes were performed: triple-negative vs non–triple-negative, HER2-enriched vs non–HER2-enriched, and luminal (A + B) vs nonluminal. The Naive Bayes machine learning scheme was employed for the classification, and the least absolute shrink age and selection operator method was used to select the most predictive features for the classifiers. Classification performance was evaluated by the area under receiver operating characteristic curve and accuracy. Results The model that used the combination of both the craniocaudal and the mediolateral oblique view images achieved the overall best performance than using either of the two views alone, yielding an area under receiver operating characteristic curve (or accuracy) of 0.865 (0.796) for triple-negative vs non–triple-negative, 0.784 (0.748) for HER2-enriched vs non–HER2-enriched, and 0.752 (0.788) for luminal vs nonluminal subtypes. Twelve most predictive features were selected by the least absolute shrink age and selection operator method and four of them (ie, roundness, concavity, gray mean, and correlation) showed a statistical significance (P Conclusions Our study showed that quantitative radiomic imaging features of breast tumor extracted from digital mammograms are associated with breast cancer subtypes. Future larger studies are needed to further evaluate the findings.

Background: The association between antibiotic use during pregnancy and neonatal birth outcomes has received considerable attention. Most of the previous assessment of antibiotic exposure during pregnancy relied on questionnaires and clinical prescriptions, and very few studies examined pregnancy exposure to antibiotics using human biomonitoring data. Objective: To explore the association between the cumulative exposure of antibiotics during the whole pregnancy and neonatal birth measurements using biomonitoring data of antibiotics in meconium. Methods: Three hundred and sixty nine pregnant women within the Maternal Psychological and Environmental Assessments of Kids Cohort Study were randomly selected into this study. Eighteen common antibiotics of six categories (six β‑lactams, three tetracyclines, four sulfonamides, one phenicols, one lincosamides and three fluoroquinolones) were selected as the target antibiotics in meconium. The measurement was conducted by ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry platform. Neonatal birth measurements were obtained from the medical records. Multiple linear regression models were used to examine the associations of antibiotic exposure with neonatal birth outcome (birth weight, birth length) and placental growth indicators (placental surface area, placental weight). Logistic regressions were used to evaluate associations with small for gestational age (SGA) and large for gestational age (LGA). Results: Twelve of the eighteen antibiotics were found in 62.1% of the meconium, with detection rates ranging from 0.3% to 43.9%. The three antibiotics with the highest detection rates were chlortetracycline (43.9%), penicillin (16.5%) and chloramphenicol (10.8%), respectively. The highest antibiotic concentration among detected antibiotics was penicillin (24,243.15 μg/kg). The concentration of penicillin was positively associated with the birth weight (β: 0.025; 95% CIs: 0.003–0.047). A significant positive association was also observed between the concentration of chlortetracycline and the placental surface area (β: 2.559; 95% CIs: 0.296–4.822). These associations were sex related and mainly observed in female newborns. Exposure to penicillin was also found to be associated with increased risk of LGA, which was consistent with changes in birth weight. Conclusions: Pregnancy exposure to certain antibiotics was associated with altered fetal growth and development, which may affect the normal growth trajectory of infants and children in later life. Keywords: Cumulative exposure of antibiotics, Meconium, Biomonitoring data, Birth outcomes, Placental growth indicators, LGA

Background: Ovarian cancer (OC) is one of the most common malignancies in women. Advanced bone metastases (BM) commonly result in the poor prognosis. We aim to evaluate the prevalence and associated factors for the de novo BM development and prognosis in OC. Materials and methods: The present study was a cohort study that used the United States based National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. SEER documented OC patients, diagnosed between 2010 and 2015, were included in the present study. Univariable and multivariable logistic regression analyses were employed to identify associated factors for BM development. Kaplan-Meier analysis was used to estimate the overall survival and multivariable proportional hazard regression was used to identify the prognostic factors for OC patients with BM. Results: A total of 32,178 eligible OC patients were included in the present study, the prevalence of de novo BM was 1.09% (N=352). Non-serous histology [Odds Ratio (OR)=3.05; 95% CI: 1.63-5.72; P=0.001], T2/T1 stage (OR=3.39; 95% CI: 1.11-10.33; P=0.03), N1/N0 stage (OR=3.17; 95% CI: 1.72-5.84; P

Background: Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan (Trp) metabolism, is generally considered to be an immunosuppressive molecule. The prognostic role of IDO expression in tumor has not been well studied in non-small cell lung cancer (NSCLC) and even not been reported in adenosquamous lung carcinoma (AdSqLC). Herein, the aim of this study is to investigate the prognostic significance of IDO expression in patients with AdSqLC. Patients and Methods: We conducted immunohistochemical analyses of IDO expression, as well as CD3 and CD8 expression, in 183 primary tumor tissue samples from patients with AdSqLC treated at our institution between July 1999 and September 2014. Patients' clinicopathological characteristics were retrospectively reviewed. Survival analysis was performed in the entire cohort of patients and those who received radical resection, respectively. Results: IDO was expressed in 146 (79.8%) tumor samples. A higher level of IDO expression was significantly associated with increased CD8+ tumor-infiltrating lymphocytes (TILs) in tumor tissues (P

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the world. Inhibitor of differentiation 1 (Id1) is overexpressed in NSCLC and involved in promoting its progression and metastasis. Identifying natural compounds targeting Id1 may have utility in NSCLC treatment. Here, we sought to determine whether the anti-tumor activities of Scutellaria flavonoids (SFs) were related to Id1. We reported that three SFs (baicalin, baicalein and wogonin) exhibited strong antitumor activity in NSCLC cells in vitro and in vivo. Id1 played a pivotal role on blockage of migration and invasion by SFs. Abrogation of invasion and migration mediated by baicalin, baicalein and wogonin were totally abolished by ectopic overexpression of Id1. Mechanistically, baicalin, baicalein and wogonin activated Rap1-GTP binding and dephosphorylated Akt and Src by suppressing a7nAChR, consequently triggering inhibition of Id1. Then attenuation of its downstream mediators, VEGF-A, N-cadherin, vimentin, combined with augment of E-cadherin led to the blockage of proliferation, EMT and angiogenesis of NSCLC. Overall, our data shed light on heretofore-undescribed role of SFs as modulators of Id1, which may be a useful strategy in the treatment of NSCLC.

Objective: The immunoscore, which is used to quantify immune infiltrates, has greater relative prognostic value than tumor, node, and metastasis (TNM) stage and might serve as a new system for classification of colorectal cancer. However, a comparable immunoscore for predicting lung adenocarcinoma (LUAD) prognosis is currently lacking. Methods: We analyzed the expression of 18 immune features by immunohistochemistry in 171 specimens. The relationship of immune marker expression and clinicopathologic factors to the overall survival (OS) was analyzed with the Kaplan-Meier method. A nomogram was developed by using the optimal features selected by least absolute shrinkage and selection operator (LASSO) regression in the training cohort (n = 111) and evaluated in the validation cohort (n = 60). Results: The indicators integrated in the nomogram were TNM stage, neuron-specific enolase, carcino-embryonic antigen, CD8center of tumor (CT), CD8invasive margin (IM), FoxP3CT, and CD45ROCT. The calibration curve showed prominent agreement between the observed 2- and 5-year OS and that predicted by the nomogram. To simplify the nomogram, we developed a new immune-serum scoring system (I-SSS) based on the points awarded for each factor in the nomogram. Our I-SSS was able to stratify same-stage patients into different risk subgroups. The combination of I-SSS and TNM stage had better prognostic value than the TNM stage alone. Conclusions: Our new I-SSS can accurately and individually predict LUAD prognosis and may be used to supplement prognostication based on the TNM stage.

Rationale and Objectives: The study investigated the potential of the combined use of dynamic contrast-enhanced MRI and diffusion-weighted imaging in predicting the pathological complete response (pCR) of neoadjuvant chemotherapy (NAC) after two cycles of NAC. Materials and methods: Eighty-seven patients with breast cancer who underwent MR examination before and after two cycles of NAC were enrolled. The patients were randomly assigned to a training cohort and a validation cohort (3:1 ratio). MRI parameters including tumor longest diameter, time-signal intensity curve, early enhanced ratio (E90), maximal enhanced ratio and ADC value were measured, and percentage change in MRI parameters were calculated. Univariate analysis and multivariate logistic regression analysis were used to evaluate independent predictors of pCR in the training cohort. The validation cohort was used to test the prediction model, and the nomogram was created based on the prediction model. Results: This study demonstrated that the ADC value after two cycles of NAC (OR = 1.041, 95% CI (1.002, 1.081); p = 0.037), percentage decrease in E90 (OR = 0.927, 95% CI (0.881, 0.977); p =0.004) and percentage decrease in tumor size (OR = 0.948, 95% CI (0.909, 0.988); p = 0.011) were significantly important for independently predicting pCR. The prediction model yielded AUC of 0.939 and 0.944 in the training cohort and the validation cohort, respectively. Conclusion: The combined use of dynamic contrast-enhanced MRI and diffusion-weighted imaging could accurately predict pCR after two cycles of NAC. The prediction model and the nomogram had strong predictive value to NAC.

Background Colorectal cancer (CRC) is a major cancer burden, and prognosis is determined by many demographic and clinicopathologic factors. The present study aimed to construct a prognostic nomogram for colorectal cancer patients with distant metastasis. Methods Colorectal cancer patients with distant metastasis diagnosed between 2010 and 2016 were selected from the Surveillance, Epidemiology, and End Results database. Cox proportional hazards regression was used to identify independent prognostic factors. A nomogram was constructed to predict survival, and validation was performed. Results A total of 7099 stage IV colorectal cancer patients were enrolled in the construction cohort. The median overall survival was 20.0 (95% CI 19.3–20.7) months. Age at diagnosis, marital status, race, primary tumour site, tumour grade, CEA level, T stage, N stage, presence of bone, brain, liver and lung metastasis, surgery for primary site and performance of chemotherapy were independent prognostic factors. The nomogram was constructed and the calibration curve showed satisfactory agreement. The C-index was 0.742 (95% CI 0.726–0.758). In the validation cohort (7098 patients), the nomogram showed satisfactory discrimination and calibration with a C-index of 0.746 (95% CI 0.730–0.762). Conclusion A series of factors associated with the survival of CRC patients with distant metastasis were found. Based on the identified factors, a nomogram was generated to predict the survival of stage IV colorectal cancer patients. The predictive model showed satisfactory discrimination and calibration, which can provide a reference for survival estimation and individualized treatment decisions.

Ethnopharmacological relevance Realgar has been used in traditional remedies for a long history in China and India. It is clinically used to treat diverse cancers, especially acute promyelocytic leukemia (APL), chronic myelogenous leukemia (CML) in China. However, paradoxic roles of realgar to increase or decrease immunity are reported. It is urgent to address this question, due to immune depression can be strongly benefit to cancer development, but detrimental to patients. Aim of the study This present work is to explore whether realgar promote or suppress immune responses, and shed light on its mode of action. Our results should provide cues for rational strategy to explore realgar for clinical use. Material and methods Infection model in vivo was established by using Enterococcus faecalis to attack Caenorhabditis elegans, then realgar was used to treat the infected worms to investigate its effects on infectivity and the underlying mechanism. Killing analysis was carried out to test whether realgar can mitigate worm infection. Thermotolerance resistance analysis was used to evaluate if realgar functions hormetic effect. Quantification of live E. faecalis in nematode intestine was employed to ascertain if realgar alleviate the bacterial load in worm gut. Quantitative real-time PCR (qRT-PCR) was used to test the expression of antibacterial effectors. Western blot was used to test the effect of realgar on the expressions of p38 and phospho-p38 in worms infected by E. faecalis. Results Realgar alleviated the infected worms in strains of N2, glp-4, and daf-2, but failed in sek-1, glp-4; sek-1, and daf-2; daf-16 when p38 MAPK or daf-16 was blocked or inactivated. Western blot assay demonstrated that realgar increased the expression of phosph-p38. Thermotolerance assay showed that realgar played a hormetic role on nemtodes, triggered protective response and reduced bacterial load after realgar treatment for 120 h qRT-PCR demonstrated that realgar significantly increased antibacterial effectors, thus leading to pathogen elimination. Conclusion Realgar increased defenses against E. faecalis in C. elegans by inducing both immune responses and protective responses. It was regulated by p38 MAPK pathway and DAF-16.

Since the outbreak of 2019 novel coronavirus (2019-nCoV) infection in Wuhan City, China, pediatric cases have gradually increased. It is very important to prevent cross-infection in pediatric fever clinics, to identify children with fever in pediatric fever clinics, and to strengthen the management of pediatric fever clinics. According to prevention and control programs, we propose the guidance on the management of pediatric fever clinics during the nCoV pneumonia epidemic period, which outlines in detail how to optimize processes, prevent cross-infection, provide health protection, and prevent disinfection of medical staff. The present consideration statement summarizes current strategies on the pre-diagnosis, triage, diagnosis, treatment, and prevention of 2019-nCoV infection, which provides practical suggestions on strengthening the management of pediatric fever clinics during the nCoV pneumonia epidemic period.

BACKGROUND The early death of patients is a global cancer issue. We aimed to identify the risk factors for early death in stage IV breast cancer. Predictive nomograms for early death evaluation were generated based on the risk factors. MATERIAL AND METHODS Based on the Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with IV breast cancer were selected. The risk factors for early death (survival time ≤1 year) were identified using logistic regression model analysis. Predictive nomograms were constructed and internal validation was performed. RESULTS A total of 5998 (32.6%) breast cancer patients were diagnosed as early death in the construction cohort. Age older than 50 years, unmarried status, black race, uninsured status, triple-negative type, grade (II and III), tumor size >5 cm, and metastasis to lung, liver, and brain were risk factors for total early death, while Luminal B subtype, N1 stage, and surgical interventions were associated with lower risk of early death. As for cancer-specific and non-cancer-specific early death, several factors were not consistent between the 2 groups. Nomograms for all-cause, cancer-specific, and non-cancer-specific early death were constructed. The calibration curve showed satisfactory agreement. The areas under the ROC curve (AUC) were 78.3% (95% CI: 77.7-78.9%), 75.8% (75.1-76.4%), and 72.3% (71.6-72.9%), respectively. In the validation cohort, a total of 689 (19.3%) patients were diagnosed as early death and the calibration curve showed satisfactory agreement. The AUCs of the all-cause, cancer-specific, and non-cancer-specific early death prediction were 74.0% (95% CI: 72.5-75.4%), 73.5% (72.0-74.9%), and 68.6% (67.0-70.1%), respectively. CONCLUSIONS Nomograms were generated to predict early death, with good calibration and discrimination. The predictive model can provide a reference for identifying cases with high risk of early death among stage IV breast cancer patients and play an auxiliary role in guiding individual treatment.

Circulating tumor cells (CTC) are known to be present in the blood of patients with glioblastoma (GBM). Here we report that GBM-derived CTC possess a cancer stem cell (CSC)-like phenotype and contribute to local tumorigenesis and recurrence by the process of self-seeding. Genetic probes showed that mouse GBM-derived CTC exhibited Sox2/ETn transcriptional activation and expressed glioma CSC markers, consistent with robust expression of stemness-associated genes including SOX2, OCT4, and NANOG in human GBM patient-derived samples containing CTC. A transgenic mouse model demonstrated that CTC returned to the primary tumor and generated new tumors with enhanced tumorigenic capacity. These CTCs were resistant to radiotherapy and chemotherapy and to circulation stress-induced cell apoptosis. Single-cell RNA-seq analysis revealed that Wnt activation induced stemness and chemoresistance in CTC. Collectively, these findings identify GBM-derived CTC as CSC-like cells and suggest that targeting Wnt may offer therapeutic opportunities for eliminating these treatment-refractory cells in GBM. Significance: These findings identify CTCs as an alternative source for in situ tumor invasion and recurrence through local micrometastasis, warranting eradication of systemic "out-of-tumor" CTCs as a promising new therapeutic opportunity for GBM.

Chemoradiotherapy combined with surgical resection is the standard treatment for locally advanced rectal cancer, but not all the patients respond to neoadjuvant treatment. Transforming acidic coiled-coil protein-3 (TACC3) is frequently aberrantly expressed in rectal cancer tissue. In this study, we investigated whether TACC3 could serve as a biomarker predictive of the efficacy of chemoradiotherapy. In all, 152 rectal cancer patients with tumor tissue collected at biopsy and set aside before treatment were enrolled in this study. All patients received chemoradiotherapy and surgical resection. Immunohistochemically detected tumoral TACC3 expression significantly decreased sensitivity to chemoradiotherapy [risk ratio (RR) = 2.236, 95% confidence interval (CI): 1.447–3.456; P = 0.001] and thus the pathological complete response rate (P = 0.001). TACC3 knockdown using specific siRNA enhanced radiotherapy-induced decreases in proliferation and colony formation by HCT116 and SW480 cells and increased the incidence of radiotherapy-induced apoptosis. Cox multivariate analysis showed that TACC3 was a significant prognostic factor for overall survival (P = 0.017) and disease-free survival (P = 0.020). These findings suggest TACC3 expression may be predictive of chemoradiotherapy sensitivity and prognosis in locally advanced rectal cancer.

BACKGROUND The aims of this study were to investigate the incidence and risk factors for the development of bone metastases and prognosis in women with cancer of the uterine cervix using database analysis. MATERIAL AND METHODS The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database was analyzed for the incidence and survival rates of women diagnosed with uterine cervical cancer in the United States between 2010-2015. Multivariate logistic regression analysis identified risk factors for bone metastases. Kaplan-Meier analysis estimated the overall survival. Proportional hazard regression analysis estimated prognostic factors associated with bone metastases. RESULTS There were 19,363 women with uterine cervical cancer, and 469 women were diagnosed with bone metastases on initial diagnosis (2.42%). Increased T-stage, N-stage, non-squamous and non-adenocarcinoma histology, high-grade tumors, and the presence of lung, liver, and brain metastases were all significantly associated with early bone metastases. There were 364 patients with cervical cancer and bone metastases on initial diagnosis who were followed-up for at least one year. Multivariate Cox regression analysis showed that unmarried status and lung, liver, and brain metastases were significantly associated with reduced overall survival. No other significant risk or prognostic associations were found. CONCLUSIONS SEER data analysis showed that women with uterine cervical cancer had some standard risk factors associated with bone metastases, and with prognosis, but a heterogeneous group of risk factors was also present. The findings of this study may have clinical application in screening for bone metastases in women with cervical cancer.

The influence of mild perioperative hypothermia on the immune function and incidence of postoperative wound infections has been suggested, but the specific mechanism is unclear. This study aimed to analyze the body temperature, immune function, and wound infection rates in patients receiving open surgery for gastric cancer. Body temperature was controlled in each patient using one of four different methods: wrapping limbs, head and neck; insulated blankets; warming infusion fluids and insulated blankets; and warming fluids without insulated blankets. One hundred patients were randomly divided into four groups of 25 patients each, and every group received a different intraoperative treatment for maintaining normal body temperature. Nasopharyngeal and rectal temperatures, transforming growth factor beta (TGF-β), interleukin 10 (IL-10) levels, and cluster of differentiation (CD)3+T and CD4+/CD25+ regulatory T cell (Treg) counts were measured before surgery and at 2 and 4 hours postoperatively. Patients were evaluated at one week after surgery for signs of infection. Intraoperative body temperature and measures of immune function varied significantly between the four groups, with the largest temperature changes observed in the group in which only the limbs were wrapped in cotton pads to control the body temperature. The lowest temperature change (i.e., close to normal temperature) and cytokine response after surgery were observed in the group in which infusion fluids and transfused blood (if needed) were heated to 37℃, peritoneal irrigation fluid was heated to 37℃, and an insulation blanket was heated to 39℃ and placed under the patient. No intergroup differences were found in the infection rates at one week after surgery. In conclusion, body temperature variation during surgery affects the immune function of patients, and maintaining body temperature close to normal results in the least variation of immune function.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins. Heterogeneous nuclear ribonucleoprotein D-like (HNRPDL) is a member of this family. Though aberrant expression of HNRPDL has been reported in a few cancers, whether HNRPDL is deregulated in colon cancer patients and what role this protein plays in these cells are not known yet. In this study, we found that HNRPDL was significantly up-regulated in colon cancer specimens than control. We also demonstrated that HNRPDL silencing inhibited the growth of SW620 cells both in vitro and in vivo. Conversely, we constructed a retroviral vector to deliver HNRPDL into non-malignant NIH-3T3 cells and injected these cells into nude mice. HNRPDL-overexpressing NIH-3T3 cells generated tumors in nude mice but not the control cells. Mechanistically, HNRPDL promoted cell-cycle progression associated with enhanced expressions of cyclin D3 and Ki-67 but decreased expressions of p53 and p21. Taken together, our data demonstrate that HNRPDL is aberrantly expressed in colon cancer cells, which promotes the growth of these cells by activating cell-cycle progression.

Objective: Although preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC), the clinical efficacy differs among patients. This study was conducted to determine the association between genetic variations in the PI3K/PTEN/AKT/mTOR pathway and clinical outcomes in LARC patients. Methods: Sixteen tagging single-nucleotide polymorphisms (SNPs) in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) were genotyped. The associations of these SNPs with tumor response to preoperative CRT, postoperative disease-free survival (DFS) and overall survival (OS) were identified. Crude odds ratios (ORs) and hazard ratios (HRs) were adjusted by age, sex, clinical stage, tumor differentiation, tumor location, cycles of preoperative chemotherapy and time interval from CRT completion to surgery. Results: In an analysis of 97 LARC patients, the G/T+G/G genotype of AKT1:rs2498804 was associated with an increased tumor response rate (adjusted OR = 2.909, 95% confidence interval (CI), 1.127-7.505, P = 0.027). At a median of 65.7 months of follow-up, the G/C+C/C genotype of AKT2:rs8100018 was associated with a reduced risk of postoperative recurrence (adjusted HR = 0.414; 95% CI, 0.187-0.914, P = 0.029). Patients carrying the G/C+C/C genotype in AKT2:rs8100018 presented a higher 5-year DFS rate than those with the wild-type genotype (79.2% vs. 62.3%, P = 0.038). None of the SNPs were significantly associated with pathological complete response (pCR) or 5-year OS. Conclusions: The current study indicates that genetic variations within the PI3K/ PTEN/AKT/mTOR signaling pathway are associated with the clinical outcomes of LARC patients undergoing preoperative CRT followed by radical surgery.

Oral administration route for treating inflammatory bowel disease (IBD) is one of the most convenient methods, especially for the chemical molecular drugs and biologics. Attempts to develop applicable oral administration method tend to focus on the construction of functional microcarriers through simple operations and employing innovative but accessible materials. Here, we report a pH-sensitive drug delivery system by microfluidics for oral administration of therapeutic antisense oligonucleotide (ASO) against TNF-α (TNF-α ASO) to treat the IBD. The microfluidics-derived cationic Konjac glucomannan (cKGM) & ASO Nanocomplex-loaded gelatin methacryloyl (GelMA) microparticles are coated by the acid-insoluble shells, i.e. Eudragit FS30D (GelMA MS/EFS & Nano ASO), which can prevent the encapsulated drugs from being early released in the stomach or small intestine, and enhance their selective accumulation in colon, as well as facilitate the macrophage uptake of drugs via receptor-mediated phagocytosis. It is demonstrated that our designed drug-loaded microcarriers can significantly reduce the production of TNF-α in the nidus of the colitis animal models, and effectively alleviate the symptoms of colitis in the mice after oral administration. These properties indicated that this therapeutic ASO oral delivery system can be a promising approach in treating colon-associated diseases.

Multiple sclerosis (MS) is one of the most famous and common demyelinating diseases in young adults, characterized by motor, sensory, and cognitive impairments. In MS patients, multifocal demyelinating lesions, inflammatory infiltrates, axonal damage, and deletion of oligodendrocytes are observed. For the solely immunomodulatory focus has exhibited unsatisfactory ability to combat the progression of MS disability. There is an absence of first-line drugs against MS to delay the progression and obtain clinical improvement. Tetrahedral framework nucleic acids (tFNAs), novel self-assembled nucleic-acid nanomaterials, have been found to exhibit broad application value. Previous studies have reported positive reactions between tFNAs and various cell types, and tFNAs are able to act the advantages of neuroprotective, anti-apoptosis and anti-inflammatory. To investigate a new research direction for remyelination and potential mechanism for MS therapies, we attempted to characterize the effects of tFNAs on remyelination. The results in vitro demonstrated that tFNAs were able to rescue oligodendroglial progenitor cells (OPCs) from interferon-γ (IFN-γ) induced cell death. In in vivo study, functional remyelination was assessed by behavior test and histological examination in cuprizone-induced mice treated with tFNAs. The tFNAs-treated groups exhibited excellent remyelination. Proteins related to the PI3K-AKT-mTOR and mitochondrial apoptotic pathways were examined to further support this finding. In conclusion, our study suggested the therapeutic potential of tFNAs for MS patients by enhancing the remyelination.

Spinal cord injury (SCI), began with a primary injury including contusion and compression, is a common disease caused by various pathogenesis. Characterized disruption of axons and irreversible loss of neurons in SCI, and further damage in spinal cord tissue caused by following secondary injuries, such as the formation of glial scar and inflammation, makes it even harder to recover for affected patients. Tetrahedral framework nucleic acid (tFNA), which possesses the capability of promoting neuroprotection and neuroregeneration in vitro, might alleviate the injuries, and facilitate the neural tissue regeneration in experimental animal models of SCI. Here, we developed a concomitant treatment of tFNA and neural stem cells (NSCs) for the synergistic therapy in treating the injury of the spinal cord. We first observed that tFNA could promote cell proliferation of NSCs then verified that the concomitant treatment of tFNA and NSCs showed the neuroprotective actions by increasing the survival of transplanted NSCs. Furthermore, the recovery of motor function and the tissue regeneration in the lesion site of the spinal cord achieved the best performance in the SCI rats treated with the combination of tFNA and NSCs than others, and the formation of glial scar was the least. Our findings provide novel evidence of a promising strategy for synergistic treatment of SCI in the future.

Background As artificial intelligence methods for the diagnosis of disease advance, we aimed to evaluate machine learning in the predictive task of distinguishing between malignant and benign breast lesions on an independent clinical magnetic resonance imaging (MRI) dataset within a single institution for subsequent use as a computer aid for radiologists. Methods Computer analysis was conducted on consecutive dynamic contrast-enhanced MRI (DCE-MRI) studies from 1483 breast cancer and 496 benign patients who underwent MRI examinations between February 2015 and October 2017; with the age ranges of the cancer and benign patients being 19 to 77 and 16 to 76 years old, respectively. Cases were separated into a training dataset (years 2015 & 2016; 1444 cases) and an independent testing dataset (year 2017; 535 cases) based solely on MRI examination date. After radiologist indication of the lesion, the computer automatically segmented and extracted radiomic features, which were subsequently merged with a support-vector machine (SVM) to yield a lesion signature. Area under the receiving operating characteristic (ROC) curve (AUC) with 95% confidence intervals (CI) served as the primary figure of merit in the statistical evaluation for this clinical classification task. Results In the task of distinguishing malignant and benign breast lesions DCE-MRI, the trained predictive model yielded an AUC value of 0.89 (95% CI: 0.858, 0.922) on the independent image set. AUC values of 0.88 (95% CI: 0.845, 0.926) and 0.90 (95% CI: 0.837, 0.940) were obtained for mass lesions only and non-mass lesions only, respectively. Compared with actual clinical management decisions, the predictive model achieved 99.5% sensitivity with 9.6% fewer recommended biopsies. Conclusion On an independent, consecutive clinical dataset within a single institution, a trained machine learning system yielded promising performance in distinguishing between malignant and benign breast lesions.

Background The objectives were to investigate the disparity in the prevalence of bone metastases (BM) between the sexes and to assess the effect of female sex on the development and prognosis of BM. Methods Cases of invasive non-sex-specific cancers diagnosed between 2010 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) program were used. The prevalence of BM was calculated by combining the prevalence of BM among different cancers. Multivariable logistic regression and proportion hazard regression were conducted to investigate the effect of female sex, and the results were pooled by meta-analysis. Results The pooled prevalence of BM among male and female patients was 2.3% (95% CI: 1.6–3.2%) and 1.8% (95% CI: 1.2–2.6%), respectively. The pooled prevalence of BM dramatically decreased for patients aged 11–40 years old, plateaued for patients aged 41–90 years old and increased for patients aged > 90 years old in both male and female patients. Meta-analysis suggested that female sex had a protective effect on the development of BM (pooled OR = 0.80; 95% CI: 0.75–0.84; p p Conclusions Female sex was associated with fewer BM in various non-sex-specific cancers, and the effect was constant with changes in age. Female sex showed a protective effect exclusively on the prognosis of respiratory system cancers.

Non-small cell lung cancer (NSCLC) is one of the most lethal cancers worldwide. Inhibitor of differentiation 1 (Id1) is the member mostly linked to tumorigenesis in Id family and a potential molecular target in cancer therapy. In the current study, we established an orthotopic lung cancer model by injecting athymic nude mice with A549 cells and evaluated the antitumor effect of baicalein and expression of Id1-related proteins in vivo and in vitro. Micro-CT images showed that tumor volume in baicalein group was significantly reduced. Western blot analysis revealed that baicalein suppressed the expression of Id1 protein, epithelial-to-mesenchymal transition (EMT) related molecules (N-Cadherin, vimentin), and angiogenesis related protein (VEGF-A), accompanied by upregulation of epithelial markers (such as E-cadherin). In addition, phosphorylation of upstream molecular Src was significantly restrained after baicalein treatment. This study firstly demonstrates that baicalein inhibits tumor growth in orthotopic human NSCLC xenografts via targeting Src/Id1 pathway.

Background Olympic weightlifting requires strength, speed, and explosive power. Vigorous physical activity such as Olympic weightlifting, for older adults has many benefits from improved strength, social interactions, and a healthy and independent lifestyle. Little is known about the training habits, health, and lifestyle of Masters weightlifters that includes top level athletes as well as beginners, and there is a dearth of data on women. Objectives The primary aim was to describe demographics, training habits, and health including prevalence of injury and chronic disease in male and female Masters athletes in Olympic weightlifting. The secondary aim was to study gender differences and the age and impact of menopause on participation in the sport. Results The 958 participants (46% men), ages 34 to 87, mostly train 3 to 4 days per week in 1 to 2 hour sessions. This is a highly educated and affluent group, 84% are white, 72% are married, 85% are post-secondary graduates. Exercise can also increase the risk of injury compared to less active older adults, but the rates of injury in weightlifting affecting training are lower than seen in other sports. The prevalence of depression and mental health is similar to a general population. Stress levels and sleep disturbances are more common among women than men. Women reach menopause at a similar age as women in industrialized countries, but menopausal symptoms constrained the training. Conclusion Older athletes are capable of rigorous training programs and top performances while adjusting to changes due to biological aging. Weightlifting athletes, coaches, and health professionals must be aware of patterns of injuries and gender differences to incorporate successful prevention strategies. Knowledge of presentations of menopause and impact of menopausal symptoms on training allows women and health care providers to make informed treatment decisions.

Backgrounds: To evaluate the predictive power of 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) derived radiomics in molecular subtype classification of breast cancer (BC). Methods: A total of 273 primary BC patients who underwent a 18F-FDG PET/CT imaging prior to any treatment were included in this retrospective study, and the values of five conventional PET parameters were calculated, including the maximum standardized uptake value (SUVmax), SUVmean, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The ImageJ 1.50i software and METLAB package were used to delineate the contour of BC lesions and extract PET/CT derived radiomic features reflecting heterogeneity. Then, the least absolute shrinkage and selection operator (LASSO) algorithm was used to select optimal subsets of radiomic features and establish several corresponding radiomic signature models. The predictive powers of individual PET parameters and developed PET/CT derived radiomic signature models in molecular subtype classification of BC were evaluated by using receiver operating curves (ROCs) analyses with areas under the curve (AUCs) as the main outcomes. Results: All of the three SUV parameters but not MTV nor TLG were found to be significantly underrepresented in luminal and non-triple (TN) subgroups in comparison with corresponding non-luminal and TN subgroups. Whereas, no significant differences existed in all the five conventional PET parameters between human epidermal growth factor receptor 2+ (HER2+) and HER2- subgroups. Furthermore, all of the developed radiomic signature models correspondingly exhibited much more better performances than all the individual PET parameters in molecular subtype classification of BC, including luminal vs. non-luminal, HER2+ vs. HER2-, and TN vs. non-TN classification, with a mean value of 0.856, 0.818, and 0.888 for AUC. Conclusions: PET/CT derived radiomic signature models outperformed individual significant PET parameters in molecular subtype classification of BC.

Background: The progression of systemic lupus erythematosus (SLE) leads to anemia in patients, adversely affecting prognosis. The diverse causes of anemia may include excessive eryptosis or premature suicidal erythrocyte death characterized by cell shrinkage and phosphatidylserine (PS) exposure on the cell surface. The present study explored if SLE enhances eryptosis and the underlying mechanisms. Materials and Methods: Eryptosis was assessed using flow cytometry in healthy volunteers (n = 20) and anemic patients hospitalized for SLE (n = 22), for parameters including PS exposure, cell volume, cytosolic calcium ion (Ca2+) levels and reactive oxygen species (ROS) and ceramide abundance. These indicators were measured in erythrocytes of experimental subjects and erythrocytes treated with plasma from healthy volunteers or SLE patients. Results: The hemoglobin and hematocrit levels were significantly lower in anemic SLE patients than in healthy volunteers (***p

AIM To investigate the heterogeneity of enhancement kinetics for breast tumour in order to demonstrate the predictive power of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) features for distant metastasis (DM) in invasive breast cancer. MATERIALS AND METHODS Time–signal intensity curve (TIC) patterns from 128 patients with invasive breast cancer were analysed by a pixel-based DCE-MRI analysis. This MRI technique enabled pixels with varying TIC patterns (persistent, plateau, washout and non-enhancement) to be categorised semi-automatically and the percentage of different TIC patterns in each breast tumour to be calculated. The percentage of TIC patterns was compared between the DM and non-DM groups. DM-free survival was estimated using Kaplan–Meier survival analysis. RESULTS This study demonstrated a larger percentage of persistent TIC and non-enhancement TIC was associated with DM in invasive breast cancer. The cut-off values of persistent TIC and non-enhancement TIC were 22.5% and 2.5%. Combining TIC patterns and traditional predictors (tumour size and axillary lymph node status) can improve the prediction efficiency. The multivariable model yielded an area under the receiver operating characteristic curve (AUC) of 0.87 with 0.70 sensitivity and 0.87 specificity in leave-one-out cross-validation (LOOCV). These predictors showed significant differences in DM-free survival by Kaplan–Meier analysis. CONCLUSION This study shows that breast tumours with higher heterogeneity are more likely to metastasise, and pixel-based TIC analysis has utility in predicting distant metastasis of invasive breast cancer.

Objectives Based on a prospective birth cohort, we aimed to investigate the associations between maternal circulating metals exposure and gestational weight gain (GWG) across pregnancy, and explore whether maternal inflammatory cytokines could contribute to the GWG changes associated with metals exposure. Methods A total of 234 pregnant women from the Shanghai Maternal-Child Pairs cohort were enrolled in this panel study. 547 blood and serum samples were collected from pregnant women during three follow-up visits, and the circulating concentrations of 27 metals were determined by using the ICP-MS method. Five inflammatory cytokines in serum samples were measured through multiplexed immunoassays. The linear mixed models were used to estimate the association between each ln-transformed metal concentration and GWG across pregnancy. Robust generalized linear regression models were used to estimate the associations among circulating metals, GWG, and inflammatory cytokines. Results The GWG during pregnancy was 13.76 ± 1.40 kg. The concentrations Co, Zn, Mo, B, Ag and Te in second or third trimesters were significantly higher than those in early second trimester. The concentration of Mg decreased with the increase of pregnant weeks and no significant statistical differences were found in the concentrations of other metals in different trimesters. Among the detected 26 metals, Li and Sr concentrations were positively associated with GWG in the third trimester. The GWG increased by 0.100 kg (95% CI 0.005, 0.195) and 0.120 kg (95% CI 0.009, 0.232) with each one ln-concentration increase in circulating Li and Sr concentrations, respectively. Concentrations of Li and Sr in the third trimester were positively associated with tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, but negatively associated with growth differentiation factor-15 (GDF-15) significantly. Besides, IL-6 and GDF-15 levels were associated with the increase or decrease of overall pregnancy GWG, respectively. Conclusions Results showed that maternal exposure to Li and Sr were associated with increased GWG, in which maternal IL-6 and GDF-15 could contribute to the associations between metal exposures and GWG in pregnant women.

To investigate the incidence and the associated factors for bone metastases (BM) development and prognosis in initial colorectal cancer (CRC) with a large sample using Surveillance, Epidemiology, and End Results (SEER) cohort. Primary CRC patients, who were initially diagnosed between 2010 and 2015 in the SEER database, were included to analyze BM incidence and risk factors for BM occurrence. The patients with at least 1-year follow-up were involved to investigate the prognostic factors for BM. Multivariable logistic and proportional hazard regression models were used to investigate the risk factors for BM development and prognosis, respectively. A total of 212,787 eligible CRC patients were included and 2557 of them were diagnosed with de novo BM (1.20%). Rectal cancer presented significantly higher BM incidence than right and left colon cancer (χ2 = 107.64, P

Angiogenesis is a hallmark of cancer. However, most malignant solid tumors exhibit robust resistance to current anti-angiogenic therapies that primarily target VEGF pathways. Here we report that endothelial-mesenchymal transformation induces glioblastoma (GBM) resistance to anti-angiogenic therapy by downregulating VEGFR-2 expression in tumor-associated endothelial cells (ECs). We show that VEGFR-2 expression is markedly reduced in human and mouse GBM ECs. Transcriptome analysis verifies reduced VEGFR-2 expression in ECs under GBM conditions and shows increased mesenchymal gene expression in these cells. Furthermore, we identify a PDGF/NF-κB/Snail axis that induces mesenchymal transformation and reduces VEGFR-2 expression in ECs. Finally, dual inhibition of VEGFR and PDGFR eliminates tumor-associated ECs and improves animal survival in GBM-bearing mice. Notably, EC-specific knockout of PDGFR-β sensitizes tumors to VEGF-neutralizing treatment. These findings reveal an endothelial plasticity-mediated mechanism that controls anti-angiogenic therapy resistance, and suggest that vascular de-transformation may offer promising opportunities for anti-vascular therapy in cancer., Resistance to anti-angiogenic therapies often occurs in patients. Here, the authors demonstrate the role of PDGF signaling in GBM resistance to anti-VEGF treatment via a mechanism that involves endothelial-mesenchymal transformation and transcriptional regulation of VEGFR-2.

AIM To evaluate indoleamine-2,3-dioxygenase 1/cyclooxygenase 2 (IDO1/COX2) expression as an independent prognostic biomarker for colorectal cancer (CRC) patients. METHODS We retrospectively studied the medical records of 95 patients who received surgical resection from August 2008 to January 2010. All patients were randomly assigned to adjuvant treatment with or without celecoxib groups after surgery. We performed standard immunohistochemistry to assess the expression levels of IDO1/COX2 and evaluated the correlation of IDO1/COX2 with clinicopathological factors and overall survival (OS) outcomes. RESULTS The expression of nuclear IDO1 was significantly correlated with body mass index (P < 0.001), and IDO1 expression displayed no association with sex, age, tumor differentiation, T stage, N stage, carcinoembryonic antigen, cancer antigen 19-9, CD3+ and CD8+ tumor infiltrating lymphocytes, and COX2. In univariate analysis, we found that nuclear IDO1 (P = 0.039), nuclear/cytoplasmic IDO1 [hazard ratio (HR) = 2.044, 95% confidence interval (CI): 0.871-4.798, P = 0.039], nuclear IDO1/COX2 (HR = 3.048, 95%CI: 0.868-10.7, P = 0.0049) and cytoplasmic IDO1/COX2 (HR = 2.109, 95%CI: 0.976-4.558, P = 0.022) all yielded significantly poor OS outcomes. Nuclear IDO1 (P = 0.041), nuclear/cytoplasmic IDO1 (HR = 3.023, 95%CI: 0.585-15.61, P = 0.041) and cytoplasmic IDO1/COX2 (HR = 2.740, 95%CI: 0.764-9.831, P = 0.038) have significantly poor OS outcomes for the CRC celecoxib subgroup. In our multivariate Cox model, high coexpression of cytoplasmic IDO1/COX2 was found to be an independent predictor of poor outcome in CRC (HR = 2.218, 95%CI: 1.011-4.48, P = 0.047) and celecoxib subgroup patients (HR = 3.210, 95%CI: 1.074-9.590, P = 0.037). CONCLUSION Our results showed that cytoplasmic IDO1/COX2 coexpression could be used as an independent poor predictor for OS in CRC.

Objectives Human salivary adenoid cystic carcinoma (SACC) is one of the most common malignant tumours of the salivary gland and has strong migratory and invasive ability, which often lead to poor prognosis and lower survival rate. Tumour tissue tends to stiffen during solid tumour progression. This study aimed to investigate the influence of various substrate stiffness on the migration and invasion of SACC. Methods Salivary adenoid cystic carcinoma cell line ACC2 cells were cultured on polydimethylsiloxane substrates (PDMS) with varying stiffness for investigating the effects of substrate stiffness on the activities of MMPs and TIMPs. The underlying mechanism was also explored. Results When ACC2 cells were cultured on various stiffness of PDMS, the expressions of matrix metalloproteinases 2 (MMP2), MMP9, MMP14, RhoA, Rac1, Rho-associated protein kinase 1 (ROCK1) and ROCK2 were up-regulated with increasing substrate stiffness, whereas that of tissue inhibitor of matrix metalloproteinase 1 (TIMP1), TIMP2 and TIMP4 were down-regulated with increasing substrate stiffness. Conclusions Our results showed that substrate stiffness regulated the activities of MMPs and TIMPs and then modulate migratory and invasive ability of ACC2 cells via RhoA/ROCK pathway. This work indicate that matrix stiffness played an important role in progression of SACC, which not only can help understand the strong invasive ability of SACC, but also suggested that therapeutically targeting matrix stiffness may help reduce migration and invasion of SACC and improve effective therapies.

Chronic myeloid leukemia (CML) originates from normal hematopoietic stem cells acquiring Philadelphia chromosome (Ph) to generate BCR-ABL fusion gene whose protein product has deregulated tyrosine kinase activity. Specific inhibitors against BCR-ABL, such as Imatinib mesylate (IM), have greatly improved CML management; however, no single agent is a cure yet. Delivery of microRNA (miRNA) using non-viral vectors has been utilized to inhibit various cancer cells; however, the efficacy of this approach to target CML stem/progenitor cells has not been elucidated. In this study, we firstly validated that spermine-introduced pullulan (Ps) was a robust non-viral vector for delivery of miRNA to CML cells, including the CD34+ cells from clinical isolates. We then found that the miR-181a/RALA (V-ral simian leukemia viral oncogene homolog A) axis was aberrantly expressed in the CML CD34+ cells. The delivery of miR-181a specifically inhibited the growth of CML CD34+ cells, possibly via the inhibition of RALA. In contrast, miR-181a did not evidently affect the normal hematopoietic CD34+ cells. In addition, miR-181a increased IM sensitivity of the CD34+ CML cells. Taken together, we have therefore demonstrated that the delivery of miR-181a using Ps to CML stem/progenitor cells leads to their growth inhibition and enhancement of IM sensitivity, which will possibly be beneficial to CML treatment.

Ischemic stroke remains a significant problem that is the major cause of death and disability worldwide. Parecoxib is clinically used for short-term management of postoperative pain. Administration of parecoxib in rats has been reported to protect against the cerebral ischemia/reperfusion. However, the neuroprotective mechanism of parecoxib is still largely unknown. In this study, we found parecoxib could protect against neurotoxicity induced by 4 h oxygen-glucose deprivation (OGD) plus reoxgenation for 20 h, a widely used in vitro model of ischemia/reperfusion. In addition, we characterized the molecular mechanism of parecoxib's neuroprotection. We found parecoxib was able to activate CREB, and subsequently maintained the expression of Bcl-2, which is an important mitochondria-associated protein. Inhibition of endogenous Bcl-2 expression by transfection of Bcl-2-shRNA significantly attenuated the neuroprotective effects of parecoxib treatment. Furthermore, ATP production assay and mitochondrial membrane potential (ΔΨm) assay suggested that parecoxib exerted neuroprotective effect against OGD/R by maintaining the function of mitochondria. These data suggested that parecoxib treatment is a potential therapeutic approach for protecting against ischemia/reperfusion injury.

BACKGROUND A recent study has demonstrated that the long non-coding RNA VPS9D1-AS1 is highly expressed in colorectal cancer and predicts poor prognosis. However, roles of VPS9D1-AS1 in gastric cancer remained poorly understood. OBJECTIVE The aim of this study is to decipher the expression of VPS9D1-AS1 in gastric cancer (GC) patients, so as to assess whether or not it could be used as a novel biomarker for prognosis in gastric cancer patients. METHODS The expression of VPS9D1-AS1 was examined in cancer tissues and paired adjacent non-tumorous tissues from 126 gastric cancer patients using qRT-PCR. Correlations between the expression of VPS9D1-AS1 and clinicopathological parameters and patients' survival were analyzed. RESULTS VPS9D1-AS1 expression was downregulated in gastric cancer tissues than that in adjacent non-tumorous tissues (P< 0.001). VPS9D1-AS1 expression level was markedly correlated with tumor size and TNM stage in gastric cancer. Kaplan-Meier analysis showed low expression of VPS9D1-AS1 were correlated with poor overall and disease free survival. On multivariate analysis, the hazard ratio of VPS9D1-AS expression was 0.30 (95% CI = 0.13-0.66, P= 0.003) for overall survival. CONCLUSIONS Overall, our data suggest that downregulated VPS9D1-AS1 may be used as a novel prognosis predictor of gastric cancer.

Early cancer diagnosis, critical to the increase survival rate of cancer patients, is still challenging although to date more than 745,000 relevant published research articles (Google Scholar database) and more than 346,000 articles (PubMed database). In recent years, the detection of Circulating Tumor Cells (CTCs) from patients’ blood samples using microfluidics is a popular non-invasive method for diagnosis and therapy monitoring of cancer. However, the translation from the research of microfluidic CTC devices to a practical CTC detection system in clinics is still challenging because of the significant variation of biological properties among different patients. From the viewpoint of nonlinear dynamic system engineering, we propose a novel methodology: new nonlinear Microfluidic Elasto-Filtration (MEF) model for patients using hyperelasticity for prediction of large deformation of CTC and biophysical measurements of blood samples from each patient for the estimation of equivalent energy dissipation parameter. In this approach, we demonstrate the patient-specific Microfluidic Elasto-Filtration (psMEF) CTC technology can overcome the barrier of translation research. The pre-clinical study of psMEF CTC technology has shown the excellent clinical sensitivity and clinical specificity according to US FDA regulation. Increasing number of clinical data can enable the continuous improvement of psMEF methodology for early cancer diagnosis.

Despite its rare incidence worldwide, penile squamous cell carcinoma (PeSCC) still presents with significant morbidity and mortality due to the limited treatment options for advanced patients, especially those in developing countries. The program death-1 (PD-1)/PD-1 ligand (PD-L1) axis has been demonstrated to play an important role in tumor immune escape, and immunotherapies targeting this pathway have shown great success in certain cancer types. Here, we analyzed the expression pattern of PD-L1 in tumor cells and tumor-infiltrating lymphocytes (TILs) in PeSCC with a multi-center cohort. We found that the majority of PeSCCs (53.4%) were PD-L1-positive and that high PD-L1 expression in tumor cells was associated with a poor prognosis. Notably, PD-L1 expression in tumor cells was significantly associated with the extent of TILs and CD8+ TILs. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) showed that PD-L1 was positively correlated with interferon-gamma (IFNγ) and CD8+ gene expression. Moreover, we defined the constitutive and inducible surface expression of PD-L1 in newly established primary PeSCC cell lines. Interestingly, two PeSCC cell lines had high intrinsic PD-L1 expression. Another cell line showed low PD-L1 expression, but the PD-L1 expression could be induced by IFNγ stimulation. Overall, our data showed that high PD-L1 expression in penile tumor cells indicated a poor prognosis. The upregulation of PD-L1 in PeSCC included both extrinsic and intrinsic mechanisms. These findings indicated that the PD-1/PD-L1 axis might be a potential therapeutic target for patients with penile squamous cell carcinoma.