Construction of prediction model for fetal growth restriction during first trimester in an Asian population.

OBJECTIVE: To construct a prediction model for fetal growth restriction (FGR) during the first trimester of pregnancy and evaluate its screening performance. METHODS: This was a prospective cohort study of singleton pregnancies that underwent routine ultrasound screening at 11 to 13 + 6 weeks at the Affiliated Suzhou Hospital of Nanjing Medical University between January 2019 and April 2022. Basic clinical information, ultrasound indicators and serum biomarkers of pregnant women were collected. Fetal weight assessment was based on the fetal growth curve for the Southern Chinese population. FGR was diagnosed according to Delphi consensus criteria. Least absolute shrinkage and selection operator (lasso) regression was used to select variables for inclusion in the model. Discrimination, calibration and clinical effectiveness of the model were evaluated in training and validation cohorts. RESULTS: A total of 1188 pregnant women were included, of whom 108 had FGR. Lasso regression identified seven predictive features, including history of maternal hypertension, maternal smoking or passive smoking, gravidity, uterine artery pulsatility index, ductus venosus pulsatility index and multiples of the median values of placental growth factor and soluble fms-like tyrosine kinase-1. The nomogram prediction model constructed from these seven variables accurately predicted FGR, and the area under the receiver-operating-characteristics curve in the validation cohort was 0.82 (95% CI, 0.74-0.90). The calibration curve and Hosmer-Lemeshow test demonstrated good calibration, and the clinical decision curve and clinical impact curve supported its practical value in a clinical setting. CONCLUSION: The multi-index prediction model for FGR has good predictive value during the first trimester. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

[Preoperative prediction of HER-2 expression status in breast cancer based on MRI radiomics model].

Objective: This study aims to explore the predictive value of T2-weighted imaging (T2WI), apparent diffusion coefficient (ADC), and early-delayed phases enhanced magnetic resonance imaging (DCE-MRI) radiomics prediction model in determining human epidermal growth factor receptor 2 status in breast cancer. Methods: A retrospective study was conducted, involving 187 patients with confirmed breast cancer by postsurgical pathology at Zhenjiang First People's Hospital during January 2021 and May 2023. Immunohistochemistry or fluorescence in situ hybridization was used to determine the HER-2 status of these patients, with 48 cases classified as HER-2 positive and 139 cases as HER-2 negative. The training set was used to construct the prediction models and the validation set was used to verify the prediction models. Layers of T2WI, ADC, and early-delayed phase DCE-MRI images were used to delineate the volumeof interest and 960 radiomic features were extracted from each case using Pyradiomic. After screening and dimensionality reduction by intraclass correlation coefficient, Pearson correlation analysis, least absolute shrinkage, and selection operator, the radiomics labels were established. Logistic regression analysis was used to construct the T2WI radiomics model, ADC radiomics model, DCE-2 radiomics model, DCE-6 radiomics model, and the joint sequence radiomics model to predict the HER-2 expression status of breast cancer, respectively. Based on the clinical, pathological, and MRI image characteristics of patients, univariate and multivariate logistic regression analysis wasused to construct a clinicopathological MRI feature model. The radscore of every patient and the clinicopathological MRI features which were statistically significant after screening were used to construct a nomogram model. The receiver operating characteristic (ROC) curve was used to evaluate the predictive performance of each model and the decision curve analysis wasused to evaluate the clinical usefulness. Results: The T2WI, ADC, DCE-2, DCE-6, and joint sequence radiomics models, the clinicopathological MRI feature model, and the nomogram model were successfully constructed to predict the expression status of HER-2 in breast cancer. ROC analysis showed that in the training set and validation set, the areas under the curve (AUC) of the T2WI radiomics model were 0.797 and 0.760, of the ADC radiomics model were 0.776 and 0.634, of the DCE-2 radiomics model were 0.804 and 0.759, of the DCE-6 radiomics model were 0.869 and 0.798, of the combined sequence radiomics model were 0.908 and 0.847, of the clinicopathological MRI feature model were 0.703 and 0.693, and of the nomogram model were 0.938 and 0.859, respectively. In the training set, the combined sequence radiomics model outperformed the clinicopathological features model (P＜0.001). In the training and validation sets, the nomogram outperformed the clinicopathological features model (P＜0.05). In addition, the diagnostic performance of the nomogram was better than that of the four single-modality radiomics models in the training cohort (P＜0.05) and was better than that of DCE-2 and ADC models in the validation cohort (P＜0.05). Decision curve analysis indicated that the value of individualized prediction models was higher than clinical and pathological prediction models in clinical practice. The calibration curve showed that the multimodal radiomics model had a high consistency with the actual results in predicting HER-2 expression. Conclusions: T2WI, ADC and early-delayed phase DCE-MRI imaging histology models for HER-2 expression status in breast cancer are expected to provide a non-invasive virtual pathological basis for decision-making on preoperative neoadjuvant regimens in breast cancer.

First-principles study of the structures and superconductivity of H-S-La systems under high pressure.

Recent experimental and theoretical studies have shown that a La-H system displays remarkable superconducting properties, and it is also possible to improve the superconducting state by introducing other elements into this system. In this study, we systematically investigated the crystal structures and physical properties of an H-S-La system by using first-principles calculations combined with the CALYPSO structure exploration technique. We predicted four stable stoichiometries containing H2SLa, H3SLa, H4Sla, and H6SLa. These compounds undergo a series of phase transitions under 50-300 GPa. The bonding characters and electronic properties were calculated. It was found that Cm-H2SLa, C2/c-H2SLa, and Cmcm-H6SLa exhibit good metallic nature, which stimulates us to further study their superconducting properties. The calculated superconducting transition temperatures (Tc) of Cm-H2SLa, C2/c-H2Sla, and Cmcm-H6SLa are 15.0 K at 200 GPa, 6.9 K at 300 GPa, and 23.6 K at 300 GPa, respectively.

Claudin 18.2 expression in digestive neuroendocrine neoplasms: a clinicopathological study.

BACKGROUND: Claudin 18.2-targeted therapy has shown significant efficacy in treating claudin 18.2-positive cancers. However, limited systematic studies have investigated characteristics of claudin 18.2 expression in neuroendocrine neoplasms (NENs). METHODS: Data and specimens from 403 cases of digestive NENs were retrospectively collected, and claudin 18.2 expression was detected using immunochemical staining. RESULTS: Claudin 18.2 was positive in 19.6% (79/403) of the digestive NENs. The highest positive rate of claudin 18.2 was observed in gastric NENs (72/259, 27.8%), accounting for 91.1% (72/79) of all positive cases. The positivity rate was significantly higher in gastric NENs compared to pancreatic (2/78, 2.6%) or colorectal NENs (2/38, 5.3%; p < 0.05). For digestive NENs, claudin 18.2 positivity was significantly higher in neuroendocrine carcinomas (NECs) (37/144, 25.7%) than in neuroendocrine tumours (NETs; 14/160, 8.8%; p < 0.001), but no significant difference was found between gastric NECs (59/213, 27.7%) and gastric NETs (13/46, 28.3%; p > 0.05). The positivity was significantly higher in large-cell NECs (LCNECs; 28/79, 35.4%) and MiNEN (mixed neuroendocrine-non- neuroendocrine neoplasms)-LCNECs (23/66, 34.8%) compared to small-cell NECs (SCNECs; 9/65, 13.8%) and MiNEN-SCNECs (5/33, 15.2%; p < 0.05). Claudin 18.2 expression was more prevalent in gastric NENs than in pancreatic (12.5 ×; p = 0.001) and colorectal NENs (5.9 ×; p = 0.021). Claudin 18.2 staining was a useful method for identify the gastric origins of NETs, with a sensitivity of 28.3% and a specificity of 99.1%. CONCLUSION: The expression characteristics of claudin 18.2 in NENs were characterized, which may provide a clinicopathological reference for targeted therapies in patients with NENs.

Prominent corneal nerves in pure mucosal neuroma syndrome, a clinical phenotype distinct from multiple endocrine neoplasia type 2B.

BACKGROUND: Pure mucosal neuroma syndrome (MNS), an autosomal dominant neurocutaneous disorder, is a rare discrete subgroup in multiple endocrine neoplasia (MEN) type 2B, which present without associated endocrinopathies of MEN2B but with typical physical features such as prominent corneal nerves. Case presentation This report describes a 41-year-old patient with complaint of itchy eyes and irritation, presenting with blocked gland orifices in the upper and lower eyelids, light conjunctival hyperemia, a semitransparent neoplasm measuring 2 mm*2 mm on the nasal limbus suggestive of neuromas, and prominent corneal nerves. In vivo confocal microscopy (IVCM) revealed structural alterations-namely a prominent hyperreflective, thickened nerve plexus and a normal endothelium-in both eyes. Testing for SOS1 mutation was positive. This patient may represent a discrete subgroup termed pure mucosal neuroma syndrome (MNS), which presents with the characteristic appearance of MEN2B but without RET gene mutations. CONCLUSION: Prominent corneal nerves have been described in some diseases, such as multiple endocrine neoplasia (MEN) type 1 and type 2A and 2B, congenital ichthyosis, Refsum's disease, leprosy, etc. Ophthalmic assessment including prominent corneal nerves has proven valuable in asymptomatic individuals of MEN2B. Our case illustrates the importance of recognizing the ocular features of MNS, a rare presentation of MEN2B, in order to prevent prophylactic thyroidectomy in these patients for prophylactic thyroidectomy is not mandatory in MNS. However, regular monitoring and genetic counseling are still necessary.

[Associations of genetic variations in pyroptosis related genes with acute adverse events in postoperative rectal cancer patients receiving concurrent chemoradiotherapy].

Objective: This study aims to investigate the associations between genetic variations of pyroptosis pathway related key genes and adverse events (AEs) of postoperative chemoradiotherapy (CRT) in patients with rectal cancer. Methods: DNA was extracted from the peripheral blood which was collected from 347 patients before CRT. Sequenom MassARRAY was used to detect the genotypes of 43 haplotype-tagging single nucleotide polymorphisms (htSNPs) in eight pyroptosis genes, including absent in melanoma 2 (AIM2), caspase-1 (CASP1), caspase-4(CASP4), caspase-5 (CASP5), caspase-11 (CASP11), gasdermin D (GSDMD), gasdermin E (GSDME) and NLR family pyrin domain containing 3 (NLRP3). The associations between 43 htSNPs and AEs were evaluated by the odd ratios (ORs) and 95% confidence intervals (CIs) by unconditional logistic regression models, adjusted for sex, age, clinical stage, tumor grade, Karnofsky performance status (KPS), surgical procedure, and tumor location. Results: Among the 347 patients with rectal cancer underwent concurrent CRT with capecitabine after surgery, a total of 101(29.1%) occurred grade ≥ 2 leukopenia. rs11226565 (OR=0.41, 95% CI: 0.21-0.79, P=0.008), rs579408(OR=1.54, 95% CI: 1.03-2.29, P=0.034) and rs543923 (OR=0.63, 95% CI: 0.41-0.98, P=0.040) were significantly associated with the occurrence of grade ≥ 2 leukopenia. One hundred and fifty-six (45.0%) had grade ≥ 2 diarrhea, two SNPs were significantly associated with the occurrence of grade ≥ diarrhea, including CASP11 rs10880868 (OR=0.55, 95% CI: 0.33-0.91, P=0.020) and GSDME rs2954558 (OR=1.52, 95% CI: 1.01-2.31, P=0.050). In addition, sixty-six cases (19.0%) developed grade ≥2 dermatitis, three SNPs that significantly associated with the risk of grade ≥2 dermatitis included GSDME rs2237314 (OR=0.36, 95% CI: 0.16-0.83, P=0.017), GSDME rs12540919 (OR=0.52, 95% CI: 0.27-0.99, P=0.045) and NLRP3 rs3806268 (OR=1.51, 95% CI: 1.03-2.22, P=0.037). There was no significant difference in the association between other genetic variations and AEs of rectal cancer patients (all P>0.05). Surgical procedure and tumor location had great impacts on the occurrence of grade ≥2 diarrhea and dermatitis (all P<0.01). Conclusion: The genetic variants of CASP4, CASP11, GSDME and NLRP3 are associated with the occurrence of AEs in patients with rectal cancer who received postoperative CRT, suggesting they may be potential genetic markers in predicting the grade of AEs to achieve individualized treatment of rectal cancer.

[Prevalence and trends of anemia among pregnant women in eight provinces of China from 2016 to 2020].

This study analyzed the anemia status and change trend of 219 835 pregnant women in eight provinces from 2016 to 2020 in the Maternal and Newborn Health Monitoring Program(MNHMP). The results showed that from 2016 to 2020, the anemia rate of pregnant women in eight provinces was 41.27%, and the rates of mild, moderate and severe anemia were 28.56%, 12.59% and 0.12% respectively; the anemia rates in eastern, central and western regions were 41.87%, 36.09% and 44.63% respectively, and the anemia rates in urban and rural areas were 39.87% and 42.23%. From 2016 to 2020, the anemia rate of pregnant women decreased from 44.93% to 38.22%, with an average annual decline of 3.86% (95%CI:-5.84%, -1.85%). The anemia rate among pregnant women of the eastern region (AAPC=-6.16%, 95%CI:-9.79%, -2.38%) fell faster than that among pregnant women of the central region (AAPC=0.71%, 95%CI:-6.59%, 8.57%) and western region (AAPC=-1.53%, 95%CI:-5.19%, 2.28%). From 2016 to 2020, the moderate anemia rate in pregnant women decreased from 14.98% to 10.74%, with an average annual decline of 8.72% (95%CI:-12.90%, -4.34%), with a statistically significant difference (P<0.05); AAPC for mild and severe anemia in pregnant women was 1.56% (95%CI: 3.44%, 0.36%) and 18.86% (95%CI: 39.88%, 9.52%), respectively, without statistically significant difference (P>0.05).

[Clinicopathological characteristics of gastric SMARCA4-deficient undifferentiated/rhabdoid carcinoma].

Objective: To investigate the clinicopathological features and immunohistochemical phenotypes of gastric SMARCA4-deficient undifferentiated carcinoma, and to discuss the daily diagnostics of this entity and analyze its prognosis. Methods: The cases of gastric SMARCA4-deficient undifferentiated carcinoma diagnosed at the Department of Pathology, Peking University Cancer Hospital, China from January 2010 to August 2022 were collected. The histological sections were reviewed, the immunohistochemical results and clinicopathological features were analyzed, and relevant literature was reviewed. Results: Pure foci of undifferentiated carcinoma were seen in 7 cases, and 1 case was accompanied by a moderately differentiated tubular adenocarcinoma component. Undifferentiated carcinoma foci showed similar sheet-like or solid diffuse growth pattern, medium-sized tumor cells characterized by 1-2 nucleoli, and abundant cytoplasm and rhabdoid appearance. The average patient age was 65±8 years. Six patients were male and 2 were female. Immunohistochemical staining showed that undifferentiated carcinoma of all 8 tumors were negative for SMARCA4 (BRG1). Among 7 patients who underwent SMARCA2 (BRM) and SMARCB1 (INI1) staining, 4 cases showed loss of BRM expression, 2 cases showed weakly positive staining, and 1 case was diffusely positive, but all 7 cases were diffusely strong positive for INI1. The neuroendocrine marker, synaptophysin, was weakly positive in 5 cases, while CgA and CD56 were negative in 8 cases. Ki-67 index was more than 70%. Two cases were mismatch repair deficient and showed the loss of MLH1/PMS2 expression, while 1 case showed only MSH2 loss. PD-L1 staining showed that combined positive score (CPS)≥1 in 4 cases (CPS ranging from 1 to 55) and CPS<1 in the other 3 cases. Four patients had clinical stage Ⅳ disease. Two of them died within 3 months after diagnosis. Conclusions: Gastric SMARCA4-deficient undifferentiated carcinoma/rhabdoid carcinoma is a rare group of highly malignant tumors with a poor prognosis. Loss of the core subunit of SWI/SNF complex may be associated with the development of dedifferentiated histological pattern and aggressive tumor progression, which may be more frequently accompanied with mismatch repair deficiency.

[Pathological significance of plasma cell infiltration in diagnosing lymph node diseases].

Objective: To investigate the value of plasma cells for diagnosing lymph node diseases. Methods: Common lymphadenopathy (except plasma cell neoplasms) diagnosed from September 2012 to August 2022 were selected from the pathological records of Changhai Hospital, Shanghai, China. Morphological and immunohistochemical features were analyzed to examine the infiltration pattern, clonality, and IgG and IgG4 expression of plasma cells in these lymphadenopathies, and to summarize the differential diagnoses of plasma cell infiltration in common lymphadenopathies. Results: A total of 236 cases of lymphadenopathies with various degrees of plasma cell infiltration were included in the study. There were 58 cases of Castleman's disease, 55 cases of IgG4-related lymphadenopathy, 14 cases of syphilitic lymphadenitis, 2 cases of rheumatoid lymphadenitis, 18 cases of Rosai-Dorfman disease, 23 cases of Kimura's disease, 13 cases of dermal lymphadenitis and 53 cases of angioimmunoblastic T-cell lymphoma (AITL). The main features of these lymphadenopathies were lymph node enlargement with various degrees of plasm cell infiltration. A panel of immunohistochemical antibodies were used to examine the distribution of plasma cells and the expression of IgG and IgG4. The presence of lymph node architecture could help determine benign and malignant lesions. The preliminary classification of these lymphadenopathies was based on the infiltration features of plasma cells. The evaluation of IgG and IgG4 as a routine means could exclude the lymph nodes involvement of IgG4-related dieases (IgG4-RD), and whether it was accompanied by autoimmune diseases or multiple-organ diseases, which were of critical evidence for the differential diagnosis. For common lesions of lymphadenopathies, such as Castleman's disease, Kimura's disease, Rosai-Dorfman's disease and dermal lymphadenitis, the expression ratio of IgG4/IgG (>40%) as detected using immunhistochemistry and serum IgG4 levels should be considered as a standard for the possibility of IgG4-RD. The differential diagnosis of multicentric Castleman's diseases and IgG4-RD should be also considered. Conclusions: Infiltration of plasma cells and IgG4-positive plasma cells may be detected in some types of lymphadenopathies and lymphomas in clinicopathological daily practice, but not all of them are related to IgG4-RD. It should be emphasized that the characteristics of plasma cell infiltration and the ratio of IgG4/IgG (>40%) should be considered for further differential diagnosis and avoiding misclassification of lymphadenopathies.

[Occupational protection effect of two protective devices for manual cleaning and oiling of dental handpieces on operators].

Objective: To explore the occupational protective effect of different protective devices on the operators during manual cleaning and oiling of dental handpieces, and to provide a basis for the selection of appropriate protective methods. Methods: From November 2020 to December 2021, 20 high-speed dental handpieces of the same brand were selected and randomly divided into disposable protective bag group and small aerosol safety cabinet group by drawing lots, with 10 in each group. After recording the model, they were distributed to the clinical fixed consulting room for use, and were collected by specially-assigned personnel every day for manual cleaning under the protection of the two devices. By measuring the number of airborne colonies, the concentrations of particulate matter and the satisfaction of operators, the occupational protection effect of the two protective devices on operators was evaluated. Results: Under the protection of the two devices, the average number of airborne colonies after operation was less than 1 CFU/ml. When no protective device was used, the number concentration of particulate matter produced during operation was (21595.70±8164.26) pieces/cm(3). The number concentrations of particles produced by disposable protective bag group [ (6800.24±515.05) pieces/cm(3)] and small aerosol safety cabinet group [ (5797.15±790.50) pieces/cm(3)] were significantly lower than those without any protective device (P<0.001). The number concentration of particle matter of small aerosol safety cabinet group was significantly lower than that of disposable protective bag group (P<0.001). In the satisfaction evaluation of operators, small aerosol safety cabinet group [ (3.53±0.82) points] was significantly better than disposable protective bag group [ (2.23±1.10) points] (P<0.001) . Conclusion: The use of small aerosol safety cabinet during manual cleaning and oiling of dental handpieces has good protective effect, superior safety performance and strong clinical applicability, and has advantages in occupational protection of clinical operators.

Integrating genome-wide association and transcriptome prediction model identifies novel target genes for osteoporosis.

In this study, we integrated large-scale GWAS summary data and used the predicted transcriptome-wide association study method to discover novel genes associated with osteoporosis. We identified 204 candidate genes, which provide novel clues for understanding the genetic mechanism of osteoporosis and indicate potential therapeutic targets. INTRODUCTION: Osteoporosis is a highly polygenetic disease characterized by low bone mass and deterioration of the bone microarchitecture. Our objective was to discover novel candidate genes associated with osteoporosis. METHODS: To identify potential causal genes of the associated loci, we investigated trait-gene expression associations using the transcriptome-wide association study (TWAS) method. This method directly imputes gene expression effects from genome-wide association study (GWAS) data using a statistical prediction model trained on GTEx reference transcriptome data. We then performed a colocalization analysis to evaluate the posterior probability of biological patterns: associations characterized by a single causal variant or multiple distinct causal variants. Finally, a functional enrichment analysis of gene sets was performed using the VarElect and CluePedia tools, which assess the causal relationships between genes and a disease and search for potential gene's functional pathways. The osteoporosis-associated genes were further confirmed based on the differentially expressed genes profiled from mRNA expression data of bone tissue. RESULTS: Our analysis identified 204 candidate genes, including 154 genes that have been previously associated with osteoporosis, 50 genes that have not been previously discovered. A biological function analysis found that 20 of the candidate genes were directly associated with osteoporosis. Further analysis of multiple gene expression profiles showed that 15 genes were differentially expressed in patients with osteoporosis. Among these, SLC11A2, MAP2K5, NFATC4, and HSP90B1 were enriched in four pathways, namely, mineral absorption pathway, MAPK signaling pathway, Wnt signaling pathway, and PI3K-Akt signaling pathway, which indicates a causal relationship with the occurrence of osteoporosis. CONCLUSIONS: We demonstrated that transcriptome fine-mapping identifies more osteoporosis-related genes and provides key insight into the development of novel targeted therapeutics for the treatment of osteoporosis.

Cross-Beam Energy Transfer Saturation by Ion Heating.

We measure cross-beam energy transfer (CBET) saturation by ion heating in a gas-jet plasma characterized using Thomson scattering. A wavelength-tunable ultraviolet (UV) probe laser beam interacts with four intense UV pump beams to drive large-amplitude ion-acoustic waves. For the highest-intensity interactions, the power transfer to the probe laser drops, demonstrating ion-acoustic wave saturation. Over this time, the ion temperature is measured to increase by a factor of 7 during the 500-ps interaction. Particle-in-cell simulations show ion trapping and a subsequent ion heating consistent with measurements. Linear kinetic CBET models are found to agree well with the observed energy transfer when the measured plasma conditions are used.

Improving probiotic spore yield using rice straw hydrolysate.

Spore-forming Bacillus sp. has been extensively studied for their probiotic properties. In this study, an acid-treated rice straw hydrolysate was used as carbon source to produce the spores of Bacillus coagulans. The results showed that this hydrolysate significantly improved the spore yield compared with other carbon sources such as glucose. Three significant medium components including rice straw hydrolysate, MnSO4 and yeast extract were screened by Plackett-Burman design. These significant variables were further optimized by response surface methodology (RSM). The optimal values of the medium components were rice straw hydolysate of 27% (v/v), MnSO4 of 0·78 g l-1 and yeast extract of 1·2 g l-1 . The optimized medium and RSM model for spore production were validated in a 5 l bioreactor. Overall, this sporulation medium containing acid-treated rice straw hydrolysate has a potential to be used in the production of B. coagulans spores.

[One-stage surgery in patients with both cardiac and non-cardiac diseases].

OBJECTIVE: To investigate the possibility and feasibility of one-stage cardiac and non-cardiac surgery. METHODS: From July 1999 to August 2018, one hundred and eleven patients suffering from cardiac and non-cardiac diseases were treated by one-stage cardiac and non-cardiac operation in Department of Cardiac Surgery and Thoracic Surgery, General Surgery, Urinary Surgery, and Gynecology, Peking University First Hospital. There were 83 males (74.8%) and 28 females (25.2%), aged 41 to 84 years [mean age: (64.64±8.97) years]. The components of the cardiac disease included coronary heart disease, valvular heart disease, cardiac tumors, chronic constrictive pericarditis and congenital heart disease. The components of the non-cardiac diseases included lung benign and malignant diseases, thymoma and thymic cyst, breast cancer, chest wall giant hemangioma, digestive tract benign and malignant diseases, urinary system carcinoma and gynecological diseases. RESULTS: Two patients died after operations in hospital; thus, the hospital mortality rate was 1.8%. One patient died of multiple organ failure on the 153th days after emergency coronary artery bypass grafting (CABG) combined with radical resection of bladder cancer. The other of pericardium stripping with lung cancer operation died of the multiple organ failure on the tenth day after surgery. The remaining 109 patients recovered and were discharged. There were 13 cases of complications during the days in hospital. The total operative morbidity was 11.7%: postoperative hemorrhage in 2 cases (1.8%), pulmonary infection and hypoxemia in 3 cases (2.7%), hemorrhage of upper digestive tract in 1 case (0.9%), incisional infection in 3 cases (2.7%), subphrenic abscess in 1 case (0.9%), and postoperative acute renal failure and hemofiltration in 3 case (2.7%). Of the 109 patients discharged, 108 patients were followed up. All the patients survived for 6 months, and 21 patients died due to tumor recurrence or metastasis within 1 to 5 years of follow-up, but no cardiogenic death. During the follow-up period, 1 patient developed cardiac dysfunction, 1 patient underwent percutaneous coronary intervention (PCI), 1 patient had cerebral hemorrhage due to excessive postoperative anticoagulation, and 1 patient suffered from incisional hernia. CONCLUSION: One-stage surgeries in patients suffering from both cardiac and non-cardiac benign or malignant diseases are safe and possible with satisfactory short-term and long-term survival.

Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study.

BACKGROUND: The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A-F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). RESULTS: Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%-71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). CONCLUSION: Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02622074.

Reconstruction and analysis of the aberrant lncRNA-miRNA-mRNA network in systemic lupus erythematosus.

OBJECTIVE: A new perspective of determining the pathophysiology of systemic lupus erythematosus (SLE) development is required. The current study explores the aberrant expression of long non-coding RNAs (lncRNA), microRNA (miRNA) and mRNA. The study further constructs and analyses the lncRNA-miRNA-mRNA network to elucidate their gene regulation roles in SLE. METHOD: We extracted mRNA, lncRNA and miRNA from the whole venous blood of 20 SLE patients and 20 normal control (NC) healthy individuals. A lncRNA-mRNA-miRNA network in SLE was constructed using a bioinformatics approach. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using the Cytoscape plug-in BinGo, the DAVID database and Cytoscape software to explore the function of mRNAs in this network. RESULT: A total of 855 mRNA, 7311 lncRNA and 134 miRNA with differentially expressed profiles were identified. Meanwhile, we established a competing endogenous RNA (ceRNA) subnetwork composed of 52 differentially expressed lncRNAs (DElncRNAs), seven differentially expressed miRNAs and 10 differentially expressed mRNAs. We extracted the subnetwork from the ceRNA network and found that three novel miRNAs were key: hsa-miR-145, hsa-miR-17 and hsa-miR-143. We also deduced that the DElncRNAs MIAT and NEAT1 might play crucial roles in the pathogenesis of SLE. The results were verified by bioinformatics analysis. CONCLUSION: Our results provide a novel perspective for studying lncRNA-related and miRNA-related ceRNA networks in SLE.

MicroRNA-142-3p attenuates hepatic ischemia/reperfusion injury via targeting of myristoylated alanine-rich C-kinase substrate.

MiR-142-3p as one key molecule in oncogenesis and inflammation plays crucial roles in hepatic fibrosis, hepatocellular carcinoma and other liver disease. However, there have no literatures to report its effects on hepatic ischemia-reperfusion (HI/R) injury. In the present work, hypoxia reoxygenation (H/R) models on AML12 and HepG2 cells, and ischemia/reperfusion model in mice were established. The methods of real-time PCR, dual luciferase reporter, mimic, inhibitor, agomir, antagomir and siRNA transfection assays were used. The expression levels of miR-142-3p were decreased in model groups in vitro and in vivo compared with control group or Sham group, which directly targeted MARCKS to regulate its expression. Then, MARCKS activated p38/JNK signal, up-regulated NF-κB expression to accelerate inflammation, and inhibited PI3K/AKT signal to promote apoptosis. Moreover, miR-142-3p mimic in vitro and agomir in vivo lowered the expression levels of MARCKS, thereby alleviating apoptosis and inflammation to relieve HI/R injury. Furthermore, miR-142- 3p inhibitor in vitro and antagomir in vivo up-regulated the expression levels of MARCKS to aggravate HI/R damage via promoting inflammation and apoptosis. Consistently, MARCKS siRNA markedly inhibited HI/R injury by restraining apoptosis and inflamm- ation in mice. MiR-142-3p played a considerable part in adjusting HI/R injury by targeting MARCKS, and miR-142-3p/MARCKS should be a new therapeutic target for HI/R injury.

MicroRNA-27a-3p aggravates renal ischemia/reperfusion injury by promoting oxidative stress via targeting growth factor receptor-bound protein 2.

Renal ischemia-reperfusion (RI/R) injury with high morbidity and mortality is one common clinical disease. Development of drug targets to treat the disorder is critical important. MiR-27a-3p plays important roles in regulating oxidative stress. However, its effects on RI/R injury have not been reported. In this paper, hypoxia/reoxygenation (H/R) models on NRK-52E and HK-2 cells, and RI/R model in C57BL/6 mice were established. The results showed that H/R in vitro decreased cell viability and increased ROS levels in cells, and RI/R caused renal injury and oxidative damage in mice. The expression levels of miR-27a-3p were up-regulated based on real-time PCR and FISH assays in model groups compared with control groups, which directly targeted Grb2 based on dual luciferase reporter assay and co-transfaction test. In addition, miR-27a- 3p markedly reduced Grb2 expression to down-regulate the expression levels of p-PI3K, p-AKT, Nrf2, HO-1, and up-regulate Keap1 expression in model groups. MiR-27a-3p mimics in vitro enhanced H/R-caused oxidative stress via increasing ROS levels and decreasing Grb2 expression to down-regulate PI3K-AKT signal. In contrary, miR-27a-3p inhibitor in vitro significantly reduced H/R-caused oxidative damage via decreasing ROS levels and increasing Grb2 expression to up-regulate PI3K-AKT signal. In vivo, miR-27a- 3p agomir exacerbated RI/R-caused renal damage by decreasing SOD level and increasing Cr, BUN, MDA levels via suppressing Grb2 expression to down-regulate PI3K- AKT signal. However, miR-27a -3p antagomir alleviated RI/R-caused oxidative damage via increasing Grb2 expression to up-regulate PI3k-AKT signal. Grb2siRNA in mice further enhanced RI/R-caused renal injury by increasing Cr, BUN, MDA levels and decreasing SOD level via inhibiting the expression levels of Grb2, Nrf2, HO-1, and increasing Keap1 expression. Our data showed that miR-27a-3p aggravated RI/R injury by promoting oxidative stress via targeting Grb2, which should be considered as one new drug target to treat RI/R injury.

MiR-20b is implicated in preeclampsia progression via the regulation of myeloid cell leukemin-1.

Preeclampsia (PE) may induce gestational failure, threatening a significant number of pregnant women. Recently, microRNAs (miRNAs) have been reported to participate in PE progression, whereas the precise functions and potential mechanisms of miR-20b in placental trophoblast cells as well as in PE progression remain poorly understood. In the present study, real-time quantitative polymerase chain reaction (RT-qPCR) analysis was used to detect expressions of miR-20b and myeloid cell leukemin- 1(MCL-1) mRNA. Cell viability was investigated by cell counting kit-8(CCK-8) assays. Cell invasion and migration abilities were determined by Transwell assays. Western blot was performed to detect MCL-1 protein expressions. The interaction between miR-20b and MCL-1 was investigated by bioinformatics analysis and luciferase activity assay. The results of the study demonstrated that miR-20b was highly expressed in placental tissues of patients with PE. Moreover, miR-20b overexpression inhibited HTR8/ SVneo cell proliferation, invasion and migration. Furthermore, MCL-1 was targeted by miR-20b, and MCL-1 restoration could partially attenuate the effect of miR-20b on HTR8/SVneo cells. In conclusion, the results indicate that miR-20b may contribute to PE through inhibiting proliferation, invasion and migration of placental trophoblast cells by targeting MCL-1. Therefore, miR-20b may be used as a notable biomarker for the diagnosis, prevention, and treatment of PE. MiR-20b targeting MCL-1 deserves further investigation in order to explore their potential role in PE.

[Whole genomic copy number variation score: an indicator of potential diagnostic and prognostic value for lung adenocarcinoma].

Objective: To verify the value of whole genomic copy number variation (WGCNV) detection and scoring system in the diagnosis and prognosis of lung adenocarcinoma. Methods: Seventy-six lung adenocarcinoma specimens including ninety-one tumor samples and twenty adjacent non-tumor lung tissue samples were collected using Laser capture microdissection (LCM). Whole genomic amplification (WGA) was used to enrich DNA and construct a sequencing library for next generation sequencing (NGS). Changes of larger than 5Mb CNV in this study were analyzed and scored. The nuclear grading and score of tumor cells in the surgery and pleural effusion cytology of lung adenocarcinoma specimens were evaluated separately. For each case, we evaluated (1) nuclear size, (2) mitotic counts, (3) nuclear atypia, (4) atypical mitoses. The data of disease-free survive (DFS) and overall survive (OS) were collected for assessing the prognostic value of WGCNV score. Meanwhile, receiver operating characteristic (ROC) and area under curve (AUC) were used to define a cut-off value and evaluate the diagnostic significance in lung adenocarcinoma. Results: The WGCNV scores of twenty adjacent non-tumor lung tissue samples were treated as normal control and all of WGCNV scores of tumor samples range from 0 to 9.95, the median score was 2.7. The WGCNV scores were divided into three groups: low score group <1.74, medium score grade 1.74~4.23, high score grade >4.23. The WGCNV score was positively associated with the nuclear grade scoring (r=0.780 90, P<0.001). The result for evaluation of prognostic value of the WGCNV scores showed that comparing with low WGCNV score group, Hazard Ratio (HR) of medium score group was 4.11 (95%CI=0.72~23.57) and high score group was 2.07 (95%CI=0.30~14.12). These results suggested that the risks of the medium and high WGCNV score group elevated. According to the analysis results of ROC curve, when the cut off value was 0.01, the sensitivity and specificity for lung adenocarcinoma diagnosis were 97.8% and 95.0% respectively, the positive predictive value (PPV) and negative predictive value (NPV) were 99.0% and 90.1%, respectively, the AUC was 0.981. In the differentiation of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) group and invasive adenocarcinoma group, when the cut off value was 1.8, the sensitivity and specificity between the two groups were 78.1% and 94.4%, and the PPV and NPV were 98.0% and 52.0%, respectively, the AUC was 0.896. Conclusion: This study verifies that WGCNV scoring system has a potential diagnostic and prognostic value in lung adenocarcinoma.