bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of Refractory Menstrual Bleeding in an Adolescent with Glanzmann Thrombasthenia: A Case Report and Review
Authors: King Luke J. , Huff Jessie , Heber Deidre , Miller Michal Ann , Marshall Brytanie
Published: September 2020

Glanzmann Thrombasthenia is a rare bleeding disorder causing life-threatening bleeding at menarche in the adolescent female. Bleeding often necessitates admission and multiple blood transfusions. Due to the rarity of the disease, management of acute bleeding in new-onset menarche poses a particular challenge. A 12-year-old menarchial female had persistent vaginal bleeding despite multiple treatment modalities including aminocaproic acid, recombinant factor VIIa, intravenous estrogen, and gonadotropin receptor hormone agonists. Although the standard treatment of bleeding in patients with GT is primarily rFVIIa, new-onset menstrual bleeding in conjunction with an immature hypothalamic-pituitary-ovarian axis often requires expanding treatment to include multiple drug modalities. In our case, a two-step approach was necessary. The first is targeting the cessation of the first menses. The second is optimizing ongoing management of long-term control of heavy menstrual bleeding to achieve amenorrhea, prevent further hospital admissions, and avoid recurrent transfusions.
Study of Wind Loads and Wind Speed Amplifications on High‐Rise Building with Opening by Numerical Simulation and Wind Tunnel Test
Authors: Chen Fu-Bin , Wang Xiao-Lu , Zhao Yun , Li Yuan-Bo , Li Qiu-Sheng , Xiang Ping , Li Yi
Published: September 2020

High‐rise buildings are very sensitive to wind excitations, and wind‐induced responses have always been the key factors for structural design. Facade openings have often been used as aerodynamic measures for wind‐resistant design of high‐rise buildings to meet the requirement of structural safety and comfort. Obvious wind speed amplifications can also be observed inside the openings. Therefore, implementing wind turbines in the openings is of great importance for the utilization of abundant wind energy resources in high‐rise buildings and the development of green buildings. Based on numerical simulation and wind tunnel testing, the wind loads and wind speed amplifications on high‐rise buildings with openings are investigated in detail. The three‐dimensional numerical simulation for wind effects on high‐rise building with openings was firstly carried out on FLUENT 15.0 platform by SST k − ε model. The mean wind pressure coefficients and the wind flow characteristics were obtained. The wind speed amplifications at the opening were analyzed, and the distribution law of wind speed in the openings is presented. Meanwhile, a series of wind tunnel tests were conducted to assess the mean and fluctuating wind pressure coefficients in high‐rise building models with various opening rates. The variation of wind pressure distribution at typical measuring layers with wind direction was analyzed. Finally, the wind speed amplifications in the openings were studied and verified by the numerical simulation results.
A Survey of Automatic Software Vulnerability Detection, Program Repair, and Defect Prediction Techniques
Authors: Shen Zhidong , Chen Si
Published: September 2020

Open source software has been widely used in various industries due to its openness and flexibility, but it also brings potential software security problems. Together with the large-scale increase in the number of software and the increase in complexity, the traditional manual methods to deal with these security issues are inefficient and cannot meet the current cyberspace security requirements. Therefore, it is an important research topic for researchers in the field of software security to develop more intelligent technologies to apply to potential security issues in software. The development of deep learning technology has brought new opportunities for the study of potential security issues in software, and researchers have successively proposed many automation methods. In this paper, these automation technologies are evaluated and analysed in detail from three aspects: software vulnerability detection, software program repair, and software defect prediction. At the same time, we point out some problems of these research methods, give corresponding solutions, and finally look forward to the application prospect of deep learning technology in automated software vulnerability detection, automated program repair, and automated defect prediction.
Simulation Parameter Test and Seepage Effect Analysis of Pile‐Anchor Support for Binary Slope
Authors: Gao Xuhe , Tian Weiping , Zhang Zhipei , Li Jiachun , Qi Hongliang
Published: September 2020

It is a difficult point in the field of geotechnical engineering to test the simulation parameters of the pile‐anchor supporting structure of slope excavation and analyze the effect of seepage on the stress of the structure. This study relies on the right side slope treatment project of a highway in Guizhou Province. Aiming at the defect that the current numerical simulation parameter selection is fuzzy, the deep displacement monitoring data and P value inspection method are used to check the simulation parameters. We establish a 2D finite element model of slope excavation and support. The superposition calculation method of pore water pressure was used to analyze the stress characteristics of the slope‐supporting structure after applying steady‐state seepage. The analysis shows the following. ① Initial support stage: the steady‐state seepage causes the axial force extreme value of the prestressed anchor cable to increase by 11.22% at this stage. ② Secondary support stage: the steady‐state seepage reduces the shear limit of the antislide pile by 3.11% and the bending moment by 14.90%. ③ Comparative analysis of the two supporting phases: the newly constructed pile‐anchor supporting structure has a significant effect on the original pile‐anchor supporting structure. At the same time, the bending and shearing resistance of the newly added antislide piles has not been fully exerted. The research results provide new ideas for the research on the safety control ability of the slope support construction process.
Experimental Investigation on Out‐of‐Plane Flexural and Shear Performance of Half Steel‐Concrete Slabs
Authors: Guo Quanquan , Zhang Peiyao , Yang Lieang
Published: September 2020

Half steel‐concrete slabs have been used in nuclear power plants and high‐rise buildings as floor and roof panels. In order to study the failure mechanism, fifteen one‐way Half‐SC slabs with different steel faceplate thicknesses, stud numbers, shear span ratios, and volume tie bar ratios were tested under three‐point or four‐point loading. Mid‐span deflections, strains of steel faceplate and concrete, and slippage between concrete and steel faceplate were measured. The result shows that Half‐SC slabs exhibited four types of failure mode: flexure, shear, balanced, and interface slippage failure. Flexural failure was initiated by the tensile yield of the steel plate and followed by concrete crushing, which was similar to reinforced concrete slabs. In shear failure, when the shear span ratio is greater than 1.5, the steel plate in the shear‐compression zone would achieve yield strength, and the ultimate failure is caused by the concrete crushing between the loading point and the support or by excessive plastic deformation of steel faceplate. This is significantly different from that of the reinforced concrete slabs. The increases in the volume tie bar ratio could postpone the occurrence of shear failure and even converted failure mode to flexural failure. The flexural strength was calculated. Based on a tie‐arch model, the calculation equation of shear strength was proposed. The calculated results agree well with the experimental data. Besides, these formulas were a good predictor of the transition between bending failure and shear failure with the shear span ratio.
Bearing Fault Diagnosis Based on Multilayer Domain Adaptation
Authors: Yang Bingru , Li Qi , Chen Liang , Shen Changqing , Natarajan Sundararajan
Published: September 2020

Bearing fault diagnosis plays a vitally important role in practical industrial scenarios. Deep learning-based fault diagnosis methods are usually performed on the hypothesis that the training set and test set obey the same probability distribution, which is hard to satisfy under the actual working conditions. This paper proposes a novel multilayer domain adaptation (MLDA) method, which can diagnose the compound fault and single fault of multiple sizes simultaneously. A special designed residual network for the fault diagnosis task is pretrained to extract domain-invariant features. The multikernel maximum mean discrepancy (MK-MMD) and pseudo-label learning are adopted in multiple layers to take both marginal distributions and conditional distributions into consideration. A total of 12 transfer tasks in the fault diagnosis problem are conducted to verify the performance of MLDA. Through the comparisons of different signal processing methods, different parameter settings, and different models, it is proved that the proposed MLDA model can effectively extract domain-invariant features and achieve satisfying results.
A Validated Liquid Chromatographic Method for Berberine Analysis in Tissue and Application
Authors: Zhou Neng , Liu Dangmei , Bao Xiaowang
Published: September 2020

Simple and rapid high-performance liquid chromatography methods were developed for the determination of berberine (BB) in various rat tissues so as to evaluate a P-gp inhibitor, glycyrrhetinic acid (GA), on BB’s oral bioavailability. Acetonitrile was used to extract BB from tissues and showed different extraction recoveries in diverse tissues. The intra- and interday precision and accuracy were less than 10%. Long-term stability, pre (post) -preparative stability, and freeze-thaw stability were evaluated, and the results showed it could meet the need of this study. The proposed methods were subsequently applied to investigate the possible drug-drug interaction of GA and BB in vivo from the aspect of tissue distribution. The results showed that no significant difference was found between the group of low dose and high dose at the same time point. The tissue distributions show a saturated model, i.e., the content of BB in tissue tends to be constant while its dose is more than 200 mg/kg. Besides, the contents of BB ranged from high to low according to the order of the liver, kidney, and spleen. The BB content in the liver is especially high as compared to other tissues.
Low-Pressure Membrane for Water Treatment Applications
Authors: AlFannakh Huda , Abdallah Heba , Ibrahim S. S. , Souayeh Basma
Published: September 2020

Three ultrafiltration membranes were prepared using phase separation techniques. The membranes were characterized by scan electron microscope, porosity, pore size distribution measurement, and mechanical properties. The membrane performance was carried out using synthetic solutions from humic acid and tap water to express the contaminated drinking water. The polyvinylidene difluoride (M2) has the highest tensile strength 33.2 MPa with elongation of 52.3%, while polyacrylonitrile (M3) has the lowest mechanical properties, tensile strength 16.4 MPa with elongation of 42.7%. Polyethersulfone membrane (M1) provides the highest removal of humic acid, which was 99.5, 98.8, and 98.2% using feed concentrations 0.1, 0.3, and 0.5 g/l, respectively, while M3 provides the highest permeate flux which was 250, 234.4, and 201.4 l/m2 h using feed concentrations 0.1, 0.3, and 0.5 g/l, respectively. Analysis of water samples indicates that the prepared membranes can be used to treat the contaminated drinking water which produced the high quality of drinking water after treatment.
Common Fixed Point Results for a Pair of Multivalued Mappings in Complex-Valuedb-Metric Spaces
Authors: Oyewole Olawale Kazeem , Aremu Kazeem Olalekan , Jolaoso Lateef Olakunle
Published: September 2020

Several fixed point results for the existence of common fixed points of multivalued contractive mappings have been established in complex-valued metric space. In this paper, we study the existence of common fixed points for a pair of multivalued contractive mappings satisfying some rational inequalities in the framework of complex-valuedb-metric spaces. The contractive condition used in this paper generalizes many contractive conditions used by other authors in the literature. Employing our results, we check the existence solution to the Riemann-Liouville equation.
β-Galactosylceramidase Promotes Melanoma Growth via Modulation of Ceramide Metabolism
Authors: Belleri Mirella , Paganini Giuseppe , Coltrini Daniela , Ronca Roberto , Zizioli Daniela , Corsini Michela , Barbieri Andrea , Grillo Elisabetta , Calza Stefano , Bresciani Roberto , Maiorano Eugenio , Mastropasqua Mauro G. , Annese Tiziana , Giacomini Arianna , Ribatti Domenico , Casas Josefina , Levade Thierry , Fabrias Gemma , Presta Marco
Published: September 2020

Disturbance of sphingolipid metabolism may represent a novel therapeutic target in metastatic melanoma, the most lethal form of skin cancer. β-Galactosylceramidase (GALC) removes β-galactose from galactosylceramide and other sphingolipids. In this study, we show that downregulation of galcb, a zebrafish ortholog of human GALC, affects melanoblast and melanocyte differentiation in zebrafish embryos, suggesting a possible role for GALC in melanoma. On this basis, the impact of GALC expression in murine B16-F10 and human A2058 melanoma cells was investigated following its silencing or upregulation. Galc knockdown hampered growth, motility, and invasive capacity of B16-F10 cells and their tumorigenic and metastatic activity when grafted in syngeneic mice or zebrafish embryos. Galc-silenced cells displayed altered sphingolipid metabolism and increased intracellular levels of ceramide, paralleled by a nonredundant upregulation of Smpd3, which encodes for the ceramide-generating enzyme neutral sphingomyelinase 2. Accordingly, GALC downregulation caused SMPD3 upregulation, increased ceramide levels, and inhibited the tumorigenic activity of human melanoma A2058 cells, whereas GALC upregulation exerted opposite effects. In concordance with information from melanoma database mining, RNAscope analysis demonstrated a progressive increase of GALC expression from common nevi to stage IV human melanoma samples that was paralleled by increases in microphthalmia transcription factor and tyrosinase immunoreactivity inversely related to SMPD3 and ceramide levels. Overall, these findings indicate that GALC may play an oncogenic role in melanoma by modulating the levels of intracellular ceramide, thus providing novel opportunities for melanoma therapy.

Significance:

Data from zebrafish embryos, murine and human cell melanoma lines, and patient-derived tumor specimens indicate that β-galactosylceramidase plays an oncogenic role in melanoma and may serve as a therapeutic target.
Transient Activation of the Hedgehog-Gli Pathway Rescues Radiotherapy-Induced Dry Mouth via Recovering Salivary Gland Resident Macrophages
Authors: Zhao Qingguo , Zhang Linying , Hai Bo , Wang Jun , Baetge Courtney L. , Deveau Michael A. , Kapler Geoffrey M. , Feng Jian Q. , Liu Fei
Published: September 2020

Irreversible hypofunction of salivary glands is a common side effect of radiotherapy for head and neck cancer and is difficult to remedy. Recent studies indicate that transient activation of Hedgehog signaling rescues irradiation-impaired salivary function in animal models, but the underlying mechanisms are largely unclear. Here, we show in mice that activation of canonical Gli-dependent Hedgehog signaling by Gli1 gene transfer is sufficient to recover salivary function impaired by irradiation. Salivary gland cells responsive to Hedgehog/Gli signaling comprised small subsets of macrophages, epithelial cells, and endothelial cells, and their progeny remained relatively rare long after irradiation and transient Hedgehog activation. Quantities and activities of salivary gland resident macrophages were substantially and rapidly impaired by irradiation and restored by Hedgehog activation. Conversely, depletion of salivary gland macrophages by clodronate liposomes compromised the restoration of irradiation-impaired salivary function by transient Hedgehog activation. Single-cell RNA sequencing and qRT-PCR of sorted cells indicated that Hedgehog activation greatly enhances paracrine interactions between salivary gland resident macrophages, epithelial progenitors, and endothelial cells through Csf1, Hgf, and C1q signaling pathways. Consistently, expression of these paracrine factors and their receptors in salivary glands decreased following irradiation but were restored by transient Hedgehog activation. These findings reveal that resident macrophages and their prorepair paracrine factors are essential for the rescue of irradiation-impaired salivary function by transient Hedgehog activation and are promising therapeutic targets of radiotherapy-induced irreversible dry mouth.

Significance:

These findings illuminate a novel direction for developing effective treatment of irreversible dry mouth, which is common after radiotherapy for head and neck cancer and for which no effective treatments are available.
Protein Arginine Methyltransferase 5 Promotes pICln-Dependent Androgen Receptor Transcription in Castration-Resistant Prostate Cancer
Authors: Beketova Elena , Fang Shuyi , Owens Jake L. , Liu Sheng , Chen Xufeng , Zhang Qingfu , Asberry Andrew M. , Deng Xuehong , Malola Jonathan , Huang Jiaoti , Li Chenglong , Pili Roberto , Elzey Bennett D. , Ratliff Timothy L. , Wan Jun , Hu Chang-Deng
Published: September 2020

The majority of advanced prostate cancer therapies aim to inhibit androgen receptor (AR) signaling. However, AR reactivation inevitably drives disease progression to castration-resistant prostate cancer (CRPC). Here we demonstrate that protein arginine methyltransferase 5 (PRMT5) functions as an epigenetic activator of AR transcription in CRPC, requiring cooperation with a methylosome subunit pICln. In vitro and in xenograft tumors in mice, targeting PRMT5 or pICln suppressed growth of CRPC cells. Full-length AR and AR-V7 transcription activation required both PRMT5 and pICln but not MEP50. This activation of transcription was accompanied by PRMT5-mediated symmetric dimethylation of H4R3 at the proximal AR promoter. Further, knockdown of PRMT5 abolished the binding of pICln (but not vice versa) to the AR proximal promoter region, suggesting that PRMT5 recruits pICln to the AR promoter to activate AR transcription. Differential gene expression analysis in 22Rv1 cells confirmed that PRMT5 and pICln both regulate the androgen signaling pathway. In addition, PRMT5 and pICln protein expression positively correlated with AR and AR-V7 protein expression in CRPC tissues and their expression was highly correlated at the mRNA level across multiple publicly available CRPC datasets. Our results suggest that targeting PRMT5 or pICln may be explored as a novel therapy for CRPC treatment by suppressing expression of AR and AR splice variants to circumvent AR reactivation.

Significance:

This study provides evidence that targeting PRMT5 can eliminate expression of AR and can be explored as a novel therapeutic approach to treat metastatic hormone-naïve and castration-resistant prostate cancer.
Targeting the PI3K/mTOR Pathway Augments CHK1 Inhibitor–Induced Replication Stress and Antitumor Activity in High-Grade Serous Ovarian Cancer
Authors: Huang Tzu-Ting , Brill Ethan , Nair Jayakumar R. , Zhang Xiaohu , Wilson Kelli M. , Chen Lu , Thomas Craig J. , Lee Jung-Min
Published: September 2020

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G2–M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC.

Significance:

Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development.
Rafting Down the Metastatic Cascade: The Role of Lipid Rafts in Cancer Metastasis, Cell Death, and Clinical Outcomes
Authors: Greenlee Joshua D. , Subramanian Tejas , Liu Kevin , King Michael R.
Published: September 2020

Lipid rafts are tightly packed, cholesterol- and sphingolipid-enriched microdomains within the plasma membrane that play important roles in many pathophysiologic processes. Rafts have been strongly implicated as master regulators of signal transduction in cancer, where raft compartmentalization can promote transmembrane receptor oligomerization, shield proteins from enzymatic degradation, and act as scaffolds to enhance intracellular signaling cascades. Cancer cells have been found to exploit these mechanisms to initiate oncogenic signaling and promote tumor progression. This review highlights the roles of lipid rafts within the metastatic cascade, specifically within tumor angiogenesis, cell adhesion, migration, epithelial-to-mesenchymal transition, and transendothelial migration. In addition, the interplay between lipid rafts and different modes of cancer cell death, including necrosis, apoptosis, and anoikis, will be described. The clinical role of lipid raft–specific proteins, caveolin and flotillin, in assessing patient prognosis and evaluating metastatic potential of various cancers will be presented. Collectively, elucidation of the complex roles of lipid rafts and raft components within the metastatic cascade may be instrumental for therapeutic discovery to curb prometastatic processes.
Validity Coefficient of Repeated Measurements of Urinary Marker of Sugar Intake Is Comparable to Urinary Nitrogen as Marker of Protein Intake in Free-living Subjects
Authors: Abreu Taymara C. , Hulshof Paul J.M. , Boshuizen Hendriek C. , Trijsburg Laura , Gray Nicola , de Vries Jeanne H.M.
Published: September 2020

Background:

Studies do not show consistent relationships between self-reported intake of sugar and outcome of disease. To overcome the drawbacks of self-reported intake methods, we investigated whether there is an agreement in ranking of individuals between their self-reported sugar intake and urinary sucrose and fructose.

Methods:

We used data of 198 Dutch adults (106 women) from the DUPLO study. Sugar intake of all foods and drinks consumed over 24-hour period was estimated by collecting duplicate portions (DP) and 24-hour recalls (24hR), telephone (24hRT) and Web-based (24hRW), while sugar excretion was based on 24-hour urine samples. Sugar content of 24hR was calculated using a newly developed sugar database and sugar content of DPs and urine samples was calculated using high-performance liquid chromatography–atomic emission spectrometry and LC/MS-MS, respectively. Measurement error models assessed validity coefficients (VC) and attenuation factors (AF). Coefficients were compared with those of protein biomarker.

Results:

The VC for the marker, using DP as reference, showed comparability with substantially better ranking of participants (0.72 for women and 0.93 for men), than 24hRT (0.57 and 0.78) or 24hRW (0.70 and 0.78) as reference in the sucrose models. The VC of the sucrose models was within 10% of the protein models, except for the model with 24hRT as reference, among women. The AF started at higher values and increased by a greater factor compared with the VC.

Conclusions:

Repeated measurements of urinary sucrose and fructose as a marker of daily sucrose intake had a ranking performance comparable to urinary nitrogen as marker of protein intake in free-living Dutch adults.

Impact:

The validation of the sugar biomarker in a free-living population with three different dietary assessment methods and its comparable ranking ability with a good recovery biomarker (i.e., protein biomarker) have important research applications. The biomarker may be used for validating dietary assessment methods, for monitoring compliance in human feeding studies, for monitoring the effect of public health interventions, and as a surrogate for ranking subjects according to sucrose intake when information on sucrose in food composition databases is lacking.
Estimating Population-Based Recurrence Rates of Colorectal Cancer over Time in the United States
Authors: Kunst Natalia , Alarid-Escudero Fernando , Aas Eline , Coupé Veerle M.H. , Schrag Deborah , Kuntz Karen M.
Published: September 2020

Background:

Population-based metastatic recurrence rates for patients diagnosed with nonmetastatic colorectal cancer cannot be estimated directly from population-based cancer registries because recurrence information is not reported. We derived population-based colorectal cancer recurrence rates using disease-specific survival data based on our understanding of the colorectal cancer recurrence-death process.

Methods:

We used a statistical continuous-time multistate survival model to derive population-based annual colorectal cancer recurrence rates from 6 months to 10 years after colorectal cancer diagnosis using relative survival data from the Surveillance, Epidemiology, and End Results Program. The model was based on the assumption that, after 6 months of diagnosis, all colorectal cancer–related deaths occur only in patients who experience a metastatic recurrence first, and that the annual colorectal cancer–specific death rate among patients with recurrence was the same as in those diagnosed with de novo metastatic disease. We allowed recurrence rates to vary by post-diagnosis time, age, stage, and location for two diagnostic time periods.

Results:

In patients diagnosed in 1975–1984, annual recurrence rates 6 months to 5 years after diagnosis ranged from 0.054 to 0.060 in stage II colon cancer, 0.094 to 0.105 in stage II rectal cancer, and 0.146 to 0.177 in stage III colorectal cancer, depending on age. We found a statistically significant decrease in colorectal cancer recurrence among patients diagnosed in 1994–2003 compared with those diagnosed in 1975–1984 for 6 months to 5 years after diagnosis (hazard ratios between 0.43 and 0.70).

Conclusions:

We derived population-based annual recurrence rates for up to 10 years after diagnosis using relative survival data.

Impact:

Our estimates can be used in decision-analytic models to facilitate analyses of colorectal cancer interventions that are more generalizable.
Phase Ib Dose-escalation/Expansion Trial of Ribociclib in Combination With Everolimus and Exemestane in Postmenopausal Women with HR+, HER2− Advanced Breast Cancer
Authors: Bardia Aditya , Modi Shanu , Oliveira Mafalda , Cortes Javier , Campone Mario , Ma Brigette , Dirix Luc , Weise Amy , Hewes Becker , Diaz-Padilla Ivan , Han Yu , Deshpande Priya , Samant Tanay S. , Lorenc Karen Rodriguez , He Wei , Su Fei , Chavez-MacGregor Mariana
Published: September 2020

Purpose:

Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).

Patients and Methods:

Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.

Results:

Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug–drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.

Conclusions:

Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2− ABC.
A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia
Authors: Zeidan Amer M. , Ridinger Maya , Lin Tara L. , Becker Pamela S. , Schiller Gary J. , Patel Prapti A. , Spira Alexander I. , Tsai Michaela L. , Samuëlsz Errin , Silberman Sandra L. , Erlander Mark , Wang Eunice S.
Published: September 2020

Purpose:

The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase Ib study of the PLK1 inhibitor, onvansertib, in combination with either low-dose cytarabine (LDAC) or decitabine in patients with relapsed or refractory (R/R) AML.

Patients and Methods:

Onvansertib was administered orally, in escalating doses, on days 1–5 in combination with either LDAC (20 mg/m2; days 1–10) or decitabine (20 mg/m2; days 1–5) in a 28-day cycle. The primary endpoint was to evaluate first-cycle dose-limiting toxicities and the MTD. Secondary and exploratory endpoints included safety, pharmacokinetics, antileukemic activity, and response biomarkers.

Results:

Forty patients were treated with onvansertib (12–90 mg/m2) in combination with LDAC (n = 17) or decitabine (n = 23). Onvansertib was well tolerated with most grades 3 and 4 adverse events related to myelosuppression. In the decitabine arm, the MTD was established at 60 mg/m2, and 5 (24%) of the 21 evaluable patients achieved complete remission with or without hematologic count recovery. Decrease in mutant circulating tumor DNA (ctDNA) during the first cycle of therapy was associated with clinical response. Engagement of the PLK1 target, TCTP, was measured in circulating blasts and was associated with greater decrease in bone marrow blasts.

Conclusions:

The onvansertib and decitabine combination was well tolerated and had antileukemic activity particularly in patients with target engagement and decreased mutant ctDNA following treatment. This combination will be further investigated in the ongoing phase II trial.
An Antibody-Tumor Necrosis Factor Fusion Protein that Synergizes with Oxaliplatin for Treatment of Colorectal Cancer
Authors: Bajic Davor , Chester Kerry , Neri Dario
Published: September 2020

We have cloned and characterized a novel fusion protein (Sm3E-TNF), consisting of the mAb, S 6m3E, in single-chain Fv fragment format, fused to murine TNF. The protein, which was expressed in mammalian cells and purified as a noncovalent stable homotrimer, bound to the cognate carcinoembryonic antigen (CEA) and retained TNF activity. A quantitative biodistribution experiment, performed in immunocompetent mice with CT26 colon carcinomas transfected with human CEA, revealed that Sm3E-TNF was able to preferentially accumulate in the tumors with excellent selectivity (tumor:blood ratio = 56:1, 24 hours after intravenous administration). The fusion protein mediated a rapid hemorrhagic necrosis of a large portion of the tumor mass, but a rim survived and eventually regrew. Surprisingly, the combination of Sm3E-TNF with 5-fluorouracil led to a reduction of therapeutic activity, while a combination with oxaliplatin led to a prolonged stabilization, with complete tumor eradication in 40% of treated mice. These therapy results were confirmed in a second immunocompetent mouse model of colorectal cancer (CEA-transfected C51 tumors) and provide a rationale for the possible clinical use of oxaliplatin in combination with fully human antibody-TNF fusions.
A Combination of BRD4 and HDAC3 Inhibitors Synergistically Suppresses Glioma Stem Cell Growth by Blocking GLI1/IL6/STAT3 Signaling Axis
Authors: Wang Qian , Jia Shengnan , Wang Ding , Chen Xuyang , Kalvakolanu Dhan V. , Zheng Hongwu , Wei Xiaodong , Wen Naiyan , Liang Hang , Guo Baofeng , Zhang Ling
Published: September 2020

Glioma stem cells (GSC) are essential for tumor maintenance, invasiveness, and recurrence. Using a global epigenetic screening with an shRNA library, we identified HDAC3 as an essential factor for GSC stemness. Here, we demonstrated that GSCs poorly respond to an HDAC3 inhibitor, RGFP966 (HDAC3i), owing to the production of IL6 and STAT3 activation. To enhance GSC sensitivity to HDAC3i, we explored whether cotreatment with a BRD4 inhibitor, JQ1 (BRD4i), in GSCs produced a better antitumor effect. BRD4i synergistically inhibits GSC growth in association with HDAC3i. HDAC3 inhibition upregulated the acetylation of H3K27, which allowed the recruitment of BRD4 to the GLI1 gene promoter and induced its expression. GLI1, a transcription factor, turned on the expression of IL6, which led to the activation of STAT3 signaling pathways. However, BRD4i inhibited transcription of the GLI1 gene, thereby blocking the GLI1/IL6/STAT3 pathway. In vivo, the HDAC3i/BRD4i combination caused stronger tumor growth suppression than either drug alone. Thus, HDAC3i/BRD4i might provide promising therapies for GBM.
Implication of ZNF217 in Accelerating Tumor Development and Therapeutically Targeting ZNF217-Induced PI3K–AKT Signaling for the Treatment of Metastatic Osteosarcoma
Authors: Smeester Branden A. , Draper Garrett M. , Slipek Nicholas J. , Larsson Alex T. , Stratton Natalie , Pomeroy Emily J. , Becklin Kelsie L. , Yamamoto Kenta , Williams Kyle B. , Laoharawee Kanut , Peterson Joseph J. , Abrahante Juan E. , Rathe Susan K. , Mills Lauren J. , Crosby Margaret R. , Hudson Wendy A. , Rahrmann Eric P. , Largaespada David A. , Moriarity Branden S.
Published: September 2020

We previously identified ZNF217 as an oncogenic driver of a subset of osteosarcomas using the Sleeping Beauty (SB) transposon system. Here, we followed up by investigating the genetic role of ZNF217 in osteosarcoma initiation and progression through the establishment of a novel genetically engineered mouse model, in vitro assays, orthotopic mouse studies, and paired these findings with preclinical studies using a small-molecule inhibitor. Throughout, we demonstrate that ZNF217 is coupled to numerous facets of osteosarcoma transformation, including proliferation, cell motility, and anchorage independent growth, and ultimately promoting osteosarcoma growth, progression, and metastasis in part through positive modulation of PI3K–AKT survival signaling. Pharmacologic blockade of AKT signaling with nucleoside analogue triciribine in ZNF217+ orthotopically injected osteosarcoma cell lines reduced tumor growth and metastasis. Our data demonstrate that triciribine treatment may be a relevant and efficacious therapeutic strategy for patients with osteosarcoma with ZNF217+ and p-AKT rich tumors. With the recent revitalization of triciribine for clinical studies in other solid cancers, our study provides a rationale for further evaluation preclinically with the purpose of clinical evaluation in patients with incurable, ZNF217+ osteosarcoma.
Anti-S100A4 Antibody Therapy Is Efficient in Treating Aggressive Prostate Cancer and Reversing Immunosuppression: Serum and BiopsyS100A4as a Clinical Predictor
Authors: Ganaie Arsheed A. , Mansini Adrian P. , Hussain Tabish , Rao Arpit , Siddique Hifzur R. , Shabaneh Ashraf , Ferrari Marina G. , Murugan Paari , Klingelhöfer Jörg , Wang Jinhua , Ambartsumian Noona , Warlick Christopher A. , Konety Badrinath R. , Saleem Mohammad
Published: September 2020

S100A4 oncoprotein plays a critical role during prostate cancer progression and induces immunosuppression in host tissues. We hypothesized that S100A4-regulated oncogenic activity in immunosuppressed prostate tumors promotes growth of neoplastic cells, which are likely to become aggressive. In the current study, we investigated whether biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive prostate cancer. Aided by DECIPHER-genomic test, we show biopsy-S100A4 overexpression as predictive of (i) poor ADT response and (ii) high risk of mortality in 228 radical prostatectomy-treated patients. Furthermore, analysis of tumor genome data of more than 1,000 patients with prostate cancer (PRAD/SU2C/FHCRC studies) validated the association of S100A4-alteration to poor survival and metastasis. We show that increased serum-S100A4 levels are associated to the prostate cancer progression in patients. The prerequisite for metastasis is the escape of tumor cells via vascular system. We show that extracellular-S100A4 protein as a growth factor induces vascular transmigration of prostate cancer cells and bone demineralization thus forms an ideal target for therapies for treating prostate cancer. By employing surface plasmon resonance and isothermal titration calorimetry, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 therapy reduced the (i) osteoblastic demineralization of bone-derived MSCs, (ii) S100A4-target (NFκB/MMP9/VEGF) levels in prostate cancer cells, and (iii) tumor growth in a TRAMPC2 syngeneic mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased Stat4+/T-bet+ and decreased GATA2+/CD68+/CD45+/CD206+ cells); (ii) modulated cytokine levels in CD4+ T cells; and (iii) decreased levels of IL5/6/12/13, sTNFR1, and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive prostate cancer in patients.
Association of Common Use Pharmaceuticals in Reducing Risk of Esophageal Adenocarcinoma: A SEER–Medicare Analysis
Authors: Loomans-Kropp Holli A. , Chaloux Matthew , Richmond Ellen , Umar Asad
Published: September 2020

Barrett's esophagus (BE), a recognized risk factor for esophageal adenocarcinoma (EAC), is routinely managed with proton pump inhibitors (PPIs) when symptomatic. Several lines of evidence suggest that PPIs may prevent malignant transformation. Chronic use of other common drugs, namely, statins nonsteroidal anti-inflammatory drugs (NSAIDs) and metformin, may also interfere with BE carcinogenesis, but confirmatory evidence is lacking. We identified 1,943 EAC cases and 19,430 controls (matched 10:1) between 2007 and 2013 that met our specified inclusion criteria in the SEER–Medicare database. Conditional logistic regression was used to generate odds ratios (OR) and 95% confidence intervals (95% CI). Wald χ2 tests were used to assess significance of covariates. Compared with controls, EAC cases had a higher prevalence of BE (26.2%). Use of PPIs, NSAIDs, statins, or metformin reduced the odds of EAC (PPIs: 0.10; 95% CI, 0.09–0.12; NSAIDs: 0.62; 95% CI, 0.51–0.74; statins: 0.15; 95% CI, 0.13–0.17; metformin: 0.76; 95% CI, 0.62–0.93). When stratified by BE, these associations persisted, though no association was found between NSAID use and EAC risk for participants with BE. Dual use of PPIs with NSAIDs or statins, and NSAID, statin, or metformin use alone also showed significant EAC risk reduction among all participants and those without BE. Use of PPIs alone and with NSAIDs, statins, or metformin was associated with reduced risk of EAC; however, a history of BE may diminish drug efficacy. These results indicate that common pharmacologic agents alone or in combination may decrease EAC development.

Prevention Relevance: The use of common drugs, such as proton pump inhibitors, statins, non-steroidal anti-inflammatory drugs, or metformin, may reduce one's risk of developing esophageal adenocarcinoma. These results suggest that repurposing agents often used for common chronic conditions may be a new strategy for cancer prevention efforts.
Outcomes of Advanced Gastroesophageal Cancer Patients with Equivocal HER2 Expression with or without ERBB2 Gene Amplification
Authors: Abdelhakeem Ahmed , Wang Xuemei , Rogers Jane E. , Trail Allison , Zhao Meina , Blum-Murphy Mariela , Estrella J.S. , Ajani Jaffer A.
Published: September 2020

Background: Prior studies have shown that patients whose tumor overexpresses Her2 at 3+ level by immunohistochemistry (IHC) fare better than those whose tumor overexpresses Her2 at 2+ level (with ERBB2 amplified). Therefore, it would be important to compare the outcome of patients whose tumor expresses Her2 at 2+ level but further classify by gene amplification studies as positive or negative. Methods: We retrospectively identified patients with advanced gastroesophageal adenocarcinoma with low Her2 protein expression (2+ by IHC) whose tumors were evaluated for gene amplification of ERBB2 by fluorescence in situ hybridization (FISH). All patients received first-line therapy, and trastuzu­mab was added according to Her2 status. We compared overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of the entire cohort and compared Her2-positive tumor patients’ outcomes with Her2-negative tumor patients’ outcomes. All patients had treatment response assessments and follow-ups at our institution. Results: We identified 87 patients whose tumors expressed Her2 at 2+ level. 51 (58.6%) were Her2-negative and 36 (41.4%) were Her2-positive by FISH. For the entire cohort, the median OS was 26 months (95% confidence interval 16.6–37.6), and the median PFS was 12.2 months (95% confidence interval 9.7–19.3). Median OS, median PFS, and ORR did not differ between Her2-positive and Her2-negative patients (p = 0.70, p = 0.60, p = 0.91, respectively). Conclusions: Our data suggest that patients with Her2 positivity or negativity when tumors have lower Her2 protein expression (2 + by IHC) have similar clinical outcomes. Further research is warranted in this cohort.
Use of Copeptin Levels to Predict the Resolution of Transient Postoperative SIADH
Authors: Jones Brandon , Corredor Margarita , Lteif Aida , Pittock Siobhan  , Bornhorst Joshua , Creo Ana 
Published: September 2020

Background: Copeptin levels reflect vasopressin activity and help classify osmoregulatory disorders. There is limited pediatric experience using copeptin to diagnose and manage diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and bi- or tri-phasic postsurgical osmoregulatory disorders. In this report, we describe serial copeptin levels in an infant who developed transient SIADH after neurosurgery. Case Description: A 4-month-old infant with no prior pituitary dysfunction underwent endoscopic fenestration of a large arachnoid cyst (3.5 × 4.7 × 3.8 cm). He developed SIADH on postoperative day 4 with seizures, hyponatremia (sodium 121 mmol/L), and concentrated urine (535 mOsm/kg). His initial copeptin level was inappropriately high in the context of his hyponatremia. Copeptin levels decreased as his SIADH resolved. Serial copeptin levels correlated to the infant’s increased ability to dilute urine. Conclusion: Copeptin levels in this infant are consistent with levels described in adults and older children. Obtaining copeptin levels may improve providers’ ability to quickly diagnose and manage SIADH amongst other heterogeneous causes of hyponatremia. Lastly, trending copeptin levels improved providers’ ability to monitor SIADH progression, and may allow preemptive fluid titration for children with bi- or tri-phasic shifts in osmoregulation after neurological procedures.
Infectious Mononucleosis Causing Acute Liver Failure and Hemolytic Anemia in a Patient with Underlying Hereditary Hemochromatosis
Authors: Forsberg Mark , Galan Mark , Kra Joshua
Published: September 2020

Infectious mononucleosis is a largely benign disease process that occurs secondary to infection with the Epstein-Barr virus. However, it can also present with more serious complications, including auto-immune hemolytic anemia and acute liver failure. Hereditary hemochromatosis is a genetic disorder that leads to organ damage via increased iron uptake and deposition. This case report describes a 25-year-old man who presented with acute liver failure and severe hemolytic anemia. Workup revealed that not only did he have a rare presentation of Epstein-Barr virus-induced acute liver failure and C3-positive IgG-negative hemolytic anemia, he also had previously undiagnosed hereditary hemochromatosis. This combined presentation of these pathologies presents a unique opportunity to study their interaction and possible synergistic pathophysiology. Furthermore, the evolving understanding of the disease mechanisms behind these disease processes is described.
Durable Response to Pazopanib in Recurrent Metastatic Carotid Body Paraganglioma
Authors: Alshamsan Bader , Atallah Jean Paul
Published: September 2020

We present the case of a 26-year-old woman living at a high altitude diagnosed initially with nonfamilial and nonsecretory localized carotid body tumor managed with surgery, which developed into a recurrent metastatic tumor treated with cyclophosphamide, vincristine, and dacarbazine. The patient continued to progress and developed a left carotid artery thrombosis and worsening of her systemic symptoms. The patient was re-evaluated, and she decided on no further surgery or systemic therapy. DOTATATE positron emission tomography/computed tomography showed widespread somatostatin-avid disease involving the left carotid bulb mass, bilateral lung nodules, and liver metastases, with the largest in the right hepatic lobe measuring 8 × 7 cm. There were peripancreatic lymph nodes and scattered skeletal metastases. The patient sought a second opinion, on the basis of which she was prescribed pazopanib, to which she showed a dramatic clinical response after 1 month, followed by a durable response for 1 year. Tyrosine kinase inhibitors such as pazopanib are potentially useful in paraganglioma, with further studies needed to understand the role of vascular endothelial growth factor receptor-directed kinase inhibitors in this setting.