bluuebunny/crossref_metadata_2025 huggingface dataset:
Electronic transport across planar gold clusters of eight and nine atoms
Authors: Ren Shi-Wei
Published: August 2023

The transport properties of gold clusters with eight and nine atoms between gold electrodes are investigated by using non-equilibrium Green’s function method combined with density functional theory. Negative differential resistance effect is found both in Au8 and Au9. From a new respect, the mechanism for the negative differential resistance effect is explored through calculating the number of electrons of the atoms in the clusters at different bias voltages. When Au9 takes vertical orientation, it is found that the voltage can change the coupling strength of the sandwiched system. When the value of the voltage is small, the current increases with decreasing of the cluster-electrode separation. But when the voltage increases to a certain value, the current decreases with decreasing of the cluster-electrode separation. When Au9 takes parallel orientation, different from other electronic transport systems, it is found that the transport behaviors for Au9 are not sensitive to the cluster-electrode separation, showing that this configuration has a better transport stability over the changes in distance, which may provide some new clues for developing future electron device.
A Hybrid Model for Classification of Skin Cancer Images After Segmentation
Authors: Mohakud Rasmiranjan , Dash Rajashree
Published: August 2023

For dermatoscopic skin lesion images, deep learning-based algorithms, particularly convolutional neural networks (CNN), have demonstrated good classification and segmentation capabilities. The impact of utilizing lesion segmentation data on classification performance, however, is still up for being subject to discussion. Being driven in this direction, in this work we propose a hybrid deep learning-based model to classify the skin cancer using segmented images. In the first stage, a fully convolutional encoder–decoder network (FCEDN) is employed to segment the skin cancer image and then in the second phase, a CNN is applied on the segmented images for classification. As the model’s success depends on the hyper-parameters it uses and fine-tuning these hyper-parameters by hand is time-consuming, so in this study the hyper-parameters of the hybrid model are optimized by utilizing an exponential neighborhood gray wolf optimization (ENGWO) technique. Extensive experiments are carried out using the International Skin Imaging Collaboration (ISIC) 2016 and ISIC 2017 datasets to show the efficacy of the model. The suggested model has been evaluated on both balanced and unbalanced datasets. With the balanced dataset, the proposed hybrid model achieves training accuracy up to 99.98%, validation accuracy up to 92.13% and testing accuracy up to 89.75%. It is evident from the findings that the proposed hybrid model outperforms previous known models in a competitive manner over balanced data.
On the fourth moment of a random determinant
Authors: Beck Dominik
Published: August 2023

In this paper, we generalize the formula for the fourth moment of a random determinant to account for entries with asymmetric distribution. We also derive the second moment of a random Gram determinant.
Part-of-speech Tagger for Assamese Using Ensembling Approach
Authors: Pathak Dhrubajyoti , Nandi Sukumar , Sarmah Priyankoo
Published: September 2023

Ensemble system for part-of-speech (POS) tagging is beneficial for many resource-poor languages that do not have enough annotated training data to train Deep Learning (DL, also named Deep Neural Network)-based POS taggers. An Ensemble system is a better choice to incorporate the linguistic features of a language and leverage the benefits of various types of POS taggers. In this work, we present our experiment of developing an ensemble tagger for Assamese, a low-resource, morphologically rich scheduled language of India, spoken by more than 15 million people. Despite the success of modern neural-network-based models in sequence tagging tasks, it has yet to receive attention in developing tasks such as POS in a resource-poor language such as Assamese. We develop a POS tagging model based on the BiLSTM-CRF architecture with a corpus of 404k tokens. We cover several word embeddings during training. Among all the experiments, the top two POS tagging models achieve tagging F1 scores of 0.746 and 0.745. We observe that the DL-based taggers are not able to achieve decent accuracy. It may be due to the inability to capture the linguistic features of the language or due to comparatively less annotated data. So, we build another POS tagger using a rule-based approach considering several morphological phenomena of the language and get an F1 score of 0.85. Subsequently, we integrate the top two DL-based taggers with the rule-based ones and develop a new POS tagger using an ensemble approach, of which we get an improved F1 score of 0.925. Performance improvement of our new ensemble POS taggers over the baseline taggers suggests that integration of the taggers combines the qualities of all taggers in the new tagger. Therefore, this study also states ensemble taggers are more suitable for highly inflectional, morphologically rich resource-poor languages.
Symmetry Analysis and Wave Solutions of the Fisher Equation Using Conformal Fractional Derivatives
Authors: Saini Shalu , Kumar Rajeev , Deeksha  , Arora Rishu , Kumar Kamal
Published: September 2023

In the present article, the time fractional Fisher equation is considered in conformal form to study the application of the Lie classical method and quantitative analysis. The Lie symmetry method has been applied to find the infinitesimal generators and symmetry reductions of the fractional Fisher equation. The obtained reduced form of the equation is solved by the method of

G

′

/
G

, which gives different forms of solutions. The theory of bifurcation has been utilized in the reduced form to check the stability and nature of critical points by transforming the equations into an autonomous system. Some phase portraits have been drawn at different critical points by the use of maple.
Functional Alterations of the Basal Ganglia Are Associated with Voluntary Activation of the Core Stabilizing Muscles in Patients with Chronic Low Back Pain: A Cross-Sectional Study
Authors: Zhang Chanjuan , Chen Xi , Yin Yi , Xie Dongfeng , Luo Jing , Ai Yinan , Zhan Wenfeng , Kan Hongjun , Zhang Shuxian , Jiang Guihua , Hu Xiquan
Published: September 2023

Purpose. Deficits in voluntary activation of the core stabilizing muscles are consistently observed in patients with chronic low back pain (CLBP); however, the underlying neural mechanism remains unclear. This cross-sectional study aimed at testing the hypothesis that the impaired voluntary activation of core stabilizing muscles is associated with structural and functional alterations in the basal ganglia, thalamus, and cortex in patients with CLBP. Methods. We obtained structural and resting-state functional magnetic resonance imaging (rs-fMRI) data from 53 patients with CLBP and 67 healthy controls and estimated the alterations in grey matter volume (GMV) and functional and effective connectivity (EC) of regions with altered GMV via whole brain analysis. The voluntary activation of the multifidus (MF) and transversus abdominis (TrA) was evaluated by ultrasound imaging in these patients. Results. Compared with the HCs, they displayed a significant decrease in GMV in the bilateral thalamus and caudate nucleus, a significant increase in GMV in the left middle frontal gyrus, and increased resting-state functional connectivity between the right caudate nucleus and the bilateral precuneus (voxel-level

p
<
0.005

, Gaussian random field-corrected

p
<
0.05

). The patients also showed increased EC from the right caudate nucleus to the bilateral precuneus, which was significantly correlated with voluntary activation of the bilateral MF and TrA (all

p
<
0.050

). Conclusions. Grey matter alterations may be confined to regions responsible for perception, motor control, and emotion regulation in patients with CLBP. The interrupted EC from the basal ganglia to the default mode network might be involved in the impairment of voluntary activation of the core stabilizing muscles.
Fabrication of C-Band High-Temperature Superconducting Microstrip Triplexer with High Accuracy
Authors: Jiang Runbo , Xie Wei , Yan Shaoqi , Li Jinding , Zhang Xiaoling , Meng Qingduan , Dai Jinhao , Yuan Yuefeng , Zhang Chi , Wang Jia , Li Chunguang , Wu Yun , Wang Xu , Sun Liang
Published: September 2023

This article presents a miniaturized C-band triplexer fabricated with high-temperature superconducting (HTS) microstrip lines and to be applied to quantum computers. The triplexer consists of three bandpass filters and branch lines. In the design of the bandpass filters, folded step impedance resonators (SIRs) are firstly used to achieve good stopband performances by harmonic suppression. Secondly, cross-coupling structures are also utilized to further improve the passband edge steepness of the bandpass filters. Finally, the parasitic transmission zeros originating from the assembling box sizes are employed to achieve a deeper out-of-band rejection. Three bandpass filters are designed and connected to the common input port of the triplexer. After that, the triplexer is coarsely optimized by advanced design system (ADS) for time-saving and is finely optimized by Sonnet for better accuracy. The optimized layout of the triplexer is fabricated on a 2-inch diameter and 0.5 mm thickness MgO wafer; here, the MgO wafer is double-sided coated with HTS YBa2Cu3O7 (YBCO) thin films. The measured passband bandwidths (return loss greater than 12 dB) of the triplexer are 6.420-6.680 GHz, 6.780-7.030 GHz, and 7.110-7.380 GHz, respectively, which satisfy the required design specifications.
Replacement of Potato Starch with Sorghum Distiller Grains Improves the Quality Characteristics of Emulsified Pork Meatballs
Authors: Huang Ying-Che , Chou Chin-Fu
Published: August 2023

Taiwanese-style emulsified pork meatballs (EPM) (Kung-wan) are the most popular restructured ready-to-eat meat products in Taiwan. However, the quality of EPM is influenced by numerous factors, especially its nonmeat ingredients. Sorghum distillers grains (SDGs) are a byproduct of Taiwanese alcoholic liquor, kaoliang liquor brewing. SDGs have comprehensive nutrients and good processing properties. However, the application of SDGs in EPM has not been reported. For this purpose, we examined the quality of EPM containing SDGs in this study. EPM containing SDGs showed substantially higher hardness (2126.67 to 3515.50 gf), gumminess (1093.79 to 1532.19 gf), chewiness (395.43 to 501.16 mJf), and lower pH values (4.98 to 5.87) compared to those of control (1917.33 gf, 930.81 gf, 389.83 mJf, and 5.99) (

p
<
0.05

); however, EPM did not affect springiness or cohesiveness. Additionally, the control EPM exhibited the highest water-holding capacity (WHC) (94.87%), which did not markedly differ from those of 20% and 40% SDGs (

p
>
0.05

). The control EPM (0% SDGs) showed the lowest cooking loss (5.58%), water loss (3.67%), fat loss (1.31%), and

L

(54.29),

a

(4.23), and

b

values (12.62), which substantially increased with increasing SDGs addition ratios (7.42 to 35.16%, 4.27 to 15.30%, 1.31 to 9.73%, 54.87 to 59.20, 4.26 to 5.67, and 13.81 to 18.51). Therefore, sorghum distiller’s grains can replace potato starch for emulsified meat products such as tribute balls, and produce high-quality products, and promote the added value of SDGs.
Sliding Mode Control of Ball Screw Meta-Action Unit Based on Disturbance Compensation and Inertia Identification
Authors: Ge Hongyu , Wang Cangfu , Zhang Chuanwei , Yang Manzhi
Published: September 2023

To solve the problems of dynamic model parameter perturbation and external disturbances during the operation of the ball screw meta-action unit, an adaptive sliding mode control method based on disturbance compensation and inertia identification is proposed in this paper. First, a model of the ball screw meta-action unit is established and the dynamic equation is derived. Taking into account the uncertainty of the dynamic parameters, a least squares method with a forgetting factor is introduced to identify the moment of inertia in real time, and the identification results are utilized to adaptively adjust the sliding mode control law. Second, a nonlinear disturbance observer is designed to effectively observe the load disturbance, and the observed value is substituted into the sliding mode control as feedforward compensation to improve the anti-interference ability of the controller. Committed to the chattering of traditional sliding mode control, an improved adaptive exponential sliding mode reaching law is exploited to construct a novel sliding mode controller, thereby suppressing the slid mode chattering more thoroughly. Finally, the superiority of the proposed method is verified by MATLAB/Simulink simulation and compared with the other two control methods; the control method proposed in this paper can effectively improve the tracking performance of the system and has good robustness.
Design and Operation Optimization of a Nuclear Heat-Driven District Cooling System
Authors: Abushamah Hussein Abdulkareem Saleh , Burian Ondřej , Škoda Radek
Published: September 2023

Carbon-free thermally driven district cooling systems (DCS) can effectively mitigate the excessive electricity consumption and carbon emissions associated with the cooling sector. This study proposes a DCS that employs nuclear heat as the primary energy source. The system comprises three main subsystems: heat station, heat transmission, and cooling station. A heat-only small modular reactor called Teplator, gas boilers, and heat storage are considered to supply the heat required to drive absorption chillers; cold storage and compression chillers are the supplementary units. The technoeconomic aspects of the system are formulated, and an algorithm is developed to determine the optimal design and operation. The method is examined for supplying a typical cooling demand profile with a peak of 2050 MWc. The resulting optimized design includes 11 nuclear plants (150 MWt each), 20 000 MWth heat storage, and 1.9 m diameter heat supply/return pipes. Absorption chillers with a total capacity of 1424 MWc are determined, covering 92% of the total cooling demand, and 244 MWc of compression chillers and 20 000 MWch of cold storage are found to cover the peak and enhance the load following. This system saved 69% of the electricity consumption and carbon emissions and 34% of the costs compared with an electric-based scenario.
Effects of the Annual Nitrogen Fertilization Rate on Vine Performance and Grape Quality for Winemaking: Insights from a Meta-Analysis
Authors: Visconti Fernando , Intrigliolo Diego S. , Mirás-Avalos José M.
Published: September 2023

Sustainability in grapevine cultivation requires the precise use of water and fertilizers, particularly nitrogen (N), to produce grapes of the highest quality for winemaking, while simultaneously avoiding harm to the surrounding waters and atmosphere by reducing NO3− losses and N2O and NH3 emissions from the vineyards. To address the challenge of optimizing N use in viticulture, many N fertilization trials have been carried out over the last decades, and a compilation and analysis of worldwide trials was therefore needed. The present study tackled this challenge through a meta-analysis of published research, which included 374 fertilization trials. From the compiled data, six vine production parameters and eight grape quality traits were extracted and normalized to enable comparisons between experiments. The Mitscherlich law of diminishing returns was able to satisfactorily describe the set of vine production parameters against nitrogen application rate, and the same occurred with the yeast assimilable nitrogen (YAN). In vines, both reproductive and vegetative growth similarly responded to the N application rate. In general, the nitrogen requirements for 95% of the maximum grape yield amounted to rates between 30 and 40 kg·N·ha−1, which increased nitrogen use efficiency (NUE) to values between 0.27 and 0.36 t·kg·N−1. Although several grape quality traits could not be described against the N rate in terms of any mathematical relationship, an N rate between 20 and 25 kg·N·ha−1 could be considered as maximizing grape quality for winemaking. Such N fertilization range increases NUE up to values between 0.41 and 0.47 t·kg·N−1, thus almost doubling the known NUE standards when grape quality is targeted instead of yield, although soil fertility could be exhausted in the mid-to-long term. Whatever the case, anthocyanins and polyphenols are well preserved in red grapes at such low N rates, although YAN is not. The results of this work will be useful for guiding new vine N nutrition research and N nutrition management in vineyards, thus increasing wine growing sustainability.
Supplementary Materials and methods from Preexisting Immunity Drives the Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma
Authors: Arbore Giuseppina , Albarello Luca , Bucci Gabriele , Punta Marco , Cossu Andrea , Fanti Lorella , Maurizio Aurora , Di Mauro Francesco , Bilello Vito , Arrigoni Gianluigi , Bonfiglio Silvia , Biancolini Donatella , Puccetti Francesco , Elmore Ugo , Vago Luca , Cascinu Stefano , Tonon Giovanni , Rosati Riccardo , Casorati Giulia , Dellabona Paolo
Published: September 2023

Supplementary Materials and methods
Data from Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor through cMYC Repression and Recruitment of the DREAM Complex
Authors: Nyquist Michael D. , Coleman Ilsa M. , Lucas Jared M. , Li Dapei , Hanratty Brian , Meade Hannah , Mostaghel Elahe A. , Plymate Stephen R. , Corey Eva , Haffner Michael C. , Nelson Peter S.
Published: September 2023

Abstract
The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer, and targeting AR has a remarkable therapeutic index. Though most approaches directed toward AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA) results in growth repression and improved outcomes in subsets of patients with prostate cancer. A better understanding of the mechanisms contributing to SPA response and resistance could help guide patient selection and combination therapies to improve efficacy. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses indicated that the dimerization partner, RB-like, E2F, and multivulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment, whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM complex. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance.
Significance:
Determining the molecular pathways by which supraphysiological androgens promote growth arrest and treatment responses in prostate cancer provides opportunities for biomarker-selected clinical trials and the development of strategies to augment responses.
Data from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis
Authors: Mukherjee Debarati , Previs Rebecca A. , Haines Corinne , Al Abo Muthana , Juras Patrick K. , Strickland Kyle C. , Chakraborty Binita , Artham Sandeep , Whitaker Regina S. , Hebert Katherine , Fontenot Jake , Patierno Steven R. , Freedman Jennifer A. , Lau Frank H. , Burow Matthew E. , Chang Ching-Yi , McDonnell Donald P.
Published: September 2023

Abstract
Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A, which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator-stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2–PDE1A–PKG1–VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Furthermore, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC.
Significance:
CaMKK2 regulates actin cytoskeletal dynamics to promote tumor invasiveness and can be inhibited to suppress metastasis of breast and ovarian cancer, indicating CaMKK2 inhibition as a therapeutic strategy to arrest disease progression.
Data from Relationship between ABO Blood Group Alleles and Pancreatic Cancer Is Modulated by Secretor (FUT2) Genotype, but Not Lewis Antigen (FUT3) Genotype
Authors: Kim Jihye , Yuan Chen , Amundadottir Laufey T. , Wolpin Brian M. , Klein Alison P. , Risch Harvey A. , Kraft Peter
Published: September 2023

AbstractBackground:
In Western populations, pancreatic ductal adenocarcinoma (PDAC) risk has been found to be greater among individuals with non-O blood types than those with O blood type. However, the association has not been fully evaluated with respect to FUT2 (determining secretor status) and FUT3 (determining Lewis antigens) status, two biologically important genes in the expression of ABO blood groups with PDAC.
Methods:
We examined interactions in data from 8,027 cases and 11,362 controls in large pancreatic cancer consortia (PanScan I-III and PanC4) by using genetic variants to predict ABO blood groups (rs505922 and rs8176746), secretor status (rs601338), and Lewis antigens (rs812936, rs28362459, and rs3894326). Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) of the risk of PDAC adjusted for age and sex. We examined multiplicative interactions of ABO with secretor status and Lewis antigens by considering each product term between ABO and secretor and between ABO and Lewis antigens individually.
Results:
We found that the increased risk associated with non-O blood groups was somewhat stronger among secretors than nonsecretors [ORs, 1.28 (95% CI, 1.15–1.42) and 1.17 (95% CI, 1.03–1.32) respectively; Pinteraction = 0.002]. We did not find any interactions between ABO and Lewis antigens.
Conclusions:
Our large consortia data provide evidence of effect modification in the association between non-O blood type and pancreatic cancer risk by secretor status.
Impact:
Our results indicate that the association between ABO blood type and PDAC risk may vary by secretor status, but not by Lewis antigens.
Data from Diabetes and Prostate Cancer Outcomes in Men with Nonmetastatic Castration-Resistant Prostate Cancer: Results from the SEARCH Cohort
Authors: Sergeyev Andrei , Gu Lin , De Hoedt Amanda M. , Amling Christopher L. , Aronson William J. , Cooperberg Matthew R. , Kane Christopher J. , Klaassen Zachary , Terris Martha K. , Guerrios-Rivera Lourdes , Freedland Stephen J. , Csizmadi Ilona
Published: September 2023

AbstractBackground:
The prognosis of diabetic men with advanced prostate cancer is poorly understood and understudied. Hence, we studied associations between diabetes and progression to metastases, prostate cancer–specific mortality (PCSM) and all-cause mortality (ACM) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Methods:
Data from men diagnosed with nmCRPC between 2000 and 2017 at 8 Veterans Affairs Health Care Centers were analyzed using Cox regression to determine HRs and 95% confidence intervals (CI) for associations between diabetes and outcomes. Men with diabetes were classified according to: (i) ICD-9/10 codes only, (ii) two HbA1c values > 6.4% (missing ICD-9/10 codes), and (iii) all diabetic men [(i) and (ii) combined].
Results:
Of 976 men (median age: 76 years), 304 (31%) had diabetes at nmCRPC diagnosis, of whom 51% had ICD-9/10 codes. During a median follow-up of 6.5 years, 613 men were diagnosed with metastases, and 482 PCSM and 741 ACM events occurred. In multivariable-adjusted models, ICD-9/10 code-identified diabetes was inversely associated with PCSM (HR, 0.67; 95% CI, 0.48–0.92) while diabetes identified by high HbA1c values (no ICD-9/10 codes) was associated with an increase in ACM (HR, 1.41; 95% CI, 1.16–1.72). Duration of diabetes, prior to CRPC diagnosis was inversely associated with PCSM among men identified by ICD-9/10 codes and/or HbA1c values (HR, 0.93; 95% CI, 0.88–0.98).
Conclusions:
In men with late-stage prostate cancer, ICD-9/10 ‘code-identified’ diabetes is associated with better overall survival than ‘undiagnosed’ diabetes identified by high HbA1c values only.
Impact:
Our data suggest that better diabetes detection and management may improve survival in late-stage prostate cancer.
Data from Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin–Drug Conjugate Response
Authors: Hu Huiyu , Ng Thomas S.C. , Kang Mikyung , Scott Ella , Li Ran , Quintana Jeremy M. , Matvey Dylan , Vantaku Venkata R. , Weissleder Ralph , Parangi Sareh , Miller Miles A.
Published: September 2023

AbstractPurpose:
Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK–ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies.
Experimental Design:
Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin. The impacts of ectopic BRAFV600E and mutant RAS, genetic PTEN silencing, and inhibitors targeting RET, BRAF, and MEK kinases were quantified. BrafV600E p53−/− ATC tumors in immunocompetent mice were used to measure efficacy of an albumin–drug conjugate comprising microtubule-destabilizing monomethyl auristatin E (MMAE) linked to serum albumin via a cathepsin-cleavable peptide (Alb-vc-MMAE).
Results:
FTC and ATC cells showed greater macropinocytosis than non-malignant and PTC cells. ATC tumors accumulated albumin at 8.8% injected dose per gram tissue. Alb-vc-MMAE, but not MMAE alone, reduced tumor size by >90% (P < 0.01). ATC macropinocytosis depended on MAPK/ERK activity and nutrient signaling, and increased by up to 230% with metformin, phenformin, or inhibition of IGF1Ri in monoculture but not in vivo. Macrophages also accumulated albumin and express the cognate IGF1R ligand, IGF1, which reduced ATC responsiveness to IGF1Ri.
Conclusions:
These findings identify regulated oncogene-driven macropinocytosis in thyroid cancers and demonstrate the potential of designing albumin-bound drugs to efficiently treat them.
Data from Clinical and Genomic Characteristics of Patients with Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer Following Progression on Cyclin-Dependent Kinase 4 and 6 Inhibitors
Authors: Rao Xi , Chen Yongmei , Beyrer Julie , Nash Smyth Emily , Morato Guimaraes Claudia , Litchfield Lacey M. , Bowman Lee , Lawrence Garreth W. , Aggarwal Amit , Andre Fabrice
Published: September 2023

AbstractPurpose:
We explored the clinical and genomic characteristics of hormone receptor–positive (HR+), HER2-negative (HER2−) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6i) ± endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options.
Experimental Design:
Patients in the United States with HR+, HER2− MBC had tumor biopsies collected from a metastatic site during routine care following progression on a CDK4 and 6i ± ET (CohortPost) or prior to initiating CDK4 and 6i treatment (CohortPre) and analyzed using a targeted mutation panel and RNA-sequencing. Clinical and genomic characteristics were described.
Results:
The mean age at MBC diagnosis was 59 years in CohortPre (n = 133) and 56 years in CohortPost (n = 223); 14% and 45% of patients had prior chemotherapy/ET, and 35% and 26% had de novo stage IV MBC, respectively. The most common biopsy site was liver (CohortPre, 23%; CohortPost, 56%). CohortPost had significantly higher tumor mutational burden (TMB; median 3.16 vs. 1.67 Mut/Mb, P < 0.0001), ESR1 alteration frequency (mutations: 37% vs. 10%, FDR < 0.0001; fusions: 9% vs. 2%, P = 0.0176), and higher copy-number amplification of genes on chr12q15, including MDM2, FRS2, and YEATS4 versus patients in the CohortPre group. In addition, CDK4 copy-number gain on chr12q13 was significantly higher in CohortPost versus CohortPre (27% vs. 11%, P = 0.0005).
Conclusions:
Distinct mechanisms potentially associated with resistance to CDK4 and 6i ± ET, including alterations in ESR1 and amplification of chr12q15 and CDK4 copy-number gain, were identified.
Data from Phase I Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment
Authors: Roschewski Mark , Patel Manish R. , Reagan Patrick M. , Saba Nakhle S. , Collins Graham P. , Arkenau Hendrik-Tobias , de Vos Sven , Nuttall Barrett , Acar Melih , Burke Kathleen , White Rafael D. , Udriste Maria , Sharma Shringi , Dougherty Brian , Stetson Daniel , Jenkins David , Mortlock Andrew , Forcina Alessandra , Munugalavadla Veerendra , Flinn Ian
Published: September 2023

AbstractPurpose:
Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL.
Patients and Methods:
Final results of the phase I study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion [Days 1, 3, 5 (Cycle 1); weekly infusions starting Day 8, Cycle 1] was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity.
Results:
Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in 1 patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n = 17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders.
Conclusions:
Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.
Data from Caveolin Gene Expression Predicts Clinical Outcomes for Early-Stage HER2-Negative Breast Cancer Treated with Paclitaxel-Based Chemotherapy in the GeparSepto Trial
Authors: Williams Terence M. , Schneeweiss Andreas , Jackisch Christian , Shen Changxian , Weber Karsten E. , Fasching Peter A. , Denkert Carsten , Furlanetto Jenny , Heinmöller Ernst , Schmatloch Sabine , Karn Thomas , Szeto Christopher W. , van Mackelenbergh Marion T. , Nekljudova Valentina , Stickeler Elmar , Soon-Shiong Patrick , Schem Christian , Mairinger Thomas , Müller Volkmar , Marme Frederik , Untch Michael , Loibl Sibylle
Published: September 2023

AbstractPurpose:
Caveolin-1 and -2 (CAV1/2) dysregulation are implicated in driving cancer progression and may predict response to nab-paclitaxel. We explored the prognostic and predictive potential of CAV1/2 expression for patients with early-stage HER2-negative breast cancer receiving neoadjuvant paclitaxel-based chemotherapy regimens, followed by epirubicin and cyclophosphamide.
Experimental Design:
We correlated tumor CAV1/2 RNA expression with pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) in the GeparSepto trial, which randomized patients to neoadjuvant paclitaxel- versus nab-paclitaxel–based chemotherapy.
Results:
RNA sequencing data were available for 279 patients, of which 74 (26.5%) were hormone receptor (HR)–negative, thus triple-negative breast cancer (TNBC). Patients treated with nab-paclitaxel with high CAV1/2 had higher probability of obtaining a pCR [CAV1 OR, 4.92; 95% confidence interval (CI), 1.70–14.22; P = 0.003; CAV2 OR, 5.39; 95% CI, 1.76–16.47; P = 0.003] as compared with patients with high CAV1/2 treated with solvent-based paclitaxel (CAV1 OR, 0.33; 95% CI, 0.11–0.95; P = 0.040; CAV2 OR, 0.37; 95% CI, 0.12–1.13; P = 0.082). High CAV1 expression was significantly associated with worse DFS and OS in paclitaxel-treated patients (DFS HR, 2.29; 95% CI, 1.08–4.87; P = 0.030; OS HR, 4.97; 95% CI, 1.73–14.31; P = 0.003). High CAV2 was associated with worse DFS and OS in all patients (DFS HR, 2.12; 95% CI, 1.23–3.63; P = 0.006; OS HR, 2.51; 95% CI, 1.22–5.17; P = 0.013), in paclitaxel-treated patients (DFS HR, 2.47; 95% CI, 1.12–5.43; P = 0.025; OS HR, 4.24; 95% CI, 1.48–12.09; P = 0.007) and in patients with TNBC (DFS HR, 4.68; 95% CI, 1.48–14.85; P = 0.009; OS HR, 10.43; 95% CI, 1.22–89.28; P = 0.032).
Conclusions:
Our findings indicate high CAV1/2 expression is associated with worse DFS and OS in paclitaxel-treated patients. Conversely, in nab-paclitaxel–treated patients, high CAV1/2 expression is associated with increased pCR and no significant detriment to DFS or OS compared with low CAV1/2 expression.
Data from Identification of a ΔNp63-Dependent Basal-Like A Subtype-Specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma
Authors: Wang Xin , Kutschat Ana P. , Aggrey-Fynn Joana , Hamdan Feda H. , Graham Rondell P. , Wixom Alexander Q. , Souto Yara , Ladigan-Badura Swetlana , Yonkus Jennifer A. , Abdelrahman Amro M. , Alva-Ruiz Roberto , Gaedcke Jochen , Ströbel Philipp , Kosinsky Robyn Laura , Wegwitz Florian , Hermann Patrick , Truty Mark J. , Siveke Jens T. , Hahn Stephan A. , Hessmann Elisabeth , Johnsen Steven A. , Najafova Zeynab
Published: September 2023

Abstract
A major hurdle to the application of precision oncology in pancreatic cancer is the lack of molecular stratification approaches and targeted therapy for defined molecular subtypes. In this work, we sought to gain further insight and identify molecular and epigenetic signatures of the Basal-like A pancreatic ductal adenocarcinoma (PDAC) subgroup that can be applied to clinical samples for patient stratification and/or therapy monitoring. We generated and integrated global gene expression and epigenome mapping data from patient-derived xenograft models to identify subtype-specific enhancer regions that were validated in patient-derived samples. In addition, complementary nascent transcription and chromatin topology (HiChIP) analyses revealed a Basal-like A subtype-specific transcribed enhancer program in PDAC characterized by enhancer RNA (eRNA) production that is associated with more frequent chromatin interactions and subtype-specific gene activation. Importantly, we successfully confirmed the validity of eRNA detection as a possible histologic approach for PDAC patient stratification by performing RNA-ISH analyses for subtype-specific eRNAs on pathologic tissue samples. Thus, this study provides proof-of-concept that subtype-specific epigenetic changes relevant for PDAC progression can be detected at a single-cell level in complex, heterogeneous, primary tumor material.
Implications:
Subtype-specific enhancer activity analysis via detection of eRNAs on a single-cell level in patient material can be used as a potential tool for treatment stratification.
Data from Targeting the ATF6-Mediated ER Stress Response and Autophagy Blocks Integrin-Driven Prostate Cancer Progression
Authors: Macke Amanda J. , Pachikov Artem N. , Divita Taylor E. , Morris Mary E. , LaGrange Chad A. , Holzapfel Melissa S. , Kubyshkin Anatoly V. , Zyablitskaya Evgeniya Y. , Makalish Tatiana P. , Eremenko Sergey N. , Qiu Haowen , Riethoven Jean-Jack M. , Hemstreet George P. , Petrosyan Armen
Published: September 2023

Abstract
Prostate cancer progression to the lethal metastatic castration-resistant phenotype (mCRPC) is driven by αv integrins and is associated with Golgi disorganization and activation of the ATF6 branch of unfolded protein response (UPR). Overexpression of integrins requires N-acetylglucosaminyltransferase-V (MGAT5)-mediated glycosylation and subsequent cluster formation with Galectin-3 (Gal-3). However, the mechanism underlying this altered glycosylation is missing. For the first time, using HALO analysis of IHC, we found a strong association of integrin αv and Gal-3 at the plasma membrane (PM) in primary prostate cancer and mCRPC samples. We discovered that MGAT5 activation is caused by Golgi fragmentation and mislocalization of its competitor, N-acetylglucosaminyltransferase-III, MGAT3, from Golgi to the endoplasmic reticulum (ER). This was validated in an ethanol-induced model of ER stress, where alcohol treatment in androgen-refractory PC-3 and DU145 cells or alcohol consumption in patient with prostate cancer samples aggravates Golgi scattering, activates MGAT5, and enhances integrin expression at PM. This explains known link between alcohol consumption and prostate cancer mortality. ATF6 depletion significantly blocks UPR and reduces the number of Golgi fragments in both PC-3 and DU145 cells. Inhibition of autophagy by hydroxychloroquine (HCQ) restores compact Golgi, rescues MGAT3 intra-Golgi localization, blocks glycan modification via MGAT5, and abrogates delivery of Gal-3 to the cell surface. Importantly, the loss of Gal-3 leads to reduced integrins at PM and their accelerated internalization. ATF6 depletion and HCQ treatment synergistically decrease integrin αv and Gal-3 expression and temper orthotopic tumor growth and metastasis.
Implications:
Combined ablation of ATF6 and autophagy can serve as new mCRPC therapeutic.
Supplementary Table S3 from Association and Prediction Utilizing Craniocaudal and Mediolateral Oblique View Digital Mammography and Long-Term Breast Cancer Risk
Authors: Chen Simin , Tamimi Rulla M. , Colditz Graham A. , Jiang Shu
Published: September 2023

Supplementary Table S3: Hazards ratio for association between baseline risk factors and breast cancer risk among postmenopausal women using Full-VPD only.
Data from HER2Δ16 Engages ENPP1 to Promote an Immune-Cold Microenvironment in Breast Cancer
Authors: Attalla Sherif Samer , Boucher Jonathan , Proud Hailey , Taifour Tarek , Zuo Dongmei , Sanguin-Gendreau Virginie , Ling Chen , Johnson Gabriella , Li Vincent , Luo Robin B. , Kuasne Hellen , Papavasiliou Vasilios , Walsh Logan A. , Barok Mark , Joensuu Heikki , Park Morag , Roux Philippe P. , Muller William J.
Published: September 2023

Abstract
The tumor–immune microenvironment (TIME) is a critical determinant of therapeutic response. However, the mechanisms regulating its modulation are not fully understood. HER2Δ16, an oncogenic splice variant of the HER2, has been implicated in breast cancer and other tumor types as a driver of tumorigenesis and metastasis. Nevertheless, the underlying mechanisms of HER2Δ16-mediated oncogenicity remain poorly understood. Here, we show that HER2∆16 expression is not exclusive to the clinically HER2+ subtype and associates with a poor clinical outcome in breast cancer. To understand how HER2 variants modulated the tumor microenvironment, we generated transgenic mouse models expressing either proto-oncogenic HER2 or HER2Δ16 in the mammary epithelium. We found that HER2∆16 tumors were immune cold, characterized by low immune infiltrate and an altered cytokine profile. Using an epithelial cell surface proteomic approach, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) as a functional regulator of the immune cold microenvironment. We generated a knock-in model of HER2Δ16 under the endogenous promoter to understand the role of Enpp1 in aggressive HER2+ breast cancer. Knockdown of Enpp1 in HER2Δ16-derived tumor cells resulted in decreased tumor growth, which correlated with increased T-cell infiltration. These findings suggest that HER2Δ16-dependent Enpp1 activation associates with aggressive HER2+ breast cancer through its immune modulatory function. Our study provides a better understanding of the mechanisms underlying HER2Δ16-mediated oncogenicity and highlights ENPP1 as a potential therapeutic target in aggressive HER2+ breast cancer.
Data from CCRL2 Expression by Specialized Lung Capillary Endothelial Cells Controls NK-cell Homing in Lung Cancer
Authors: Sozio Francesca , Schioppa Tiziana , Laffranchi Mattia , Salvi Valentina , Tamassia Nicola , Bianchetto-Aguilera Francisco M. , Tiberio Laura , Bonecchi Raffaella , Bosisio Daniela , Parmentier Marc , Bottazzi Barbara , Leone Roberto , Russo Eleonora , Bernardini Giovanni , Garofalo Stefano , Limatola Cristina , Gismondi Angela , Sciumè Giuseppe , Mantovani Alberto , Del Prete Annalisa , Sozzani Silvano
Published: September 2023

Abstract
Patterns of receptors for chemotactic factors regulate the homing of leukocytes to tissues. Here we report that the CCRL2/chemerin/CMKLR1 axis represents a selective pathway for the homing of natural killer (NK) cells to the lung. C–C motif chemokine receptor-like 2 (CCRL2) is a nonsignaling seven-transmembrane domain receptor able to control lung tumor growth. CCRL2 constitutive or conditional endothelial cell targeted ablation, or deletion of its ligand chemerin, were found to promote tumor progression in a Kras/p53Flox lung cancer cell model. This phenotype was dependent on the reduced recruitment of CD27– CD11b+ mature NK cells. Other chemotactic receptors identified in lung-infiltrating NK cells by single-cell RNA sequencing (scRNA-seq), such as Cxcr3, Cx3cr1, and S1pr5, were found to be dispensable in the regulation of NK-cell infiltration of the lung and lung tumor growth. scRNA-seq identified CCRL2 as the hallmark of general alveolar lung capillary endothelial cells. CCRL2 expression was epigenetically regulated in lung endothelium and it was upregulated by the demethylating agent 5-aza-2′-deoxycytidine (5-Aza). In vivo administration of low doses of 5-Aza induced CCRL2 upregulation, increased recruitment of NK cells, and reduced lung tumor growth. These results identify CCRL2 as an NK-cell lung homing molecule that has the potential to be exploited to promote NK cell–mediated lung immune surveillance.
Supplementary Methods from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Authors: Nair Pramod C. , Piehler Jacob , Tvorogov Denis , Ross David M. , Lopez Angel F. , Gotlib Jason , Thomas Daniel
Published: September 2023

Supplementary Information: Figure S1 X-ray crystal structure of JNJ-77006621(ball and stick, C-atoms in green) bound to JAK2-PK domain (cartoon, yellow). Key residues are displayed in sticks [C-atoms in green near the optimisation domain (Peuleo et al. 2017, Liosi et al 2020) and C-atoms in yellow at the dimerization domain]. Supplementary Methods.
Plasma cell myeloma: Pendekatan diagnosis dari aspek kliniko-morfologik dan imunofenotipe
Authors: Angelina Aina , Retnani Diah
Published: September 2023

Plasma cell myeloma (PCM)/Mutiple myeloma (MM) merupakan keganasan hematologi ditandai proliferasi sel plasma neoplastik pada sumsum tulang. Manifestasinya berupa lesi litik multifokal tulang, peningkatan M protein serum atau urin, kerusakan organ target, dan bisa didapatkan pembentukan massa di ekstrameduler. Biopsi massa tumor ekstrameduler dapat menujukkan morfologi mikroskopik yang tumpang tindih dengan neoplasma sel plasma lainnya maupun limfoma maligna, hal ini merupakan tantangan diagnosis tersendiri terutama jika keterangan klinis maupun radiologis tidak lengkap. Kerusakan organ target akibat proliferasi sel plasma abnormal dikenal dengan istilah CRAB terdiri atas hiperkalsemia, insufisiensi renal, anemia dan lesi tulang. Spektrum klinis seringkali bervariasi sehingga diagnosis PCM memerlukan integrasi data klinis, laboratorium, radiologi, morfologi, dan imunofenotipe. Pemeriksaan histopatologi dari bahan biopsi sumsum tulang maupun biopsi massa tumor perlu dikonfirmasi dengan pemeriksaan imunohistokimia serta tes klonalitas untuk penegakan diagnosis yang akurat. Tinjauan ini bermaksud menjelaskan aspek klinis, morfologi dan immunofenotipe serta merangkai suatu pendekatan diagnosis PCM.