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The primary goal of an exploratory oncology clinical trial is to identify an effective drug for further development. To expedite the drug development process and increase the chance of finding acti...

Background It has been demonstrated that ischemic preconditioning (IPC), and ischemic postconditioning (IPost) have a significant protective effect on myocardial ischemia/reperfusion (MI/R) injury by alleviating oxidative stress and mitochondrial disturbances, although the underlying molecular mechanisms are not clear. To demonstrate that cardioprotection against anoxia/reoxygenation (A/R) injury is transduced via the Notch1/Hes1/VDAC1 signaling pathway. Methods Using proteomics techniques, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and tandem affinity purification (TAP), to screen for differentially expressed proteins associated with Hes1, followed by standard bioinformatics analysis. The co-immunoprecipitation (Co-IP) assay confirmed an interaction between Hes1 and VDAC1 proteins. H9c2 cells were transfected with Hes1 adenoviral N-terminal TAP vector (AD-NTAP/Hes1) and Hes1-short hairpin RNA adenoviral vector (AD-Hes1-shRNA) to establish A/R injury, ischemic preconditioning (IPC), and ischemic postconditioning (IPost) models, respectively. The expression of Hes1 and VDAC1 proteins were measured by western blotting, while the levels of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and apoptosis were evaluated by flow cytometry. Results AD-NTAP/Hes1 can activate the exogenous protein expression of Hes1, thus decreasing creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) activity and promoting cell viability. The study found that VDAC1 was a potential target protein for Hes1 and the overexpression of Hes1 protein expression downregulated protein expression levels of VDAC1, reduced ROS production, stabilized ΔΨm, and inhibited apoptosis in H9c2 cells. Additionally, downregulation of Hes1 protein expression also upregulated VDAC1 protein expression, increased ROS production, imbalanced ΔΨm, promoted cell apoptosis, and attenuated the cardioprotection afforded by IPC and IPost. Conclusions The Notch1/Hes1 signaling pathway activated by IPC/IPost can directly downregulate the protein expression of VDAC1 and consequently relieve A/R injury.

Pulmonary arterial hypertension (PAH) is a fatal disease whose molecular mechanism is unknown. The trimethylation of lysine 36 on histone 3 (H3K36me3) catalyzed by SETD2 and the modification of N6-methyladenine (m6A) mRNA mediated by METTL14 play important roles in a variety of normal and pathological biological processes. However, the role of these epigenetic controls in the pathogenesis of PAH remains unclear. In this study, the expression of SETD2 and METTL14 was elevated in pulmonary artery smooth muscle cells (PASMCs) of hypoxia-induced PAH mice. We further constructed a mouse model with SETD2 specific knockout in smooth muscle cells (SETD2SM22α Cre). Our results suggest that the lack of SETD2 in SMCs protected mice from hypoxia-induced PAH and significantly reduced right ventricular systolic pressure (RVSP), right ventricular/left ventricular plus septum [RV/(LV+S)] weight ratio, and pulmonary median width. In addition, the absence of SETD2 in SMCs alleviates the level of METTL14 expression and the m6A RNA methylation level in PAH SMCs. These results obtained from mice suggest that strategies that target the inhibition of SETD2/METTL14 activity may be a viable treatment for PAH in a clinical setting.

Myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) is a subtype of MDS/MPN that exhibits a combination of the features of both MDS and MPN. To date, no curative treatment is available for MDS/MPN-U; however, previous studies have suggested a potential survival advantage for ruxolitinib and hypomethylating agents. We reported a case of a JAK2-negative but KRAS-positive MDS/MPN-U patient treated with ruxolitinib plus decitabine. After treatment, the patient's clinical symptoms were moderated, and the size of the spleen and the peripheral blood cell counts were reduced. These effects might be due to the regimen's ability to reduce STAT5 activation and upregulate microRNA-181c to downregulate the variant allele frequency (VAF) of KRAS.

Increased expression and activity of cardiac and circulating cathepsin D and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) have been demonstrated to induce and promote peripartum cardiomyopathy (PPCM) via promoting cleavage of 23‐kD prolactin (PRL) to 16‐kD PRL and neutralizing vascular endothelial growth factor (VEGF), respectively. We hypothesized that activation of Hes1 is proposed to suppress cathepsin D via activating Stat3, leading to alleviated development of PPCM. In the present study, we aimed to investigate the role of Notch1/Hes1 pathway in PPCM. Pregnant mice between prenatal 3 days and postpartum 3 weeks were fed with LY‐411575 (a notch inhibitor, 10 mg/kg/d). Ventricular function and pathology were evaluated by echocardiography and histological analysis. Western blotting analysis was used to examine the expression at the protein level. The results found that inhibition of Notch1 significantly promoted postpartum ventricular dilatation, myocardial hypertrophy and myocardial interstitial fibrosis and suppressed myocardial angiogenesis. Western blotting analysis showed that inhibition of Notch1 markedly increased cathepsin D and sFlt‐1, reduced Hes1, phosphorylated Stat3 (p‐Stat3), VEGFA and PDGFB, and promoted cleavage of 23k‐D PRL to 16‐kD PRL. Collectively, inhibition of Notch1/Hes1 pathway induced and promoted PPCM via increasing the expressions of cathepsin D and sFlt‐1. Notch1/Hes1 was a promising target for prevention and therapeutic regimen of PPCM.

Background Contemporary Phase I oncology trials often include efficacy expansion in various tumor indications post dose finding. Preliminary anti-tumor activity from efficacy expansion can aid Go/No-Go decision for Phase 2 or Phase 3 initiation. Tumor cohorts in efficacy expansion are commonly analyzed independently in practice, which are often underpowered due to small sample size. Pooled analysis is also sometimes conducted, but it ignores the heterogeneity of the anti-tumor activity across cohorts. Methods We propose an optimal one-stage design and analysis strategy for the efficacy expansion to assess whether the treatment is effective. Allowing heterogeneous anti-tumor effects across tumor cohorts, inactive cohorts are pruned, and the potentially active cohorts are pooled together to gain study power. For a prospective design with a target power, the total sample size across all cohorts is minimized; or for an ad hoc analysis with pre-specified sample size for each cohort, the pruning criteria are optimized to achieve maximum power. The global type I error is controlled after proper multiplicity adjustment, and a penalty adjusted significance level is used for the pooled test. Results Simulation studies show that the proposed optimal design has desirable operating characteristics in increasing the overall power and detecting more true positive tumor cohorts. Conclusion The proposed optimal design and analysis strategy provides a practical approach to design and analyze heterogeneous efficacy expansion cohorts in a basket setting with global type I and type II error being controlled.

Aortic dissection (AD) is a catastrophic cardiovascular emergency with a poor prognosis, and little preceding symptoms. Abnormal lipid metabolism is closely related to the pathogenesis of AD. However, comprehensive lipid alterations related to AD pathogenesis remain unclear. Moreover, there is an urgent need for new or better biomarkers for improved risk assessment and surveillance of AD. Therefore, an untargeted lipidomic approach based on ultra-high-performance liquid chromatograph-mass spectrometry was employed to unveil plasma lipidomic alterations and potential biomarkers for AD patients in this study. We found that 278 of 439 identified lipid species were significantly altered in AD patients (n = 35) compared to normal controls (n = 32). Notably, most lipid species, including fatty acids, acylcarnitines, cholesteryl ester, ceramides, hexosylceramides, sphingomyelins, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylcholines, phosphatidylinositols, diacylglycerols, and triacylglycerols with total acyl chain carbon number ≥54 and/or total double bond number ≥4 were decreased, whereas phosphatidylethanolamines and triacylglycerols with total double bond number

PURPOSEWe evaluated the activity of intratumoral Coxsackievirus A21 (V937) in 57 patients with unresectable stage IIIC or IV melanoma.PATIENTS AND METHODSIn this multicenter, open-label, phase II study, patients received up to a total V937 dose of 3 × 108TCID50(50% tissue culture infectious dose) in a maximum 4.0-mL volume by intratumoral injection. Ten sets of V937 injections were administered between days 1 and 127 ( NCT01227551 ). Patients who had stable disease or were responding could continue treatment in an extension study ( NCT01636882 ). Response and progression status were based on contrast-enhanced computed tomography, magnetic resonance imaging, or caliper measurement and were categorized using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Other evaluations included monitoring of adverse events and serum levels of V937 and anti-V937 antibody titers. The primary efficacy end point was 6-month progression-free survival (PFS) rate per irRECIST.RESULTSThe primary efficacy end point, 6-month PFS rate per irRECIST, was 38.6% (95% CI, 26.0 to 52.4). Durable response rate (partial or complete response for ≥ 6 months) was 21.1% per irRECIST. Best overall response rate (complete plus partial response) was 38.6% (unconfirmed) and 28.1% (confirmed) per irRECIST. Regression of melanoma was observed in noninjected lesions. Based on Kaplan-Meier estimation, 12-month PFS was 32.9% (95% CI, 19.5 to 46.9) per irRECIST and 12-month overall survival was 75.4% (95% CI, 62.1 to 84.7). No treatment-related grade ≥ 3 adverse events occurred. Viral RNA was detected in serum within 30 minutes of administration. Neutralizing antibody titers increased to > 1:16 in all patients after day 22, without effect on clinical or immunologic response.CONCLUSIONV937 was well tolerated and warrants further investigation for treatment of patients with unresectable melanoma. Studies of combination approaches with V937 and immune checkpoint inhibitors are ongoing.

Thalassemia and myeloproliferative neoplasias (MPNs) are recognized as two separate diseases. Thalassemia is a hemolytic disease caused by abnormal goblin genes, which results in the deficiency of globin chains. MPNs are clonal hematopoietic stem cell diseases characterized by the proliferation of multiple myeloid lineages. The coexistence of thalassemia and myeloproliferative neoplasia are rarely reported. We herein describe a case of a 24-year-old woman, previously diagnosed as β-thalassemia, with a lifelong history of thrombocytosis. She was subsequently diagnosed as low-risk essential thrombocythemia (ET), one of the MPNs. The patient was treated with folic acid supplementation and Iron-chelating therapy, without aspirin or cytoreductive therapy. Up to date, no thrombotic events or disease-related bleeding are happening to the patient, who remains in good health. Furthermore, we found three novel genes mutations EP300, CUX1, and FGFR3 after next-generation sequencing. We presume that the mutations of these genes in β-thalassemia might have an impact on the happening of ET and therefore need further investigations.

To determine the incidence, risk factors, and relative survival of acute myeloid leukemia (AML) secondary to myelodysplastic syndrome (MDS) in the Surveillance, Epidemiology, and End Results (SEER) database. Retrospective analysis of all patients with new MDS onset in the SEER‐18 database from 2001 to 2013. We identified 36 558 patients with primary MDS. The rate of secondary AML (sAML) was 3.7% among patients 40 years or younger and 2.5% among those older than 40 (P = .039). The median transformation interval was significantly shorter for the younger group (4.04 vs 13.1 mo; P < .001). For both age groups, median overall and cancer‐specific survival were significantly longer for patients who did not develop sAML. Although the younger patients survived longer than the older patients, sAML development had a more negative effect on the survival of younger patients. Female sex, age, and World Health Organization (WHO) type MDS with single lineage dysplasia (MDS‐SLD) were associated with a decreased risk of sAML for older but not younger patients. Among older patients with MDS, a married status, Black race, female sex, shorter time to sAML, and WHO type MDS‐SLD or MDS with ringed sideroblasts were favorable prognostic factors for survival. In the SEER database, the rate of sAML among patients with MDS is lower than that in previous reports, but these patients still have worse survival. Risk assessment should include clinical and demographic factors.

Background Immune thrombocytopenia (ITP) is an immune-mediated acquired autoimmune hemorrhagic disease. About one-third of patients are unresponsive to first-line therapies. Thalidomide (THD) as an immunomodulatory agent is now used to treat several autoimmune disorders. Therefore, we assessed the safety and efficacy of THD in corticosteroid-resistant or relapsed ITP patients, and preliminarily explore its mechanism. Methods 50 newly-diagnosed ITP patients and 47 healthy volunteers were enrolled in this study. Additionally, 17 corticosteroid-resistant or relapsed ITP patients were recruited, with 7 cases in the rhTPO + THD group and 10 cases in the THD monotherapy group. Overall response rate at 6, 12, and 24 months were assessed. Levels of Neuropilin-1(NRP-1), regulatory T cells (Tregs) and regulatory B cells (Bregs) were detected. Results Expression of NRP-1, Tregs and Bregs were reduced in newly-diagnosed ITP patients. In vitro, THD treatment upregulated expression of NRP-1and Tregs only in ITP patients. As for corticosteroid-resistant or relapsed ITP patients, overall response rate at 6, 12, and 24 months was 85.7%, 57.1% and 100% in the rhTPO + THD group and 60%, 75% and 83.3% in the THD group, respectively. Additionally, rhTPO plus THD or THD therapy significantly increased the levels of NRP-1, Tregs and Bregs in responders. Conclusions Our study shows for the first time that NRP-1 is involved in the pathogenesis of ITP, THD could induce response in ITP patients by upregulating NRP-1 expression and restoring the proportion of Tregs and Bregs. THD might be served as a novel therapeutic agent in corticosteroid-resistant or relapsed ITP patients.

Nuclear receptor binding SET domain 2 (NSD2)-mediated metabolic reprogramming has been demonstrated to regulate oncogenesis via catalyzing the methylation of histones. The present study aimed to investigate the role of NSD2-mediated metabolic abnormality in pulmonary arterial hypertension (PAH). Monocrotaline (MCT)-induced PAH rat model was established and infected with adeno-associated virus carrying short hairpin RNA (shRNA) targeting NSD2. Hemodynamic parameters, ventricular function, and pathology were evaluated by microcatheter, echocardiography, and histological analysis. Metabolomics changes in lung tissue were analyzed by LC–MS. The results showed that silencing of NSD2 effectively ameliorated MCT-induced PAH and right ventricle dysfunction, and partially reversed pathological remodeling of pulmonary artery and right ventricular hypertrophy. In addition, the silencing of NSD2 markedly reduced the di-methylation level of H3K36 (H3K36me2 level) and inhibited autophagy in pulmonary artery. Non-targeted LC–MS based metabolomics analysis indicated that trehalose showed the most significant change in lung tissue. NSD2-regulated trehalose mainly affected ABC transporters, mineral absorption, protein digestion and absorption, metabolic pathways, and aminoacyl-tRNA biosynthesis. In conclusion, we reveal a new role of NSD2 in the pathogenesis of PAH related to the regulation of trehalose metabolism and autophagy via increasing the H3K36me2 level. NSD2 is a promising target for PAH therapy.

BACKGROUND For initial respiratory management, continuous positive airway pressure (CPAP) is increasingly used for preterm infants, especially for gestational age less than 32 weeks. However, neonatologists are concerned about the potential risks of CPAP support failure. OBJECTIVES To examine the association between different initial respiratory support modalities and the outcomes of preterm infants at

Hepatocellular carcinoma (HCC) is the most common cancer and its prognosis is poor due to metastasis and recurrence. EMT is associated with metastasis. A deep understanding of regulatory mechanism of EMT is critical. LncRNA is involved in regulation of various biological processes including EMT. This study aimed to investigate the regulatory signal axis among lncRNA SNHG12, miR-516a-5p and the target gene HEG1 during EMT. Cell cycle and apoptosis were analyzed by flow cytometry. Tumorigenesis was analyzed by clone formation assay. Wound healing assay and transwell assay was performed to detect migration and invasion, respectively. Interaction among SNHG12, miR-516a-5p and HEG1 were analyzed by dual luciferase assay and RIP assay. We also detected expression of RNA and protein by QPCR and western blotting. Finally, tumor growth was analyzed by tumorigenesis assay in vivo. Ki-67 and HEG1 level in tumor tissues was analyzed by IHC. SNHG12 and HEG1 were upregulated, miR-516a-5p was downregulated in HCC cell lines. SNHG12 could interact with and inhibit miR-516a-5p. MiR-516a-5p could interact with HEG1 and inhibit HEG1 expression. Knock down SNHG12 inhibited proliferation, migration, invasion, EMT and promoted apoptosis of HCC cells. Such effects were antagonized by inhibiting miR-516a-5p. SNHG12 overexpression lead to opposite results. Similar results were observed in mice. SNHG12 could promote EMT in HCC through targeting and inhibiting miR-516a-5p, which eventually upregulated HEG1 expression, in both cell and mice.

A 54 year old male, with multiple diseases(such as severe obesity, severe edema, atrial fibrillation, high atrioventricular block, global enlargement (lA55mm LV 62mm RA 69*55mm RV 46mm)), was diagnosed as heart failure with preserved ejection fraction (HFpEF). After treatment with drugs and implanting permanent cardiac pacemaker, the patient’s edema completely disappeared, weight loss of 42kg, heart failure symptoms disappeared left ventricular shrinkage (LV 59mm).

An unprecedented number of new cancer targets are in development, and most are being developed in combination therapies. Early oncology development is strategically challenged in choosing the best combinations to move forward to late stage development. The most common early endpoints to be assessed in such decision-making include objective response rate, duration of response and tumor size change. In this paper, using independent-drug-action and Bliss-drug-independence concepts as a foundation, we introduce simple models to predict combination therapy efficacy for duration of response and tumor size change. These models complement previous publications using the independent action models (Palmer 2017, Schmidt 2020) to predict progression-free survival and objective response rate and serve as new predictive models to understand drug combinations for early endpoints. The models can be applied to predict the combination treatment effect for early endpoints given monotherapy data, or to estimate the possible effect of one monotherapy in the combination if data are available from the combination therapy and the other monotherapy. Such quantitative work facilitates strategic planning and decision making in early stage oncology drug development.

This paper points out the significance of cooling in injection molding and briefly reviews the development of cooling systems. The focus of this survey is on the physical model, development, and optimization of conformal cooling systems which have curved cooling circuits following the shape of mold cavity. Compared with traditional cooling systems, conformal cooling can greatly reduce the warpage defect and shorten the cooling cycle time. The computational design methods and additive manufacturing techniques that prompt the development of conformal cooling are deeply investigated. At the end of this survey, the future perspectives for conformal cooling design and manufacturing are discussed.

rRecently, novel drugs like venetoclax plus 5-azacytidine (VA) were reported to have promising efficacy in refractory acute myeloid leukemia (AML). However, there are still some cases presented with novel drugs resistance, and its genetics composition and clinical phenotype are urging to study. We described a 58-year-old patient who was resistant to intensive chemotherapy. This refractory AML was presented with the persistence of RUNX1, IDH1 and DNMT3A mutations. RUNX1 mutations disappeared and leukemia cutis ensued after multiple chemotherapies. Leukemia cutis exhibited NRAS mutations in addition to IDH1 and DNMT3A mutations. With the VA salvage treatment, platelets were recovered to the normal level and blasts in bone marrow and peripheral blood were moderately controlled. However, leukemia cutis did not resolve. Unexpectedly, BM blasts obtained the new NRAS mutations after VA treatment, and consequently experienced leukostasis with two distinct leukemia clones. After survival of 230 days, this patient died because of spontaneous cerebral hemorrhage. This case highlights presentation of leukemia cutis with simultaneous mutations of IDH1, DNMT3A and NRAS in AML patients might act as a resistant niche to avoid the toxicity of multiple drugs including VA. There is unmet need to validate this result in the clinical trials or a large cohort of patients in the future.

Wilson’s disease (WD) is an autosomal recessive disease caused by mutation of the ATPase copper transporting β (ATP7B) gene, resulting in abnormal copper metabolism. We aimed to investigate the protective effect of GanDouLing (GDL) on neural stem cell (NSC) function in a mouse model of WD. NSCs were treated with different concentrations of GDL alone or in combination with penicillamine, following which we evaluated cellular growth, apoptosis, and differentiation. Nuclear factor E2-related factor 2 (Nrf2) pathway and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation were analyzed via Western blotting. Treatment with GDL alone or in combination with penicillamine significantly increased proliferation and inhibited apoptosis of NSCs in a dose-dependent manner. In addition, GDL treatment remarkably promoted differentiation of NSCs. Consistently, levels of class III β-tubulin (Tuj1) and microtubule-associated protein 2 (MAP2) were significantly elevated, whereas glial fibrillary acidic protein (GFAP) levels were obviously suppressed in the presence of GDL or penicillamine. In vivo assays confirmed that GDL increased the ratio of Ki67+, Tuj1+, and MAP2+ cells and suppressed apoptosis in the hippocampal region in WD mice. Behavioral assays revealed that both GDL and penicillamine improved memory ability in WD models. Mechanistically, GDL treatment led to activation of Nrf2 signaling and suppression of the NLRP3 inflammasome in WD mice. Notably, inhibition of Nrf2 signaling reversed the protective effects of GDL on hippocampal NSCs. Collectively, these findings demonstrate that GDL exerts a protective effect on NSCs and promotes neurogenesis by targeting Nrf2 signaling and the NLRP3 inflammasome in WD.

In patients with chronic kidney disease, the abnormal activation of inflammatory pathways is usually an important factor leading to renal fibrosis and further deterioration of renal function. Finding effective intervention targets of the inflammatory signaling pathway is an important way to treat chronic kidney disease. As a newly discovered lysosomal membrane protein, the correlation between SID1 transmembrane family member 2 (Sidt2) and the inflammatory signaling pathway has not been reported. The aim of this study was to investigate the effect of Sidt2 on inflammation by inhibiting the expression of the Sidt2 gene in a mouse mesangial cell line mediated by a lentiviral CRISPR/Cas9 vector. Hematoxylin and eosin staining and microscopy found that the mesangial cells lost their normal morphology after inhibiting the expression of Sidt2, showing that the cell body became smaller, the edge between the cells was unclear, and part of the nucleus was pyknotic and fragmented, appearing blue-black. The expressions of IKK β, p-IKK α/β, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the NF-κB pathway of the Sidt2-/- group were higher than those of the Sidt2+/+ group. p-Jak2 and IL6 increased in the Jak/Stat pathway, and p-ERK and p-P38 increased in the MAPK pathway. The expressions of IKK β, p-IKK α/β, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the NF-κB pathway of the Sidt2+/++LPS group were significantly higher than those in the Sidt2+/+ group. The expressions of IKK β, p-IKK α/β, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the Sidt2-/-+LPS group were higher than those in the Sidt2-/- group. The expressions of p-IKK α/β, NF-κB p65, p-NF-κB p65, p-IκBα, IκBα, and TNF-α in the Sidt2-/-+LPS group were higher than those in the Sidt2+/++LPS group. In the Jak/Stat pathway, the protein expressions of p-Jak2 and IL6 in the Sidt2+/++LPS group were higher than those in the Sidt2+/+ group. The expressions of p-Jak2 and IL6 in the Sidt2-/-+LPS group were higher than those in the Sidt2-/- group. The expressions of p-Jak2 and IL6 in the Sidt2-/-+LPS group were higher than those in the Sidt2+/++LPS group. The expressions of p-JNK, p-ERK, p-P38, and ERK in the MAPK pathway in the Sidt2+/++LPS group were higher than those in the Sidt2+/+ group. The expressions of p-JNK, p-ERK, p-P38, and ERK in the Sidt2-/-+LPS group were higher than those in the Sidt2-/- group. The expressions of p-JNK, p-ERK, p-P38, and ERK in the Sidt2-/-+LPS group were higher than those in the Sidt2+/++LPS group. These data suggested that deletion of the Sidt2 gene changed the three inflammatory signal pathways, eventually leading to the damage of glomerular mesangial cells in mice.

The present study aimed at investigating the relationship between the shape and size of ablation zone and the ablation time during radiofrequency ablation (RFA) at different tip temperatures (80, 85, 90, and 95 °C). A two-dimensional simulation model of liver RFA using single-electrode was first built by finite element method (FEM). A closed-loop proportional-integral (PI) controller was employed in the FEM model. The heat transfer issues were solved based on Pennes biological equation. To improve simulation accuracy of the FEM models, temperature-dependent forms of the electrical conductivity and the thermal conductivity were adopted in the model. The ablation zone was assessed by 54 °C isothermal contour (IT54). The ablation zone sizes obtained from the numerical simulations and ex vivo experiments were compared to evaluate the validity of the numerical model. All the four tip temperatures (80, 85, 90, and 95 °C) were tested using 3 ex vivo porcine livers respectively. According to numerical simulation results, the characterization functions of the ablation volume and the ablative margin (AM) were derived. The proposed curve functions could precisely characterize the shape and size of ablation zone at different preset tip values, and the statistical results showed that the prediction curves had a good consistency with simulation curves. This paper proposed the prediction models of the ablation zone in the RFA process, which could be used to achieve accurate planning of RFA needle placements and optimize patient care during temperature-controlled RFA therapy.

BackgroundThe objective of this prospective, multicentre, observational cohort study was to evaluate the association between admission hypothermia and neonatal outcomes in very low-birth weight (VLBW) infants in multiple neonatal intensive care units (NICUs) in China.MethodsSince January 1, 2018, a neonatal homogeneous cooperative research platform-Shandong Neonatal Network (SNN) has been established. The platform collects clinical data in a prospective manner on preterm infants with birth weights (BWs) ResultsA total of 1247 VLBW infants were included in this analysis, of which 1100 infants (88.2%) were included in the hypothermia group, 554 infants (44.4%) in the mild hypothermia group and 546 infants (43.8%) in the moderate/severe hypothermia group. Small for gestational age (SGA), caesarean section, a low Apgar score at 5 min and intubation in the delivery room (DR) were related to admission hypothermia (AH). Mortality was the lowest when their admission temperature was 36.5 ~ 37.5 °C, and after adjustment for maternal and infant characteristics, mortality was significantly associated with AH. Compared with infants with normothermia (36.5 ~ 37.5 °C), the adjusted ORs of all deaths increased to 4.148 (95%CI1.505–11.437) and 1.806 (95%CI0.651–5.009) for infants with moderate/severe hypothermia and mild hypothermia, respectively. AH was also associated with a high likelihood of respiratory distress syndrome (RDS), intraventricular haemorrhage (IVH), and late-onset neonatal sepsis (LOS).ConclusionsAH is still very high in VLBW infants in NICUs in China. SGA, caesarean section, a low Apgar score at 5 min and intubation in the DR were associated with increased odds of hypothermia. Moderate/severe hypothermia was associated with mortality and poor outcomes, such as RDS, IVH, LOS.

Mitochondrial quality control is a new target for myocardial protection. Notch signaling plays an important role in heart development, maturation, and repair. However, the role of Notch in the myocardial mitochondrial quality control remains elusive. In this study, we isolated myocardial cells from rats and established myocardial ischemia reperfusion injury (IRI) model. We modulated Notch1 expression level in myocardial cells via infection with recombinant adenoviruses Ad-N1ICD and Ad-shN1ICD. We found that IR reduced myocardial cells viability, but Notch1 overexpression increased the viability of myocardial cells exposed to IRI. In addition, Notch1 overexpression improved ATP production, increased mitochondrial fusion and decreased mitochondrial fission, and inhibited mitophagy in myocardial cells exposed to IRI. However, N1ICD knockdown led to opposite effects. The myocardial protection role of Notch1 was related to the inhibition of Pink1 expression and Mfn2 and Parkin phosphorylation. In conclusion, Notch1 exerts myocardial protection and this is correlated with the maintenance of mitochondrial quality control and the inhibition of Pink1/Mfn2/Parkin signaling.

Histone lysine methylation plays an important role in the regulation of ventricular remodelling. NSD2 is involved in many types of tumours through enhancing H3K36me2 expression. However, the role of NSD2 in the regulation of histone lysine methylation during ventricular remodelling remains unclear. In this study, we established cardiac hypertrophy model in C57BL/6 mice by transverse aortic constriction and found that histone lysine methylation participated in ventricular remodelling regulation via the up‐regulation of H3K27me2 and H3K36me2 expression. In addition, we constructed transgenic C57BL/6 mice with conditional knockout of NSD2 (NSD2−/−) in the myocardium. NSD2−/− C57BL/6 mice had milder ventricular remodelling and significantly improved cardiac function compared with wild‐type mice, and the expression of H3K36me2 but not H3K27me2 was down‐regulated. In conclusion, NSD2 promotes ventricular remodelling mediated by the regulation of H3K36me2.

Previous studies have reported that genes relating to JAK-STAT pathway (IFIH1, TYK2 and IL-10) conferred the susceptibility to SLE. In this study, we performed a meta-analysis (including 43 studies) to evaluate the association between IFIH1 (9288 patients and 24,040 controls), TYK2 (4928 patients and 11,536 controls), IL-10 (3623 patients and 4907 controls) polymorphisms and systemic lupus erythematosus (SLE) in a comprehensive way. We found that IFIH1 rs1990760_T allele was associated with risk of SLE in overall population under three models (allelic: P = 2.56 × 10−11, OR 1.135, 95% CI 1.094–1.179, dominant: P = 1.8 × 10−8, OR 1.203, 95% CI 1.128–1.284, recessive: P = 2.6 × 10−7, OR 1.163, 95% CI 1.098–1.231). A strong association had been observed between TYK2 polymorphism rs2304256_C allele and SLE in Europeans (P = 5.82 × 10−5, OR 1.434, 95% CI 1.203–1.710). When coming to overall population, TYK2 rs2304256_C showed a significant association with SLE under recessive model (P = 8.05 × 10−3, OR 1.314, 95% CI 1.074–1.608). However, the other two SNPs (rs12720270, rs280519) of TYK2 were not significant. The results also indicated an association between IL-10 rs1800896_G allele and SLE in Asians under recessive model (P = 4.65 × 10−3, OR 2.623, 95% CI 1.346–5.115), while, IL-10 rs1800896_G had a trend of association with SLE in European population in dominant model (P = 1.21 × 10−2, OR 1.375, 95% CI 1.072–1.764). In addition, we found IL-10 rs1800896 GG homozygote might be associated with increased susceptibility to SLE (GG vs AA, P = 4.65 × 10−3, OR 1.539, 95% CI 1.142–2.072). We concluded that IFIH1 rs1990760_T and TYK2 rs2304256_C alleles were significantly associated with SLE, and IL-10 rs1800896 GG homozygote might have an enhancement effect on SLE risk.

Symptoms of disseminated intravascular coagulation (DIC) include thromboembolism, acute attrition bleeding and multiple organ failure. Genistein isolated from leguminous plants has been shown to be effective in oxidation resistance and tumor inhibition. The present study was designed to evaluate the therapeutic effects of genistein in DIC and preliminarily discuss the mechanisms regarding the anti-inflammatory and anticoagulant effect of genistein. Swiss mice were randomly divided into the following groups-(1) lipopolysaccharide (LPS), (2) genistein, (3) dimethyl sulfoxide (DMSO, the non-major solvent component of genistein), (4) DMSO + LPS, (5) saline control group, and (6) heparin control group. LPS was injected intraperitoneally in all the groups except the DMSO group and saline control group. Our results significantly showed that the morphological structure of the liver and kidneys was improved and the fiber protein deposition was decreased, with remarkable improvement of coagulation indicators, function indicators and inflammatory factors in the genistein treatment group compared with the LPS group. In vitro phosphorylated-nuclear factor kappa-light-chain-enhancer of activated B cells and interleukin-6 were obviously reduced in the genistein treatment group compared with the LPS group in RAW 264.7 murine macrophage cells. All the results suggested that genistein has the function of alleviating and treating LPS-induced DIC by anti-inflammatory and anticoagulation effects. We tentatively propose that genistein is a potential drug for auxiliary treatment of DIC.

Currently, the role of Notch signaling during myocardial infarction (MI) remains controversy. In this study we used in vitro and in vivo approaches to investigate the role of Notch signaling in MI. Using cultured human umbilical vein endothelial cells exposed to hypoxia/reoxygenation (H/R), we demonstrated that H/R inhibited the proliferation, VEGF secretion, and tube formation of HUVECs, and these effects were correlated with the inhibition of Notch signaling. Furthermore, these effects were antagonized by overexpression of NICD but aggravated by knockdown of NICD. In addition, in MI model rats we found that heart dysfunction and angiogenesis in model rats was partly improved by NICD overexpression but was aggravated by knockdown of NICD. In conclusion, these data demonstrate that Notch signaling is downregulated in H/R injury in the hearts. Artificial activation of Notch signaling could promote myocardial survival and angiogenesis and improve cardiac function following H/R injury.

Myocardial fibrosis after myocardial infarction (MI) is a leading cause of heart diseases. MI activates cardiac fibroblasts (CFs) and promotes CF to myofibroblast transformation (CMT). This study aimed to investigate the role of miR‐21 in the regulation of CMT and myocardial fibrosis. Primary rat CFs were isolated from young SD rats and treated with TGF‐β1, miR‐21 sponge or Jagged1 siRNA. Cell proliferation, invasion and adhesion were detected. MI model was established in male SD rats using LAD ligation method and infected with recombinant adenovirus. The heart function and morphology was evaluated by ultrasonic and histological analysis. We found that TGF‐β1 induced the up‐regulation of miR‐21 and down‐regulation of Jagged1 in rat CFs. Luciferase assay showed that miR‐21 targeted 3′‐UTR of Jagged1 in rat CFs. miR‐21 sponge inhibited the transformation of rat CFs into myofibroblasts, and abolished the inhibition of Jagged1 mRNA and protein expression by TGF‐β1. Furthermore, these effects of miR‐21 sponge on rat CFS were reversed by siRNA mediated knockdown of Jagged1. In vivo, heart dysfunction and myocardial fibrosis in MI model rats were partly improved by miR‐21 sponge but were aggravated by Jagged1 knockdown. Taken together, these results suggest that miR‐21 promotes cardiac fibroblast‐to‐myofibroblast transformation and myocardial fibrosis by targeting Jagged1. miR‐21 and Jagged1 are potential therapeutic targets for myocardial fibrosis.

Background This study aims to investigate the effects of exogenous interleukin (IL)-37 on the biological characteristics of human lung adenocarcinoma A549 cells and the chemotaxis of regulatory T (Treg) cells. Methods After isolating the CD4+ CD25+ Treg cells from the peripheral blood, flow cytometry was used to detect the purity of the Treg cells. A549 cells were divided into blank (no transfection), empty plasmid (transfection with pIRES2-EGFP empty plasmid) or IL-37 group (transfection with pIRES2-EGFP-IL-37 plasmid). RT-PCR was used to detect mRNA expression of IL-37 and ELISA to determine IL-37 and MMP-9 expressions. Western blotting was applied to detect the protein expressions of PCNA, Ki-67, Cyclin D1, CDK4, cleaved caspase-3 and cleaved caspase-9. MTT assay, flow cytometry, scratch test and transwell assay were performed to detect cell proliferation, cycle, apoptosis, migration and invasion. Effect of exogenous IL-37 on the chemotaxis of Treg cells was measured through transwell assay. Xenograft models in nude mice were eastablished to detect the impact of IL-37 on A549 cells. Results The IL-37 group had a higher IL-37 expression, cell apoptosis in the early stage and percentage of cells in the G0/G1 phase than the blank and empty plasmid groups. The IL-37 group had a lower MMP-9 expression, optical density (OD), percentage of cells in the S and G2/M phases, migration, invasion and chemotaxis of CD4+CD25+ Foxp3+ Treg cells. The xenograft volume and weight of nude mice in the IL-37 group were lower than those in the blank and empty plasmid groups. Compared with the blank and empty plasmid groups, the IL-37 group had significantly reduced expression of PCNA, Ki-67, Cyclin D1 and CDK4 but elevated expression of cleaved caspase-3 and cleaved caspase-9. Conclusion Therefore, exogenous IL-37 inhibits the proliferation, migration and invasion of human lung adenocarcinoma A549 cells as well as the chemotaxis of Treg cells while promoting the apoptosis of A549 cells.

Acute promyelocytic leukemia (APL) remains a challenge to cure due to the side effects of cytotoxic chemotherapy and drug resistance. The present study demonstrated that vernodalol, an active compound isolated from Centratherum anthelminticum, suppresses APL cell proliferation and induces cell cycle arrest in the G2/M phase through the upregulation of p21 and cell division cycle 25. In addition, vernodalol induced cellular apoptosis via the mitochondrial pathway as observed by the cleavage of caspase-9 as well as the release of cytochrome c and Smac/DIABLO into the cytosol. A mechanistic study revealed that vernodalol may exert its antitumor activity through the suppression of phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin signaling. In conclusion, vernodalol may be developed as a potential therapeutic compound for the treatment of APL.

Air quality in the Chinese urban areas has been worsened severely in the past few years and serious haze problems have been experienced frequently. Here, filter-contained urban updraft tower (FUUT) is proposed to be an approach to govern the air pollution and generate electricity. Due to buoyancy with the help of urban heat island (UHI), the air with air pollution can flow into the tower, and the air pollution mainly being particulate matters less than 10 µm in diameter (PM 10 ) is then intercepted by the filter. FUUTs are assumed to be introduced in the typical metropolitan city in China, i.e., Beijing in 2012, and then the methods to predict the performance and estimate the health and economic benefits are established. Under these conditions, the design value of air velocity in FUUT is 5.00 m/s. The initial yearly mean PM 10 concentration is 109 µg/m 3 , and the reduction is 6.72 µg/m 3 in the first year brought by one FUUT, which contributes to the reduction in premature mortality to 227.8 and in respiratory hospital admissions to 1051.9 and the equivalent economic benefits estimated to be 211.48 million RMB yuan in total. It would take 3.45, 7.81, and 13.22 years to meet the second- and first- class China national ambient air quality standards (CNAAQS), and the standard regulated by the World Health Organization (WHO) guideline. Furthermore, the economic capability analyses of FUUT, including the levelized electricity cost (LEC) and return on investment (ROI) on different factors, are also conducted.

Caffeine is neuroprotective in animal models of PD and caffeine intake is inversely associated with the risk of Parkinson’s disease (PD). This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p = 0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD.

Radiofrequency ablation (RFA) and microwave ablation (MWA) have become an important means for treating liver tumors. RFA and MWA are a minimally invasive therapy which involves an ablation applicator or needle (i.e., radiofrequency electrode or microwave antenna) inserted percutaneously into a tumor under the guidance of medical imaging, so as to destroy the tumor in situ by heating-induced coagulation necrosis. Treatment planning, particularly needle trajectory planning, is crucial to RFA and MWA. In clinical procedures, however, needle trajectory planning still relies on the personal experience of clinicians. Manual needle trajectory planning is tedious and may cause inter-operator difference. Therefore, computer-assisted needle trajectory planning techniques are of clinical value and have been extensively explored. However, a literature review that focuses on computer-assisted needle trajectory planning for liver tumor RFA and MWA has not been reported. In this paper, we conducted an extensive review on computer-assisted needle trajectory planning for RFA and MWA of liver tumors. Fundamentals of needle trajectory planning are summarized. Algorithms for single-needle and multi-needle trajectory planning are analyzed. Shortcomings of current computer-assisted needle trajectory planning algorithms are discussed and future developments are suggested.

Mitochondrial fusion and fission dynamic are critical to the myocardial protection against ischaemia‐reperfusion injury. Notch1 signalling plays an important role in heart development, maturation and repair. However, the role of Notch1 in the myocardial mitochondrial fusion and fission dynamic remains elusive. Here, we isolated myocardial cells from rats and established myocardial ischaemia‐reperfusion injury (IRI) model. We modulated Notch1, MFN1 and DRP1 expression levels in myocardial cells via infection with recombinant adenoviruses. The results showed that Notch1 improves the cell viability and mitochondrial fusion in myocardiocytes exposed to IRI. These improvements were dependent on the regulation of MFN1 and DRP1. On the mechanism, we found that MNF1 is transcriptionally activated by RBP‐Jk in myocardiocytes. Notch1 also improves the mitochondrial membrane potential in myocardiocytes exposed to IRI. Moreover, we further confirmed the protection of the Notch1‐MFN1/Drp1 axis on the post‐ischaemic recovery of myocardial performance is associated with the preservation of the mitochondrial structure. In conclusion, this study presented a detailed mechanism by which Notch1 signalling improves mitochondrial fusion during myocardial protection.

Breast microcalcifications are one of the important imaging features of early breast cancer and are a key to early breast cancer diagnosis. Ultrasound imaging has been widely used in the detection and diagnosis of breast diseases because of its low cost, nonionizing radiation, and real-time capability. However, due to factors such as limited spatial resolution and speckle noise, it is difficult to detect breast microcalcifications using conventional B-mode ultrasound imaging. Recent studies show that new ultrasound technologies improved the visualization of microcalcifications over conventional B-mode ultrasound imaging. In this paper, a review of the literature on the ultrasonic detection methods of microcalcifications was conducted. The reviewed methods were broadly divided into high-frequency B-mode ultrasound imaging techniques, B-mode ultrasound image processing techniques, ultrasound elastography techniques, time reversal techniques, high spatial frequency techniques, second-order ultrasound field imaging techniques, and photoacoustic imaging techniques. The related principles and research status of these methods were introduced, and the characteristics and limitations of the various methods were discussed and analyzed. Future developments of ultrasonic breast microcalcification detection are suggested.

Research has suggested that individuals with greater dispositional mindfulness (i.e., nonjudgmental, present-focused attention) are more likely to quit smoking, but the underlying mechanisms are unclear. This study investigated mechanisms linking mindfulness and early smoking abstinence using ecological momentary assessment (EMA). Participants were 355 smokers (33% Caucasian, 33% African American, 32% Latino; 55% female) receiving smoking cessation treatment. Mindfulness was assessed at baseline and on the quit date. For 4 days prequit and 1 week postquit, participants completed up to 4 EMAs per day indicating levels of negative affect (NA), positive affect (PA), smoking urges, and affect regulation expectancies. Mean, slope, and volatility were calculated for each prequit and postquit EMA variable. Associations among mindfulness, EMA parameters, and abstinence on the quit day and 7 days postquit, as well as indirect effects of mindfulness on abstinence through EMA parameters, were examined. Mindfulness predicted higher odds of abstinence in unadjusted but not covariate-adjusted models. Mindfulness predicted lower NA, higher PA, and lower affective volatility. Lower stress mediated the association between mindfulness and quit-day abstinence. Higher ratings of happy and relaxed, and lower ratings of bored, sad, and angry, mediated the association between mindfulness and postquit abstinence. Mindfulness appeared to weaken the association between craving and postquit abstinence. This study elucidates real-time, real-life mechanisms underlying dispositional mindfulness and smoking abstinence. During the early process of quitting smoking, more mindful individuals appeared to have more favorable emotional profiles, which predicted higher likelihood of achieving abstinence 1 week after the quit date. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death worldwide. Despite recent advances in imaging techniques and therapeutic intervention for HCC, the low overall 5-year survival rate of HCC patients remains unsatisfactory. This study aims to find a gene signature to predict clinical outcomes in HCC. Methods Bioinformatics analysis including Cox’s regression analysis, Kaplan-Meier (KM) and receiver operating characteristic curve (ROC) analysis and the random survival forest algorithm were performed to mine the expression profiles of 553 hepatocellular carcinoma (HCC) patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) public database. Results We selected a signature comprising eight protein-coding genes (DCAF13, FAM163A, GPR18, LRP10, PVRIG, S100A9, SGCB, and TNNI3K) in the training dataset (AUC = 0.77 at five years, n = 332). The signature stratified patients into high- and low-risk groups with significantly different survival in the training dataset (median 2.20 vs. 8.93 years, log-rank test P P = 0.004, n = 221, GSE14520). Further multivariate Cox regression analysis showed that the signature was an independent prognostic factor for patients with HCC. Compared with TNM stage and another reported three-gene model, the signature displayed improved survival prediction power in entire dataset (AUC signature = 0.66 vs. AUC TNM = 0.64 vs. AUC gene model = 0.60, n = 553). Stratification analysis shows that it can be used as an auxiliary marker for many traditional staging models. Conclusions We constructed an eight-gene signature that can be a novel prognostic marker to predict the survival of HCC patients.

Purpose: Wilson’s disease (WD) is a genetic disorder of copper metabolism with pathological copper accumulation in the brain. The purpose of the present study was to evaluate the relationship between the damaged white matter and the impaired cognitive function in WD patients. Materials and methods: Thirty WD adolescents and thirty age- and sex-matched healthy controls (HC) were enrolled. All subjects had received brain MRI, including conventional and diffusion-tensor imaging (DTI) scans. The DTI parameter of fractional anisotropy (FA) was calculated by diffusion kurtosis estimator software. The t test was used to compare the differences between two groups. The correlation between cognitive function and whiter matter disorders were analyzed by linear regression. The results of FA parameter and MD parameter intergroup analysis were both corrected with False Discovery Rate (FDR) simulations by SPSS. Results: WD adolescents showed significantly lower scores of time-based prospective memory (TBPM) and verbal fluency test (VFT) compared with HC. We found significantly higher FA in the right thalamus, right lentiform nucleus, left thalamus, left lentiform nucleus, and brain stem in WD adolescents. Besides, WD adolescents exhibited significantly lower FA in right cerebellum and cingulum and left middle frontal lobe compared with controls (P

Background: Coxsackievirus A21 (V937) is an RNA oncolytic virus targeting ICAM-1 receptors. Pharmacodynamic effects of oncolytic viruses in the tumor microenvironment (TME), including increased CD8+ T cells and PD-L1 expression, support their use in combination with checkpoint inhibitors. We present updated clinical and correlative data from the multicenter phase 1b CAPRA study (NCT02565992) of V937 + pembro in pts with advanced melanoma. Methods: Eligible pts had metastatic/unresectable stage IIIB-IV melanoma and ≥1 cutaneous/subcutaneous tumor or lymph node amenable to V937 intratumoral injection. Pts received V937 on days 1, 3, 5, and 8; then Q3W for up to 19 injections (maximum dose, 3 × 108 50% TCID50). Pts received IV pembro 2 mg/kg Q3W on day 8, continuing for up to 2 y. Primary endpoints were incidence of AEs, serious AEs (SAEs), and dose-limiting toxicities (DLTs). Secondary endpoints were ORR, duration of response (DOR), PFS, and OS. Biomarkers were an exploratory endpoint. Results: 36 pts were enrolled (mean age, 68.5 y; 75% male; 22% had prior immunotherapy). As of 4 Nov 2019, median (range) time from first dose to data cutoff was 32.0 (10.7−45.3) mo. No DLTs occurred. Grade 3-5 treatment-related AEs occurred in 5 (14%) pts. 3 (8%) pts had treatment-related SAEs (autoimmune encephalitis and septic shock in 1 pt, keratoacanthoma, autoimmune hepatitis); 1 died from septic shock. Efficacy results included ORR of 47% (CR, 22%; PR, 25%; Table 1). In comparing responders vs nonresponders, baseline tumor samples showed no difference in PD-L1 expression and lower CD3+CD8- infiltrate in responders. Conclusions: V937 + pembro had manageable safety and promising efficacy in pts with advanced melanoma. Response was not associated with an inflamed TME at baseline, indicating that V937 may induce an immune responsive TME. The combination is being studied in the neoadjuvant setting in pts with stage III melanoma (KEYMAKER-U02). Table 1.Efficacy OutcomesV937 + Pembro (N = 36)ORR,a % (95% CI)b47 (30-65)- CR22 (10-39)- PR25 (12-42)DOR,c median (range), moNR (1.4+ to 22.0+)PFS,c,d median (95% CI), mo11.9 (3.4-NR)12-mo PFS,c % (95% CI)45 (28-60)OS,c median (95% CI), mo30.9 (20.3-40.5)12-mo OS,c % (95% CI)85 (68-94)+ indicates no PD by the time of last disease assessment. NR, not reached.aBest overall response with confirmation based on investigator assessment per immune-related response criteria; imaging was performed Q6W.bBased on the exact method for binomial data.cKaplan-Meier estimate.dBased on investigator assessment per immune-related response criteria. Citation Format: Ann W. Silk, Steven J. O'Day, Howard L. Kaufman, Jennifer Bryan, Jacqueline T. Norrell, Casey Imbergamo, Daniella Portal, Edwin Zambrano-Acosta, Marisa Palmeri, Seymour Fein, Cai Wu, Leslie Guerreiro, Daniel Medina, Praveen K. Bommareddy, Andrew Zloza, Bernard A. Fox, Carmen Ballesteros-Merino, Darren Shafren, Mark Grose, Joshua A. Vieth, Janice M. Mehnert. Intratumoral oncolytic virus V937 in combination with pembrolizumab (pembro) in patients (pts) with advanced melanoma: Updated results from the phase 1b CAPRA study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT139.

Key Points Question Does duration of response (DOR), a rigorous metric combining both tumor responses and duration, better inform decisions about continuing or discontinuing before starting phase 3 immuno-oncology clinical trials? Findings This simulated modeling study, which was based on simulated randomized phase 2 trials that resampled patients from completed randomized phase 3 trials of immune checkpoint inhibitors, found that restricted mean DOR consistently outperformed progression-free survival and objective response rate in correctly estimating positive overall survival benefits without inflating type I errors. Meaning These findings suggest that restricted mean DOR may be a sensitive and informative early efficacy end point in randomized phase 2 trials in immuno-oncology., This simulated modeling study examines whether using restricted mean duration of response in phase 2 trials can better inform decisions about continuing or discontinuing before starting phase 3 immuno-oncology clinical trials compared with progression-free survival and objective response rate., Importance Phase 2 trials and early efficacy end points play a crucial role in informing decisions about whether to continue to phase 3 trials. Conventional end points, such as objective response rate (ORR) and progression-free survival (PFS), have demonstrated inconsistent associations with overall survival (OS) benefits in immune checkpoint inhibitor (ICI) trials. Restricted mean duration of response (DOR) is a rigorous metric that combines both response status and duration information. However, its utility in clinical development has not been comprehensively explored. Objective To determine whether using restricted mean DOR in phase 2 trials can advance promising regimens to phase 3 trials sooner and eliminate unfavorable regimens earlier and with a higher degree of confidence compared with PFS and ORR. Design, Setting, and Participants This simulated modeling study randomized phase 2 screening trials by resampling 1376 patients from 2 completed randomized phase 3 trials of ICIs. Data were analyzed from August 2019 to July 2020. Exposures Use of ICIs. Main Outcomes and Measures Restricted mean DOR, PFS, ORR, and OS were estimated and compared between groups. Three scenarios were considered: (1) significant differences in OS, PFS, and ORR; (2) significant differences in OS and noticeable differences in ORR but not PFS; and (3) no differences in OS, PFS, or ORR. For each setting, 5000 randomized phase 2 trials with different sample sizes were simulated, with additional censoring applied to mimic staggered accruals and ensure fair comparisons between different analysis methods. Probabilities of concluding positive phase 2 trials using PFS, ORR, and DOR were summarized and compared. Results The restricted mean DOR difference correctly estimated a positive OS benefit more frequently than did the ORR or PFS tests, across different sample sizes, significance levels, and censoring levels evaluated. When both OS and PFS differed, the ranges of true-positive or power rates were 79.2% to 98.7% for DOR, 56.3% to 93.2% for PFS, and 67.0% to 96.0% for ORR. When OS differed but PFS did not, the ranges of power rates were 24.0% to 76.0% for DOR, 3.0% to 19.0% for PFS, and 10.5% to 38.0% for ORR. When OS was similar, the false-positive rate of restricted mean DOR test was close to the chosen significance level. Conclusions and Relevance These findings suggest that restricted mean DOR in randomized phase 2 trials is potentially more sensitive and useful than PFS and ORR in estimating the subsequent phase 3 conclusions and, thus, may be considered to complementarily facilitate decision-making in future clinical development.

Doxorubicin (DOX) is a commonly used anticancer drug, but it is inefficient as a therapeutic due to a lack of targeting. Peptide-tuned self-assembly of DOX offers a strategy to improve targeting for greater efficacy. In this work, we designed and prepared an amphiphilic tumor cell-targeting peptide, P14 (AAAAFFFHHHGRGD), able to encapsulate DOX by self-assembly to form tumor cell-targeting and pH-sensitive nano-micelles. The results showed a critical P14-micelle concentration of 1.758 mg l−1 and an average particle size of micelles of 121.64 nm, with entrapment and drug-loading efficiencies of 28.02% ± 1.35% and 12.06% ± 0.59%, respectively. The prepared micelles can release 73.52 ± 1.27% DOX within 24 h in pH 4.5 medium, and the drug cumulative release profile of micelles can be described by the first-order model. Compared with free DOX, the micelles exhibited an increased ability to inhibit tumor cell growth and cause tumor apoptosis in vitro, with IC50 values of DOX and P14-DOX micelles against human breast cancer cells (MCF-7) of 0.91 ± 0.07 and 0.75 ± 0.06 μg ml−1, respectively, and cellular apoptotic rates of DOX and P14-DOX micelles of 70.3% and 42.4%, respectively. Cellular uptake experiments revealed high concentrations of micelles around and inside MCF-7 cells, demonstrating that micelles can target tumor cells. These results indicate the excellent potential for the application of this amphiphilic peptide as a carrier for small-molecule drugs and suggest a strategy for the design of effective anti-tumor drugs.

Paper spray mass spectrometry (PSMS) has been widely used for rapid analysis of complex samples, particularly in rapid analysis of clinical samples for point-of-care diagnostics. In this study, heating PSMS was developed for enhanced detection of propranolol in dried blood samples (DBS). Prepared DBS were first placed on an aluminum plate and organic solvent was added. The plate was then heated using a heating probe. Heating was revealed to play two roles in detection of propranolol in DBS: (1) improving the diffusion of propranolol from paper to solvent and (2) improving release of propranolol from protein–propranolol complex. Heating efficiency evaluated at different temperatures showed that detection of propranolol in DBS significantly improved (about 30 times) under optimized temperature. Using an isotopic internal standard, the limit of detection (LOD) and limit of quantitation (LOQ) of propranolol were found to be less than 0.4 ng mL−1 (S/N > 3) and less than 1 ng mL−1 (S/N > 10), respectively. The dynamic ranges of propranolol were found to be in the range of 1.0–500 ng mL−1 with an excellent correlation coefficient (R2 > 0.999). This method also showed good precision (5.2–18.5%, n = 5) and acceptable recovery (70.0–81.5%, n = 5). Furthermore, clinical DBS collected from volunteer patients before and after oral doses of propranolol were successfully analyzed. This study demonstrated that heating PSMS is a promising method for rapid detection of propranolol in DBS for point-of-care diagnostics.

Background: Halo nevus (HN) has been shown to be associated with vitiligo, but no standard signs are currently available to identify HN patients at risk of vitiligo, and the relevant data obtained in previous studies are somewhat conflicting. This study aimed to identify factors affecting the presence of vitiligo in HN patients. Methods: We performed a retrospective study on consecutive patients with HN at the First Affiliated Hospital of Sun Yat-sen University between January 2011 and December 2016. Detailed demographic and clinical data were collected to identify the factors associated with the presence of vitiligo in this cohort of patients using uni- and multi-variate logistic regression analyses. Results: A total of 212 HN patients were included, 101 of whom had vitiligo-associated HN (HNV). Univariate analysis indicated that a personal history of thyroid diseases was positively associated with HNV (odds ratio [OR] = 10.761, P = 0.025), while the onset age of HN was negatively associated with HNV (OR = 0.537, P = 0.026). Multivariate analysis demonstrated that the Koebner phenomenon (KP; OR = 10.632, P < 0.0001), multiple HN (OR = 3.918, P < 0.0001), and a familial history of vitiligo (OR = 3.222, P = 0.014) were independent factors associated with HNV. Conclusions: HN without vitiligo has clinical features distinct from HN associated with vitiligo. HN patients with KP, multiple lesions, or familial history of vitiligo are more likely to develop vitiligo and therefore should be monitored for clinical signs of such accompanied conditions.

PM2.5 and PM10 samples were collected in a rural area from December 2014 to August 2015 near a coal-fired power plant on the southeast coast of China. The total mercury concentrations in PM2.5 ranged from 116.2 to 1070.9 pg/m3 and in PM10 from 173.4 to 1456.8 pg/m3, with averages of 309.5 ± 94.9 and 387.5 ± 133.5 pg/m3, respectively. These were much higher than those found in many foreign cities. The concentrations of mercury in PM2.5 and PM10 varied seasonally, with the highest average concentration in winter. This was probably due to the seasonal variation of meteorological conditions and concentration of particulates. The highest mass-based concentration of mercury in PM2.5 and PM10 was observed in spring. This result might be related to the prevailing sea winds in spring. The spatial variation of particulate mercury conformed to the concentration distribution characteristics of pollutant discharged from coal-fired power plant elevated source at the downwind area. The seasonal variation in the concentrations of the four mercury species (including exchangeable particulate mercury: EXPM, HCl-soluble particulate mercury: HPM, elemental particulate mercury: EPM, and residual particulate mercury: RPM) were all identical to the seasonal variation of total particulate mercury (TPM) in PM2.5 and PM10 (winter > spring > summer). Owing to the variation of meteorological conditions, the proportion of different mercury species in TPM followed different seasonal trends. In contrast to RPM, the percentage of both HPM and EPM in PM2.5 was higher than in PM10.

LncRNA-ROR has been reported to be involved in many kinds of human cancers. However, whether LncRNA-ROR is involved in gallbladder cancer progression remains largely unknown. The objective of this study is to investigate the role of LncRNA-ROR in gallbladder cancer. We found that LncRNA-ROR expression level was upregulated in gallbladder cancer tissues (P

Gallbladder carcinoma (GBC) is an aggressive neoplasm, and the treatment options for advanced GBC are limited. Recently, long non‐coding RNAs (lncRNAs) have emerged as new gene regulators and prognostic markers in several cancers. In this study, we found that metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) expression was up‐regulated in GBC tissues (P < 0.05). Luciferase reporter assays and RNA pull down assays showed that MALAT1 is a target of miR‐363‐3p. Real‐time quantitative PCR and Western blot analysis indicated that MALAT1 regulated Myeloid cell leukaemia‐1 (MCL‐1) expression as a competing endogenous RNA (ceRNA) for miR‐363‐3p in GBC cells. Furthermore, MALAT1 silencing decreased GBC cell proliferation and the S phase cell population and induced apoptosis in vitro. In vivo, tumour volumes were significantly decreased in the MALAT1 silencing group compared with those in the control group. These data demonstrated that the MALAT1/miR‐363‐3p/MCL‐1 regulatory pathway controls the progression of GBC. Inhibition of MALAT1 expression may be to a novel therapeutic strategy for gallbladder cancer.

Previous investigations demonstrated that Chinese wheat cv. Ning7840 confers a high level of broad-spectrum resistance to rusts and powdery mildew diseases at the adult plant stage mediated by a spontaneously occurring hypersensitive reaction-like phenotype (also called lesion mimic, LM). In this study, two EMS-induced mutants of cv. Ning7840, Dlm1 and Dlm2, showed the LM deficiency phenotype. These two mutants were susceptible to powdery mildew. At heading stage when the LM symptoms appear on the leaves of Ning7840, the RNAs were harvested from the flag leaves of Dlm1, Dlm2 and Ning7840 leaves and were sequenced to decipher the molecular mechanisms underlying LM phenotypes. The results suggest that the diterpenoid-related stress response acts as an indirect regulator of the LM phenotype and may be associated with broad-spectrum resistance in Ning7840. Oxidative phosphorylation, proteasome, and chlorophyll were involved in the suppression of the LM expression in the Dlm mutants. These results provide new insight into the molecular mechanism of LM and broad-spectrum resistance in wheat.