bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-time ultrasound guidance versus fluoroscopic guidance in thoracic epidural catheter placement: a single-center, non-inferiority, randomized, active-controlled trial
Authors: Kwon Hyun-Jung , Lee Jung-Bok , Lee Kunhee , Shin Jae Young , Jeong Sung-Moon , Lee Jong-Hyuk , Kim Doo-Hwan
Published: June 2023

Introduction

Fluoroscopy can improve the success rate of thoracic epidural catheter placement (TECP). Real-time ultrasound (US)-guided TECP was recently introduced and showed a high first-pass success rate. We tested whether real-time US-guided TECP results in a non-inferior first-pass success rate compared with that of fluoroscopy-guided TECP.

Methods

In this single-center, non-inferiority, randomized trial, the primary outcome was the comparison of the first-pass success rate of TECP between real-time US guidance (US group) and fluoroscopic guidance (fluoroscopy group). Secondary outcomes included time to identifying epidural space, procedure time, total number of needle passes, number of skin punctures, final success, and cross-over success.

Results

We randomly assigned 132 patients to the allocated groups. The difference in the first-pass success rate between the groups did not exceed the non-inferiority margin of 15% (US group: 66.7% vs fluoroscopy group: 68.2%; difference −1.5%, 95% exact CI: −14.9% to 11.9%). The difference in the final success rate also did not differ between the groups (98.5% vs 100.0%; difference −1.5%, 95% exact CI: −4.0% to 1.0%). The time to identifying epidural space (45.6 (34–62) vs 59.0 (42–77) s, p=0.004) and procedure time (39.5 (28–78) vs 112.5 (93–166) s, p<0.001) were significantly shorter in the US group.

Conclusions

Real-time US guidance provided a non-inferior success rate and shorter time spent on preparation and procedure compared with fluoroscopic guidance in TECP.

Trial registration number

KCT0006521.
$${{\rho }}$$ exchange contribution to neutrinoless double beta decay
Authors: Mahajan Namit
Published: June 2023

We consider $$\rho $$
ρ
meson contributions to neutrinoless double beta decay amplitude stemming from the hadronization of the short distance quark-electron currents. These contributions are evaluated within vacuum dominance approximation. The one and two $$\rho $$
ρ
exchange contributions affect the Fermi transition nuclear matrix element in a way that lead to near cancellations in the same chirality, left–left and right–right, short range amplitudes when these new contributions are combined with the conventional short range amplitudes, while the left–right amplitude almost triples. A rough estimate comparing this contribution to the long range pion exchange contribution indicates that $$\rho $$
ρ
exchange contribution can easily be $$\mathcal {O}(10\%)$$

O
(
10
%
)

of the pion contribution. When considering precision predictions, $$\rho $$
ρ
exchange amplitudes should be included in any phenomenological study, like in left–right theories.
Exclusive dilepton production in photon-induced interactions at RHIC
Authors: Xie Ya-Ping , Gonçalves V. P.
Published: June 2023

The exclusive dilepton photoproduction in pp and pAu collisions at RHIC is investigated considering the contribution of the Bethe–Heitler (BH) and the timelike Compton scattering (TCS) processes. The TCS amplitude is estimated at next-to-leading-order of the strong running coupling constant $$\alpha _s$$

α
s

and assuming the Goloskokov–Kroll model for the quark and gluon generalized parton distributions. The TCS differential cross section is estimated as well the contribution associated to the interference between the TCS and BH amplitudes. Predictions for the TCS, BH and interference contributions are presented considering the kinematical range covered by the RHIC detectors.
A First Look at Dark Mode in Real-world Android Apps
Authors: Ma Suyu , Chen Chunyang , Khalajzadeh Hourieh , Grundy John
Published: June 2023

Android apps often have a “dark mode” option used in low-light situations, for those who find the conventional color palette problematic, or because of personal preferences. Typically developers add a dark mode option for their apps with different backgrounds, text, and sometimes iconic forms. We wanted to understand the actual provision of this dark mode in real-world Android apps through an empirical study of posts from Stack Overflow and real-world Android app analysis. Using these approaches, we identified the aspects of dark mode that developers implemented as well as the key difficulties they experienced in implementing it. We performed a quantitative analysis using open-coding of more than 300 discussion threads to create a taxonomy regarding the aspects discussed by developers with respect to dark mode in Android. Our quantitative analysis of over 6,000 Android apps highlights which dark mode features are typically provided in Android apps and which aspects developers care about during dark mode design. We also examined four app development support tools to see how well they aid Android app development for dark mode. From our analysis, we distilled some key lessons to guide further research and actions in aiding developers with supporting users who require such assistive features. For example, developers should be aware of the potential risks in using unsuitable dark mode design schema and researchers should take dark mode features into consideration when developing app development support tools.
The Effects of Small Amounts of Cobalt in LiNi1−xCoxO2 on Lithium-ion Diffusion
Authors: Zsoldos Eniko S. , Cormier Marc M. E. , Ball Mitchell , Rathore Divya , Dahn J. R.
Published: June 2023

Cobalt substitution for nickel in the positive electrode material LiNi1-xCoxO2 at 0 ≤ x ≤ 0.10 is investigated to determine the impact of cobalt on Li diffusivity, measured using the Atlung Method for Intercalant Diffusion (AMID) in coin cells. Cobalt was found to have little to no impact on Li diffusivity in the intermediate voltage range (4.2 V to 3.7 V). At high voltage (4.3 V to 4.2 V), 0 to 10% cobalt incrementally suppresses the H2–H3 phase transition and enables faster lithium diffusion. Additionally, at low voltage in the kinetic hindrance region (3.7 V to 3.0 V) cobalt can improve lithium diffusion by reducing cation mixing (nickel in the lithium layer). However, cation mixing can also be minimized through synthesis conditions, improving diffusivity without using cobalt. Cobalt was found to have minimal impact on the following material properties of LiNi1-xCoxO2: crystallinity, surface impurities, particle size, and electronic conductivity. Cobalt substituted for nickel from 0% to 10% was found to decrease first cycle discharge capacity in the voltage range between 4.3 V to 3.0 V and improve capacity retention in coin cell cycling vs Li metal negative electrodes. The latter impact is most likely due to the suppression of the H2–H3 phase transition as Co is added.
MoS2-TiO2 Nanocomposites for Enhanced Photo-electrocatalytic Hydrogen Evolution
Authors: Chacko Levna , Joseph Anju , Tadi Kiran Kumar , Kumar Amar , Narayanan T. N. , Aneesh P. M.
Published: June 2023

The investigation on the designing and fabrication of highly efficient electrocatalysts for hydrogen evolution reaction (HER) is critical for future applications in renewable sustainable energy. The present work reports the hydrothermal synthesis of two-dimensional MoS2 and MoS2-TiO2 nanostructures. The as-prepared nanostructures were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), Raman analysis, UV–vis-NIR, and photoluminescence spectrophotometry and vibrating sample magnetometer (VSM). Systematic electrochemical measurements for HER were performed and MoS2-TiO2 nanocomposites demonstrated the lowest onset potential in comparison with MoS2. The results suggest that the nanofusion interface between MoS2 nanoflakes and TiO2 nanoparticles induced an efficient charge transfer from the conduction band of MoS2 to TiO2 and favored the reduction of H+ at active sites. We believe the present work can open up new possibilities that would provide deep insights for the rational design of 2D materials-based catalysts for energy storage and conversion applications.
Sustainable SiC Composite Anodes, Graphite Accelerated Lithium Storage
Authors: Yu Mengjie , Temeche Eleni , Indris Sylvio , Laine Richard M.
Published: June 2023

Realizing more holistic electrification in society to disengage current dependence on nonrenewable fuels requires balancing between energy storage mechanisms and actual environmental benefits gained from the transition from traditional resources. Given that the majority of greenhouse gas emissions in battery value chains originate from material mining and production, silicon carbide (SiC) derived from the agricultural waste, rice hull ash (RHA), is introduced as an environmentally-benign alternate anode material. SiC with hard carbon (SiC/HC) exhibits capacity increases on long-term cycling, reaching capacities of >950 mAh g−1 competitive with elemental Si with complementary porosity. Herein, a relatively low amount (<30 wt%) of graphite added to SiC/HC composites greatly promotes capacity increases while retaining sustainability. Comparison between graphite contents were optimal at ≈30 wt% graphite (SiC/HC/30G) boosted performance, doubling capacity increase rates and subsequently saving >70% time to reach target specific capacities at C/10. At 2C, SiC/HC/30G offers enhanced specific capacities at ≈220 mAh g−1. The positive effects from the coincidentally formed HC are demonstrated by oxidizing HC to form SiC/O, followed by graphite addition. Experimental post-mortem analyses support that SiC/graphite composites provide a promising solution for implementing agricultural waste-derived material for next-generation lithium storage.
Spontaneous Recession Repair after Orthodontic Treatment: Case Report with the Use of Digital Approach for Quantification of Soft Tissue Changes
Authors: Goncharuk-Khomyn Myroslav , Krasnokutskyy Oleksandr , Boichuk Mykola , Rusyn Vitaliy , Hliudzyk-Shemota Marharyta
Published: June 2023

The article presents a case of spontaneous recession repair in a male patient with Class II malocclusion, division 1, after orthodontic treatment with aligners. The difference in digital recession depth was measured before and at the end of treatment by means of automatic intraoral scans superimposition within adapted software while using “Cross section” and “Measuring” instruments. Digital analysis of intraoral scans obtained before and at the end of treatment has revealed that recessions within the area of teeth 1.5, 1.4, 1.3, 1.2, 1.1, 2.1, 2.2, 2.3, 2.4, and 2.5 have improved, and recession depth reduced by

0.73
±
0.08

 mm,

1.02
±
0.09

 mm,

1.86
±
0.13

 mm,

0.72
±
0.09

 mm,

0.73
±
0.04

 mm,

0.67
±
0.06

 mm,

0.66
±
0.07

 mm,

1.50
±
0.12

 mm,

1.10
±
0.05

 mm, and

0.45
±
0.04

 mm, appropriately. The present case report emphasizes that orthodontic correction of altered tooth position (angulation, inclination, and rotation) under certain clinical conditions may be considered as an effective method for soft tissue contour optimization in cases when pre-treatment tooth position could be interpreted as a causative factor or associated with diagnosed recession. The following outcomes could be related, but not limited to creeping attachment mechanism, bone-housing centering effects, optimization of occlusal load distribution with ruling out peak zones of strain accumulation, and mucogingival stress leveling. Due to the authors’ knowledge, the present case report is the first one where the signs of spontaneous recession repair after orthodontic treatment were evidenced with the intraoral scans and quantified by the specifically implemented digital analysis approach.
Modeling and Analysis of Unsteady Casson Fluid Flow due to an Exponentially Accelerating Plate with Thermal and Solutal Convective Boundary Conditions
Authors: Endalew Mehari Fentahun , Sarkar Subharthi
Published: June 2023

We intend to analyze the consequence of considering thermal radiation on time-dependent flow of the Casson fluid due to an exponentially accelerated inclined surface along with thermal as well as solutal convective boundary conditions. Fundamental equations governing an isotropic incompressible radiative Casson fluid flow are defined through a set of linear partial differential equations, and exact solutions are derived by using the Laplace transform approach. The numerical findings, obtained using MATLAB software, are presented in graphical and tabular representations based on the obtained analytical solutions of the fundamental equations. This investigation shows that the increment in thermal radiation results in the increment in fluid velocity and temperature distribution including thermal and momentum boundary layer thicknesses. Most interestingly, increasing the mass transfer coefficient results in an increment in the species concentration, velocity profiles, and mass transfer rate. However, the fluid velocity diminishes near the plate upon the increase in plate inclination. The scientific community will benefit greatly from this work since the findings can serve as benchmark solutions using numerical approaches to solve fully nonlinear flow governing problems.
Outcomes of Combined Heart-Kidney Transplantation in Older Recipients
Authors: Sherard Curry , Sama Vineeth , Kwon Jennie H. , Shorbaji Khaled , Huckaby Lauren V. , Welch Brett A. , Inampudi Chakradhari , Tedford Ryan J. , Kilic Arman
Published: June 2023

Objectives. The upper limit of recipient age for combined heart-kidney transplantation (HKT) remains controversial. This study evaluated the outcomes of HKT in patients aged ≥65 years. Methods. The United Network of Organ Sharing (UNOS) was used to identify patients undergoing HKT from 2005 to 2021. Patients were stratified by age at transplantation: <65 and ≥ 65 years. The primary outcome was one-year mortality. Secondary outcomes included 90-day and 5-year mortality, postoperative new-onset dialysis, postoperative stroke, acute rejection prior to discharge, and rejection within one-year of HKT. Survival was compared using Kaplan–Meier analysis, and risk adjustment for mortality was performed using Cox proportional hazards modeling. Results. HKT in recipients aged ≥65 significantly increased from 5.6% of all recipients in 2005 to 23.7% in 2021 (

p
=
0.002

). Of 2,022 HKT patients in the study period, 372 (18.40%) were aged ≥65. Older recipients were more likely to be male and white, and fewer required dialysis prior to HKT. There were no differences between cohorts in unadjusted 90-day, 1-year, or 5-year survival in Kaplan–Meier analysis. These findings persisted after risk-adjustment, with an adjusted hazard for one-year mortality for age ≥65 of 0.91 (95% CI (0.63–1.29),

p
=
0.572

). As a continuous variable, increasing age was not associated with one-year mortality (HR 1.01 (95% CI (1.00–1.02),

p
=
0.236

) per year). Patients aged ≥65 more frequently required new-onset dialysis prior to discharge (11.56% vs. 7.82%,

p
=
0.051

). Stroke and rejection rates were comparable. Conclusion. Combined HKT is increasing in older recipients, and advanced age ≥65 should not preclude HKT.
Gallbladder Clear Cell Carcinoma: Report of a Rare Case and Literature Review
Authors: Papatheodorou Panayiotis , Frantzeskou Kyriakos , Konstantinou Kyriaki , Theophanous Elena
Published: June 2023

Carcinoma of the gallbladder is the most common biliary tract cancer. The majority of gallbladder cancers are adenocarcinomas, whereas clear-cell carcinoma of the gallbladder (CCG) is a rarely recorded variant. Usually, diagnosis is established incidentally after cholecystectomy, performed for another reason. Clinically, the different histological types of carcinomas are impossible to be recognized preoperatively, since they present with a wide and common range of symptoms. We present a male patient who underwent an emergency cholecystectomy due to suspected perforation. After an uneventful postoperative period, the histopathological report led to the diagnosis of CCG, but the surgical margins were infiltrated by the tumor. The patient decided not to proceed with any additional treatment and passed away 8 months after the operation. In conclusion, it is of great necessity to record such unusual cases and enriches global knowledge with information clinically and educationally noteworthy.
Estimation of the Heritabilities for Body Shape and Body Weight in Yellow River Carp (Cyprinus carpio haematopterus) Based on a Molecular Pedigree
Authors: Wang Xinhua , Yu Xiaomu , Feng Jianxin , Zhang Qin , Qu Changyi , Liu Qingshan , Tong Jingou , Xu Wenyan
Published: June 2023

Estimation of the heritability for a given phenotype would provide basic information for potential breeding programs. As one of the most precious common carp strains, Yellow River carp was subject to selection for fast growth and a slender body to meet market demands. In the present study, heritabilities for body shape (body length, BL and body height, BH) and body weight (BW) were estimated based on a molecular parentage assignment for 750 progenies from 58 half-sib and full-sib Yellow River carp families. Eight highly polymorphic microsatellites were used for the construction of the molecular pedigree, and the average observed heterozygosity (Ho), expected heterozygosity (He), and the polymorphism information content (PIC) were 0.841, 0.792, and 0.763, respectively. All 750 progenies were successfully assigned to single parental pairs with 100% accuracy. Using the linear mixed model, the heritabilities were estimated to be 0.268, 0.338, and 0.340 for BL, BH, and BW, respectively. High phenotypic (0.831–0.927) and genetic (0.952–0.987) correlations among these three traits suggested that selection for BW could also largely affect the body shape and vice versa. Moderate heritabilities and high genetic corrections revealed by this study strongly indicate substantial potentials for genetic improvement of both growth rate and body formation in Yellow River carp breeding programs.
Structural and Psychological Empowerment in Explaining Job Satisfaction and Burnout in Nurses: A Two-Level Investigation
Authors: Orlowska Agnieszka , Laguna Mariola
Published: June 2023

Aim. The aim of the study was to test a two-level model of the relationships between structural empowerment in a hospital department and job satisfaction and burnout in nurses. We tested whether psychological empowerment is a mediator of these relationships. Background. We drew on empowerment theory to examine whether psychological empowerment mediates the association between organizational-level structural empowerment and nurses’ job satisfaction and burnout at the individual level. The proposed two-level model takes into account the effect of both contextual and individual factors on individual nurse’s job satisfaction and burnout. Methods. The study was conducted in 29 public hospital departments and included 309 participants employed as nurses or midwives. To analyze the results, we applied multilevel modeling and cross-level mediation analysis, with nurses as Level 1 and hospital departments as Level 2. Results. Structural empowerment at the hospital department level is positively related to nurses’ individual sense of competence and autonomy, namely, to their psychological empowerment. Structural empowerment is also positively related to job satisfaction and negatively related to burnout in nurses. Psychological empowerment is a mediator between structural empowerment and nurses’ job satisfaction as well as two dimensions of burnout: exhaustion and disengagement from work. Conclusions. These findings suggest that psychological empowerment is an underlying mechanism that may explain why structural empowerment in the hospital department is positively related to job satisfaction and negatively related to burnout in nurses. This has implications for theory by extending the multilevel nomological network of the constructs and for management practice by highlighting the role of structural empowerment for work design in public health institutions. Implications for Nursing Management. The results indicate that structural and psychological empowerment can play a significant role in creating supportive workplace conditions in hospitals. Organizing nurses’ work in a way that empowers them promotes their sense of competence and autonomy, which in turn promotes their job satisfaction and reduces burnout.
Data from N6-Methyladenosine Promotes Translation of VEGFA to Accelerate Angiogenesis in Lung Cancer
Authors: Zhang Haisheng , Zhou Jiawang , Li Jiexin , Wang Zhaotong , Chen Zhuojia , Lv Ziyan , Ge Lichen , Xie Guoyou , Deng Guoming , Rui Yalan , Huang Hongbing , Chen Likun , Wang Hongsheng
Published: June 2023

Abstract
Angiogenesis is hijacked by cancer to support tumor growth. RNA modifications such as N6-methyladenosine (m6A) can regulate several aspects of cancer, including angiogenesis. Here, we find that m6A triggers angiogenesis in lung cancer by upregulating VEGFA, a central regulator of neovasculature and blood vessel growth. m6A-sequencing and functional studies confirmed that m6A modification of the 5′UTR (untranslated region) of VEGFA positively regulates its translation. Specifically, methylation of a 5′UTR internal ribosome entry site (IRES) recruited the YTHDC2/eIF4GI complex to trigger cap-independent translation initiation. Intriguingly, the m6A methylation site A856 of the 5′UTR was located within the conserved upstream open reading frame (uORF) of VEGFA IRES-A, which overcomes uORF-mediated translation suppression while facilitating G-quadruplex–induced translation of VEGFA. Targeted specific demethylation of VEGFA m6A significantly decreased expression of VEGFA and reduced lung cancer cell–driven angiogenesis. In vivo and clinical data confirmed the positive effects of m6A modification of VEGFA on angiogenesis and tumor growth of lung cancer. This study not only reveals that the m6A/VEGFA axis is a potential target for lung cancer therapy but also expands our understanding of the impact of m6A modification of IRES in the 5′UTR of mRNA on translation regulation.
Significance:
Methylation of the 5′UTR IRES of VEGFA mRNA increases cap-independent translation via recruitment of the YTHDC2/eIF4GI complex, which stimulates angiogenesis to promote lung tumor growth.
Data from Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma
Authors: Tran Gia-Buu , Ding Jane , Ye Bingwei , Liu Mengling , Yu Yajie , Zha Yunhong , Dong Zheng , Liu Kebin , Sudarshan Sunil , Ding Han-Fei
Published: June 2023

Abstract
High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and nonsterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and nonsterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth. Blocking the mevalonate pathway by simvastatin, a cholesterol-lowering drug, impeded neuroblastoma growth in neuroblastoma cell line xenograft, patient-derived xenograft (PDX), and TH-MYCN transgenic mouse models. Transcriptional profiling revealed that the mevalonate pathway was required to maintain the FOXM1-mediated transcriptional program that drives mitosis. High FOXM1 expression contributed to statin resistance and led to a therapeutic vulnerability to the combination of simvastatin and FOXM1 inhibition. Furthermore, caffeine synergized with simvastatin to inhibit the growth of neuroblastoma cells and PDX tumors by blocking statin-induced feedback activation of the mevalonate pathway. This function of caffeine depended on its activity as an adenosine receptor antagonist, and the A2A adenosine receptor antagonist istradefylline, an add-on drug for Parkinson's disease, could recapitulate the synergistic effect of caffeine with simvastatin. This study reveals that the FOXM1-mediated mitotic program is a molecular statin target in cancer and identifies classes of agents for maximizing the therapeutic efficacy of statins, with implications for treatment of high-risk neuroblastoma.
Significance:
Caffeine treatment and FOXM1 inhibition can both enhance the antitumor effect of statins by blocking the molecular and metabolic processes that confer statin resistance, indicating potential combination therapeutic strategies for neuroblastoma.

See related commentary by Stouth et al., p. 2091
Data from TGF-β antagonizes IFN-γ-mediated adaptive immune evasion via activation of the AKT-Smad3-SHP1 axis in lung adenocarcinoma
Authors: Ye Fan , Cai Zihao , Wang Boyu , Zeng Chenxi , Xi Yu , Hu Shaojie , Qu Rirong , Yuan Zhiwei , Yue Jiaqi , Tian Yitao , Wang Xue , Fu Xiangning , Li Lequn
Published: June 2023

Abstract
IFN-γ-mediated signaling in tumor cells can induce immunosuppressive responses and cause tumor resistance to immunotherapy. Blocking TGF-β promotes T lymphocyte infiltration and turns immunologically cold tumors into hot tumors, thereby improving the efficacy of immunotherapy. Several studies have shown that TGF-β inhibits IFN-γ signaling in immune cells. We thus sought to determine whether TGF-β affects IFN-γ signaling in tumor cells and plays a role in the development of acquired resistance to immunotherapy. TGF-β stimulation of tumor cells increased SHP1 phosphatase activity in an AKT-Smad3-dependent manner, decreased IFN-γ-mediated tyrosine phosphorylation of JAK1/2 and STAT1, and suppressed the expression of STAT1-dependent immune evasion-related molecules, e.g., PD-L1, IDO1, HVEM, and Gal-9. In a lung cancer mouse model, dual blockade of TGF-β and PD-L1 led to superior antitumor activity and prolonged survival compared to anti-PD-L1 therapy alone. However, prolonged combined treatment resulted in tumor resistance to immunotherapy and increased expression of PD-L1, IDO1, HVEM, and Gal-9. Interestingly, after initial anti-PD-L1 monotherapy, dual TGF-β and PD-L1 blockade promoted both immune evasion gene expression and tumor growth compared to that in tumors treated with continuous PD-L1 monotherapy. Alternatively, treatment with JAK1/2 inhibitor following initial anti-PD-L1 therapy effectively suppressed tumor growth and downregulated immune evasion gene expression in tumors, indicating the involvement of IFN-γ signaling in immunotherapy resistance development. These results demonstrate an unappreciated effect of TGF-β on the development of IFN-γ-mediated tumor resistance to immunotherapy.
Data from TGFβ Antagonizes IFNγ-Mediated Adaptive Immune Evasion via Activation of the AKT–Smad3–SHP1 Axis in Lung Adenocarcinoma
Authors: Ye Fan , Cai Zihao , Wang Boyu , Zeng Chenxi , Xi Yu , Hu Shaojie , Qu Rirong , Yuan Zhiwei , Yue Jiaqi , Tian Yitao , Wang Xue , Fu Xiangning , Li Lequn
Published: June 2023

Abstract
IFNγ-mediated signaling in tumor cells can induce immunosuppressive responses and cause tumor resistance to immunotherapy. Blocking TGFβ promotes T lymphocyte infiltration and turns immunologically cold tumors into hot tumors, thereby improving the efficacy of immunotherapy. Several studies have shown that TGFβ inhibits IFNγ signaling in immune cells. We thus sought to determine whether TGFβ affects IFNγ signaling in tumor cells and plays a role in the development of acquired resistance to immunotherapy. TGFβ stimulation of tumor cells increased SHP1 phosphatase activity in an AKT–Smad3-dependent manner, decreased IFNγ-mediated tyrosine phosphorylation of JAK1/2 and STAT1, and suppressed the expression of STAT1-dependent immune evasion–related molecules, e.g., PD-L1, IDO1, herpes virus entry mediator (HVEM), and galectin-9 (Gal-9). In a lung cancer mouse model, dual blockade of TGFβ and PD-L1 led to superior antitumor activity and prolonged survival compared with anti–PD-L1 therapy alone. However, prolonged combined treatment resulted in tumor resistance to immunotherapy and increased expression of PD-L1, IDO1, HVEM, and Gal-9. Interestingly, after initial anti–PD-L1 monotherapy, dual TGFβ and PD-L1 blockade promoted both immune evasion gene expression and tumor growth compared with that in tumors treated with continuous PD-L1 monotherapy. Alternatively, treatment with JAK1/2 inhibitor following initial anti–PD-L1 therapy effectively suppressed tumor growth and downregulated immune evasion gene expression in tumors, indicating the involvement of IFNγ signaling in immunotherapy resistance development. These results demonstrate an unappreciated effect of TGFβ on the development of IFNγ-mediated tumor resistance to immunotherapy.
Significance:
Blocking TGFβ facilitates IFNγ-mediated resistance to anti–PD-L1 therapy due to the role of TGFβ in inhibiting IFNγ-induced immunoevasion by increasing SHP1 phosphatase activity in tumor cells.
Data from MEN1 degradation induced by neddylation and the CUL4B-DCAF7 axis promotes pancreatic neuroendocrine tumor progression
Authors: Xu Junfeng , Ye Zeng , Zhuo Qifeng , Gao Heli , Qin Yi , Llou Xin , Zhang Wuhu , Wang Fei , Wang Yan , Jing Desheng , Fan Guixiong , Zhang Yue , Chen Xuemin , Chen Jie , Xu Xiaowu , Yu Xianjun , Ji Shunrong
Published: June 2023

Abstract
Pancreatic neuroendocrine tumors (PanNETs) are a group of rare sporadic malignant tumors in the pancreas. MEN1 is the most frequently mutated gene in PanNETs. The MEN1-encoded protein is a typical tumor suppressor that forms a complex with epigenetic and transcription factors and is an attractive target for therapeutic interventions for PanNET patients. A better understanding of the regulation of MEN1 protein expression in PanNETs could identify strategies for targeting MEN1. Here, we found that the neddylation pathway and DCAF7-mediated ubiquitination regulated MEN1 protein expression. Increased expression of members of the neddylation pathway and DCAF7 were found in PanNET tissues compared to paired-adjacent tissues and were associated with poor prognosis in PanNET patients. Suppression of neddylation using the neddylation inhibitor MLN4924 or RNA interference significantly induced MEN1 accumulation and repressed cancer-related malignant phenotypes. CUL4B and DCAF7 promoted MEN1 degradation by binding and catalyzing its ubiquitination. In PanNET cells resistant to everolimus, a pharmacological mTOR inhibitor widely used for advanced PanNET patient treatment, the downregulation of DCAF7 expression overcame resistance and synergized with everolimus to suppress mTOR activation and inhibit cancer cell growth. The effects of DCAF7 loss could be counteracted by the simultaneous knockdown of MEN1 both in vitro and in vivo. The inverse correlation between DCAF7 and MEN1 was further validated in clinical specimens. This study revealed that the posttranslational control of MEN1 expression in PanNET is mediated by neddylation and the CUL4B-DCAF7 axis and identifies potential therapeutic targets in MEN1-associated PanNET patients.
Data from β-catenin-driven differentiation is a tissue-specific epigenetic vulnerability in adrenal cancer
Authors: Mohan Dipika R. , Borges Kleiton S. , Finco Isabella , LaPensee Christopher R. , Rege Juilee , Solon April L. , Little Donald W. , Else Tobias , Almeida Madson Q. , Dang Derek , Haggerty-Skeans James , Apfelbaum April A. , Vinco Michelle , Wakamatsu Alda , Mariani Beatriz M. P. , Amorim Larissa Costa. , Latronico Ana Claudia. , Mendonca Berenice B. , Zerbini Maria Claudia N. , Lawlor Elizabeth R. , Ohi Ryoma , Auchus Richard J. , Rainey William E. , Marie Suely K.N. , Giordano Thomas J. , Venneti Sriram , Fragoso Maria Candida Barisson Villares , Breault David T. , Lerario Antonio Marcondes. , Hammer Gary D.
Published: June 2023

Abstract
Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes and the epigenome. On chromatin, β-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, β-catenin bound histone methyltransferase EZH2. SF1/β-catenin and EZH2/β-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/β-catenin from chromatin and favored EZH2/β-catenin assembly, erasing differentiation and restraining cancer growth in vitro and in vivo. These studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.
Data from Attenuation of sialylation augments antitumor immunity and improves response to immunotherapy in ovarian cancer
Authors: Cao Kankan , Zhang Guodong , Yang Moran , Wang Yiying , He Mengdi , Zhang Chen , Huang Yan , Lu Jiaqi , Liu Haiou
Published: June 2023

Abstract
Aberrant sialylation functions as an important modulator of all steps of malignant transformation. Therefore, targeting sialylation regulators, such as sialyltransferases and neuraminidases, is a potential strategy for treating cancer. Here, we found that elevated α2,3-sialyltransferase III (St3gal3) was associated with dismal prognosis in high-grade serous ovarian carcinoma (HGSC). St3gal3 knockdown antagonized subcutaneous tumor growth in immunocompetent, but not immunodeficient mice, with enhanced accumulation of functional CD8+ T cells and anti-tumor immune gene signatures. St3gal3 knockdown inhibited intraperitoneal tumor growth and repolarized tumor-associated macrophages from a pro-tumorigenic M2-like to a tumor-suppressive M1-like phenotype. In vitro, St3gal3 knockdown tumor cells guided bone marrow-derived macrophages (BMDM) toward the M1-like phenotype under both direct contact and distant transwell co-culture conditions. Depletion of macrophages rescued the suppressed tumor growth induced by St3gal3 knockdown and completely suppressed infiltration of functional CD8+ T cells that rely on macrophage-derived CXCL10. St3gal3 engendered an immunosuppressive HGSC microenvironment characterized by an abundance of pro-tumorigenic macrophages and reduced cytotoxic T cell infiltration. In vivo, St3gal3 knockdown improved effectiveness of dual immune checkpoint blockade (ICB) with αPD-1 and αCTLA-4 antibodies. Preclinical inhibition of sialylation with ambroxol resulted in decreased tumor growth and prolonged the survival of tumor-bearing mice, which was enhanced by the addition of dual ICB. These findings indicate that altered sialylation induced by St3gal3 upregulation promotes a tumor suppressive microenvironment in HGSC and targeting α2,3-sialylation may reprogram the immunosuppressive tumor microenvironment and improve the efficacy of immunotherapy.
Figure S12 from Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma
Authors: Saliby Renee Maria , El Zarif Talal , Bakouny Ziad , Shah Valisha , Xie Wanling , Flippot Ronan , Denize Thomas , Kane M. Harry , Madsen Katrine N. , Ficial Miriam , Hirsch Laure , Wei Xiao X. , Steinharter John A. , Harshman Lauren C. , Vaishampayan Ulka N. , Severgnini Mariano , McDermott David F. , Lee Gwo-Shu Mary , Xu Wenxin , Van Allen Eliezer M. , McGregor Bradley A. , Signoretti Sabina , Choueiri Toni K. , McKay Rana R. , Braun David A.
Published: June 2023

Supplementary Figure 12
Data from Small gene networks delineate immune cell states and characterize immunotherapy response in melanoma
Authors: Egan Donagh , Kreileder Martina , Nabhan Myriam , Iglesias-Martinez Luis F. , Dovedi Simon J. , Valge-Archer Viia , Grover Amit , Wilkinson Robert W. , Slidel Timothy , Bendtsen Claus , Barrett Ian P. , Brennan Donal J. , Kolch Walter , Zhernovkov Vadim
Published: June 2023

Abstract
Single-cell technologies have elucidated mechanisms responsible for immune checkpoint inhibitor (ICI) response, but are not amenable to a clinical diagnostic setting. In contrast, bulk RNA sequencing (RNA-seq) is now routine for research and clinical applications. Our workflow uses transcription factor (TF)-directed co-expression networks (regulons) inferred from single-cell RNA-seq data to deconvolute immune functional states from bulk RNA-seq data. Regulons preserve the phenotypic variation in CD45+ immune cells from metastatic melanoma samples (n=19, discovery dataset) treated with ICIs, despite reducing dimensionality by > 100-fold. Four cell states, termed exhausted T cells, monocyte lineage cells, memory T cells, and B cells were associated with therapy response; and were characterized by differentially active and cell-state specific regulons. Clustering of bulk RNA-seq melanoma samples from four independent studies (n=209, validation dataset) according to regulon-inferred scores identified four groups with significantly different response outcomes (p < 0.001). An intercellular link was established between exhausted T cells and monocyte lineage cells, whereby their cell numbers were correlated, and exhausted T cells predicted prognosis as a function of monocyte lineage cell number. The ligand–receptor expression analysis suggested that monocyte lineage cells drive exhausted T cells into terminal exhaustion through programs that regulate antigen presentation, chronic inflammation, and negative co-stimulation. Together, our results demonstrate how regulon-based characterization of cell states provide robust and functionally informative markers that can deconvolve bulk RNA-seq data to identify ICI responders.
Data from Small Gene Networks Delineate Immune Cell States and Characterize Immunotherapy Response in Melanoma
Authors: Egan Donagh , Kreileder Martina , Nabhan Myriam , Iglesias-Martinez Luis F. , Dovedi Simon J. , Valge-Archer Viia , Grover Amit , Wilkinson Robert W. , Slidel Timothy , Bendtsen Claus , Barrett Ian P. , Brennan Donal J. , Kolch Walter , Zhernovkov Vadim
Published: June 2023

Abstract
Single-cell technologies have elucidated mechanisms responsible for immune checkpoint inhibitor (ICI) response, but are not amenable to a clinical diagnostic setting. In contrast, bulk RNA sequencing (RNA-seq) is now routine for research and clinical applications. Our workflow uses transcription factor (TF)–directed coexpression networks (regulons) inferred from single-cell RNA-seq data to deconvolute immune functional states from bulk RNA-seq data. Regulons preserve the phenotypic variation in CD45+ immune cells from metastatic melanoma samples (n = 19, discovery dataset) treated with ICIs, despite reducing dimensionality by >100-fold. Four cell states, termed exhausted T cells, monocyte lineage cells, memory T cells, and B cells were associated with therapy response, and were characterized by differentially active and cell state–specific regulons. Clustering of bulk RNA-seq melanoma samples from four independent studies (n = 209, validation dataset) according to regulon-inferred scores identified four groups with significantly different response outcomes (P < 0.001). An intercellular link was established between exhausted T cells and monocyte lineage cells, whereby their cell numbers were correlated, and exhausted T cells predicted prognosis as a function of monocyte lineage cell number. The ligand–receptor expression analysis suggested that monocyte lineage cells drive exhausted T cells into terminal exhaustion through programs that regulate antigen presentation, chronic inflammation, and negative costimulation. Together, our results demonstrate how regulon-based characterization of cell states provide robust and functionally informative markers that can deconvolve bulk RNA-seq data to identify ICI responders.
Data from Siglec-15 Promotes Evasion of Adaptive Immunity in B-cell Acute Lymphoblastic Leukemia
Authors: Pillsbury Claire E. , Dougan Jodi , Rabe Jennifer L. , Fonseca Jairo A. , Zhou Chengjing , Evans Alyssa N. , Abukharma Hasan , Ichoku Ona , Gonzalez-Flamenco Gloria , Park Sunita I. , Aljudi Ahmed , DeRyckere Deborah , Castellino Sharon M. , Rafiq Sarwish , Langermann Solomon , Liu Linda N. , Henry Curtis J. , Porter Christopher C.
Published: June 2023

Siglec-15 (Sig15) has been implicated as an immune checkpoint expressed in solid tumor-infiltrating macrophages and is being targeted in clinical trials with mAbs to normalize the tumor immune microenvironment and stimulate antitumor immunity. However, the role of Sig15 in hematologic malignancies remains undefined. Sig15 mRNA and protein expression levels in hematologic malignancies were determined from publicly available databases, cell lines, and primary patient samples. Human B-cell acute lymphoblastic leukemia (B-ALL) cell lines were used to identify signaling pathways involved in the regulation of Sig15 expression. Secreted/soluble Sig15 and cytokine levels were measured from the plasma of children with leukemia and healthy controls. Knockdown and knockout of Siglec15 in a murine model of B-ALL was used to evaluate the effect of leukemia-derived Sig15 on the immune response to leukemia. We observed pathologic overexpression of Sig15 in a variety of hematologic malignancies, including primary B-ALL samples. This overexpression was driven by NFκB activation, which also increased the surface localization of Sig15. Secreted/soluble Sig15 was found to circulate at elevated levels in the plasma of children with B-ALL and correlated with an immune-suppressive cytokine milieu. Genetic inhibition of Sig15 in murine B-ALL promoted clearance of the leukemia by the immune system and a marked reversal of the immune-privileged leukemia bone marrow niche, including expanded early effector CD8+ T cells and reduction of immunosuppressive cytokines. Thus, Sig15 is a novel, potent immunosuppressive molecule active in leukemia that may be targeted therapeutically to activate T lymphocytes against leukemia cells.
Significance:
We demonstrate that Sig15 is overexpressed in hematologic malignancies driven by NFκB, is required for immune evasion in a mouse model of leukemia, and, for the first time, that it circulates at high levels in the plasma of children with leukemia.
Data from Sequential Chromogenic IHC: Spatial Analysis of Lymph Nodes Identifies Contact Interactions between Plasmacytoid Dendritic Cells and Plasmablasts
Authors: Claudio Natalie , Nguyen My-Tien , Wanner Adrian , Pucci Ferdinando
Published: June 2023

Recent clinical observations have emphasized the critical role that the spatial organization of immune cells in lymphoid structures plays in the success of cancer immunotherapy and patient survival. However, implementing sequential chromogenic IHC (scIHC) to analyze multiple biomarkers on a single tissue section has been limited because of a lack of a standardized, rigorous guide to the development of customized biomarker panels and a need for user-friendly analysis pipelines that can extract meaningful data. In this context, we provide a comprehensive guide for the development of novel biomarker panels for scIHC, using practical examples and illustrations to highlight the most common complications that can arise during the setup of a new biomarker panel, and provide detailed instructions on how to prevent and detect cross-reactivity between secondary reagents and carryover between detection antibodies. We also developed a novel analysis pipeline based on non-rigid tissue deformation correction, Cellpose-inspired automated cell segmentation, and computational network masking of low-quality data. We applied this biomarker panel and pipeline to study regional lymph nodes from patients with head and neck cancer, identifying novel contact interactions between plasmablasts and plasmacytoid dendritic cells in vivo. Given that Toll-like receptors, which are highly expressed in plasmacytoid dendritic cells, play a key role in vaccine efficacy, the significance of this cell–cell interaction decisively warrants further studies. In summary, this work provides a streamlined approach to the development of customized biomarker panels for scIHC that will ultimately improve our understanding of immune responses in cancer.
Significance:
We present a comprehensive guide for developing customized biomarker panels to investigate cell–cell interactions in the context of immune responses in cancer. This approach revealed novel contact interactions between plasmablasts and plasmacytoid dendritic cells in lymph nodes from patients with head and neck cancer.
Development of Instruction – Augmenting Project for Faculty Members of the Department of Management Studies: An Action Research
Authors: Vitobina Crugie Boy A. , Ronas Sunny May S. , Navales Bhrendelyn B. , Dela Rea Kirk T.
Published: June 2023

This study aimed to assess the developed e-class record system to help the academic staff of the Cavite State University – CCAT Campus. The researchers wanted to evaluate the said system to determine the effectiveness and ease of use of the e-class record system. This study employed quasi-experimental and phenomenological designs to understand user experience to augment the Technology Acceptance Model (TAM). The intervention employed by the researchers was efficient and saved 0:25:51 of time in minutes, as indicated by the average cumulative usage time of 58:20.8 minutes. The goal of setting the intervention was to use e-class records, which had the desired result. This action research revealed the efficiency with regard to the time stamping with intervention, which helped the faculty improve their target goal of efficiency in recording grades. This study recommended having more knowledge and learning among the faculty using the said e-class record system.
Level of Awareness, Acceptance, and Congruency with the Vision, Mission, Goals, and Program Outcomes of the College of Education of Capiz State University (CAPSU)
Authors: Joaquin Cleo Jude A. , BESA Ellen Mae D. , Joaquin Hazel D.
Published: June 2023

This research evaluated the level of awareness, acceptance, and congruence with the Vision, Mission, and Goals (VMGO) and Program Outcomes of the College of Education at Capiz State University (CAPSU). It adopted a mixed-method research design, utilizing a descriptive-quantitative approach, with both internal and external stakeholders of CAPSU as the primary data source. Through a survey questionnaire employing a five-point Likert scale, this study measures stakeholders' awareness, acceptability, and congruence with CapSU's VMG and the program outcomes of the College of Education. The gathered data were analyzed using weighted mean, T-test, and Pearson Correlation via SPSS software (version 20). Findings suggest a high level of awareness and acceptance of CAPSU’s VMGO among internal and external stakeholders, and a high congruence between the VMGO and actual educational practices. Interestingly, external stakeholders showed moderate acceptance of the College of Education's program outcomes. No significant difference was found between internal and external stakeholders' levels of awareness and acceptance, nor any correlation among these variables. The study concludes by highlighting the necessity for continuous efforts to enhance stakeholders' awareness, acceptance, and congruence with the VMGO and program outcomes. Additionally, it emphasizes the importance of stakeholder involvement in any revision process related to the VMGO. Lastly, the study recommends periodic assessments of stakeholders' awareness and acceptance of the VMG for sustainable institutional development.