bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is There Any Relationship between Plasma IL-6 and TNF-α Levels and Lumbar Disc Degeneration? A Retrospective Single-Center Study
Authors: Guo Youfeng , Li Chao , Shen Beiduo , Zhu Ziqi , Chen Xianzhen , Hu Tao , Wu Desheng 
Published: January 2022

Intervertebral disc degeneration (IDD) is one of the most common degenerative diseases all over the world. A growing number of studies have proved that large amounts of cytokines are produced during the development of IDD, and the inflammatory responses induced by these cytokines aggravate the occurrence and development of the disc degeneration. In this retrospective single-center study, a total of 182 lumbar spine cases were retrospectively reviewed between July 2020 and October 2021. An appropriate cutoff value was found for discriminating severity of IDD by William rank-sum test and locally weighted scatterplot smoothing algorithm. The cumulative grade was also calculated by summing Pfirrmann grades for all lumbar spine intervertebral discs. It was found that high-score group (total

score
>
18

) plasma interleukin-6 (IL-6) concentration was significantly higher than that of the low-score group (total

score
≤
18

) (

9.6
±
1.75

vs.

5.40
±
0.61

pg/ml,

p
=
0.002

), tumor necrosis factor-α (TNF-α) following the same trend (

5.27
±
1.48

vs.

2.97
±
0.23

,

p
=
0.006

), which was most pronounced in the upper lumbar intervertebral discs (L1-3). In the entire sample, preoperative IL-6 concentration was significantly higher than that of the postoperation (

p
<
0.001

), while the TNF-α was the opposite (

p
=
0.039

). It was also found that there were significant differences in the two groups with respect to age and hypertension (

p
<
0.001

and

p
=
0.037

). In conclusion, this study preliminarily indicated the relationship between IL-6 and TNF-α and the severity of lumbar disc degeneration.
A Frequency Reconfigurable Compact Planar Inverted-F Antenna for Portable Devices
Authors: Ghaffar Adnan , Altaf Ahsan , Aneja Aayush , Li Xue Jun , Khan Salahuddin , Alibakhshikenari Mohammad , Flalcone Francisco , Limiti Ernesto 
Published: January 2022

In this paper, a low-profile, compact size, inexpensive, and easily integrable frequency reconfigurable antenna system is proposed. The proposed antenna consists of an inverted-F shape antenna, capacitors, and switching PIN diodes. The designed antenna element is fabricated on easy available and less expensive FR-4 substrate (

ε

r

= 4.4, tan

δ

= 0.02). The switching diodes are incorporated within the radiating structure of the antenna design, and by changing the different states of PIN diodes, frequency reconfigurable response is achieved. While adjusting the different states of the diodes, the antenna resonates between 0.841 GHz and 2.12 GHz and covers six different frequency bands. The proposed system has compact size of

44
×
14
×
3.2

mm

3

. The gain of the antenna is between 1.89 and 2.12 dBi. The measurement results shows the good agreement with simulated results for different key performance parameters. Additionally, the proposed antenna shows omni-directional far-field characteristics for various different frequencies.
CircRPN2 Inhibits Aerobic Glycolysis and Metastasis in Hepatocellular Carcinoma
Authors: Li Jia , Hu Zhi-Qiang , Yu Song-Yang , Mao Li , Zhou Zheng-Jun , Wang Peng-Cheng , Gong Yu , Su Sheng , Zhou Jian , Fan Jia , Zhou Shao-Lai , Huang Xiao-Wu 
Published: January 2022

Abstract

Although circular RNAs (circRNA) are known to modulate tumor initiation and progression, their role in hepatocellular carcinoma (HCC) metastasis remains poorly understood. Here, three metastasis-associated circRNAs identified in a previous circRNA-sequencing study were screened and validated in two HCC cohorts. CircRPN2 was downregulated in highly metastatic HCC cell lines and HCC tissues with metastasis. Patients with HCC with lower circRPN2 levels displayed shorter overall survival and higher rates of cumulative recurrence. Mechanistic studies in vitro and in vivo revealed that circRPN2 binds to enolase 1 (ENO1) and accelerates its degradation to promote glycolytic reprogramming through the AKT/mTOR pathway, thereby inhibiting HCC metastasis. CircRPN2 also acted as a competing endogenous RNA for miR-183–5p, which increases forkhead box protein O1 (FOXO1) expression to suppress glucose metabolism and tumor progression. In clinical samples, circRPN2 expression negatively correlated with ENO1 and positively correlated with FOXO1, and expression of circRPN2, either alone or in combination with ENO1 and FOXO1, was a novel indicator of HCC prognosis. These data support a model wherein circRPN2 inhibits HCC aerobic glycolysis and metastasis via acceleration of ENO1 degradation and regulation of the miR-183–5p/FOXO1 axis, suggesting that circRPN2 represents a possible therapeutic target in HCC.

Significance:
The circRNA circRPN2 is a potential prognostic biomarker and therapeutic target in hepatocellular carcinoma that suppresses aerobic glycolysis and metastasis.
Phase I Trial Combining Chemokine-Targeting with Loco-Regional Chemoimmunotherapy for Recurrent, Platinum-Sensitive Ovarian Cancer Shows Induction of CXCR3 Ligands and Markers of Type 1 Immunity
Authors: Orr Brian , Mahdi Haider , Fang Yusi , Strange Mary , Uygun Ibrahim , Rana Mainpal , Zhang Lixin , Suarez Mora Adria , Pusateri Alexandra , Elishaev Esther , Kang Chaeryon , Tseng George , Gooding William , Edwards Robert P. , Kalinski Pawel , Vlad Anda M. 
Published: January 2022

Abstract

Purpose:
Increased prevalence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts positive outcomes in patients with epithelial ovarian cancer (EOC), whereas the regulatory T cells (Treg) predict poor outcomes. Guided by the synergistic activity of TLR3 ligands, IFNα, and COX-2 blockers in selectively enhancing CTL-attractants but suppressing Treg-attractants, we tested a novel intraperitoneal chemoimmunotherapy combination (CITC), to assess its tolerability and TME-modulatory impact in patients with recurrent EOC.

Patients and Methods:
Twelve patients were enrolled in phase I portion of the trial NCT02432378, and treated with intraperitoneal cisplatin, intraperitoneal rintatolimod (dsRNA, TLR3 ligand), and oral celecoxib (COX-2 blocker). Patients in cohorts 2, 3, and 4 also received intraperitoneal IFNα at 2, 6, and 18 million units (MU), respectively. Primary objectives were to evaluate safety, identify phase 2 recommended dose (P2RD), and characterize changes in the immune TME. Peritoneal resident cells and intraperitoneal wash fluid were profiled via NanoString and Meso Scale Discovery (MSD) multiplex assay, respectively.

Results:
The P2RD of IFNα was 6 MU. Median progression-free survival and overall survival were 8.4 and 30 months, respectively. Longitudinal sampling of the peritoneal cavity via intraperitoneal washes demonstrated local upregulation of IFN-stimulated genes (ISG), including CTL-attracting chemokines (CXCL-9, -10, -11), MHC I/II, perforin, and granzymes. These changes were present 2 days after chemokine modulation and subsided within 1 week.

Conclusions:
The chemokine-modulating intraperitoneal-CITC is safe, tolerable, and associated with ISG changes that favor CTL chemoattraction and function. This combination (plus DC vaccine) will be tested in a phase II trial.
See related commentary by Aranda et al., p. 1993
Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment
Authors: Hoes Louisa R. , van Berge Henegouwen Jade M. , van der Wijngaart Hanneke , Zeverijn Laurien J. , van der Velden Daphne L. , van de Haar Joris , Roepman Paul , de Leng Wendy J. , Jansen Anne M.L. , van Werkhoven Erik , van der Noort Vincent , Huitema Alwin D.R. , Gort Eelke H. , de Groot Jan Willem B. , Kerver Emile D. , de Groot Derk Jan , Erdkamp Frans , Beerepoot Laurens V. , Hendriks Mathijs P. , Smit Egbert F. , van der Graaf Winette T.A. , van Herpen Carla M.L. , Labots Mariette , Hoeben Ann , Morreau Hans , Lolkema Martijn P. , Cuppen Edwin , Gelderblom Hans , Verheul Henk M.W. , Voest Emile E. 
Published: January 2022

Abstract

Purpose:
Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers.

Experimental Design:
In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks).

Results:
Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup.

Conclusions:
Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.
Tumor Microenvironment Acidity Triggers Lipid Accumulation in Liver Cancer via SCD1 Activation
Authors: Ding Ming , Zhang Shuwei , Guo Yajuan , Yao Jingjing , Shen Qinghong , Huang Min , Chen Wenbo , Yu Shaofang , Zheng Yaqiu , Lin Yuefang , Yan Wenxin , Liu Zhongqiu , Su Tao , Lu Linlin 
Published: January 2022

Abstract

Acidification is recognized as the predominant characteristic of the tumor microenvironment (TME) and contributes to tumor progression. However, the mechanism of extracellular acidic TME directly influences intercellular pathologic responses remains unclear. Meanwhile, acidic TME is mainly ascribed to aberrant metabolism of lipids and glucose, but whether and how acidity affects metabolic reprogramming, especially for lipid metabolism, is still unknown. We found that lipid was significantly accumulated in liver cancer cells when exposed to acidic TME. Moreover, proteomic analysis showed that differentially expressed proteins were mainly clustered into fatty acid pathways. Subsequently, we found that acidification increased the expression of SCD1 by activating PI3K/AKT signaling pathway. Interestingly, we found that SCD1 directly bound to PPARα in the acidic TME, which vanished after 2-day reverse incubation in pH 7.4 medium, implying extracellular acidosis might influence intercellular function by mediating the binding affinity between SCD1 and PPARα under different pH gradients. In summary, our data revealed that acidosis could significantly trigger fatty acid synthesis to promote liver tumorigenesis by upregulating SCD1 in a PI3K/AKT activation dependent manner and simultaneously promote SCD1 binding to PPARα. Our study not only provides direct mechanistic evidence to support the vital role of acidosis in lipid metabolic reprogramming, but also provides novel insights for determining the binding affinity of functional proteins as a molecular mechanism to better understand the role of the acidic TME in tumor development.

Implications:
The acidic TME contributes to lipid accumulation in liver cancer by activating the PI3K/AKT signaling pathway and promoting SCD1–PPARα binding.
MOB3A Bypasses BRAF and RAS Oncogene-Induced Senescence by Engaging the Hippo Pathway
Authors: Dutchak Kendall , Garnett Sam , Nicoll Mary , de Bruyns Angeline , Dankort David 
Published: January 2022

AbstractOncogenic activation of the RTK–RAS–RAF–MEK–ERK pathway occurs in approximately 25% of all human cancers, yet activated RAS, BRAF, or MEK expression in primary cells leads to a prolonged and predominantly irreversible cell-cycle arrest termed oncogene-induced senescence (OIS). OIS acts as an intrinsic tumor suppressor mechanism, serving as a barrier to tumor progression. Screening a library of activated kinases and kinase-regulatory proteins we identified MOB3A, a Mps-one binder coactivator (MOB) protein family member, whose constitutive expression permits proliferation and suppresses senescence in response to oncogenic RAS and BRAF signals. MOB3A is one of seven human MOB genes, which are highly conserved from yeast to human and that function to activate the Hippo pathway kinases (MST/LATS) or NDR kinases through direct association. Here we show that within the MOB family of genes MOB3A and C are unique in their ability to allow primary cell proliferation in the face of sustained oncogene signaling. Unlike the canonical MOB1A/B proteins, MOB3A inhibits Hippo/MST/LATS signaling and constitutive MOB3A membrane localization phenocopies OIS bypass seen with elevated YAP expression. Moreover, inhibition of MOB3 family member expression results in decreased proliferation and tumor growth of cancer cell lines. Together these data identify MOB3A's role in bypass of oncogene induced senescence and its role as a Hippo pathway inhibitor.Implications:These results suggest that MOB3 targeting to re-engage the Hippo pathway, or direct targeting of YAP/TAZ, may be viable therapeutic strategies potential for RAS-pathway driven tumours.
A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation
Authors: Simanshu Dhirendra K. , Morrison Deborah K. 
Published: January 2022

Abstract

The RAS GTPases are frequently mutated in human cancer, with KRAS being the predominant tumor driver. For many years, it has been known that the structure and function of RAS are integrally linked, as structural changes induced by GTP binding or mutational events determine the ability of RAS to interact with regulators and effectors. Recently, a wealth of information has emerged from structures of specific KRAS mutants and from structures of multiprotein complexes containing RAS and/or RAF, an essential effector of RAS. These structures provide key insights regarding RAS and RAF regulation as well as promising new strategies for therapeutic intervention.

Significance:
The RAS GTPases are major drivers of tumorigenesis, and for RAS proteins to exert their full oncogenic potential, they must interact with the RAF kinases to initiate ERK cascade signaling. Although binding to RAS is typically a prerequisite for RAF to become an activated kinase, determining the molecular mechanisms by which this interaction results in RAF activation has been a challenging task. A major advance in understanding this process and RAF regulation has come from recent structural studies of various RAS and RAF multiprotein signaling complexes, revealing new avenues for drug discovery.
Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment during Chemoradiotherapy Is Prognostic in HPV16+ Cancers
Authors: Colbert Lauren E. , El Molly B. , Lynn Erica J. , Bronk Julianna , Karpinets Tatiana V. , Wu Xiaogang , Chapman Bhavana V. , Sims Travis T. , Lin Daniel , Kouzy Ramez , Sammouri Julie , Biegert Greyson , Delgado Medrano Andrea Y. , Olvera Adilene , Sastry K. Jagannadha , Eifel Patricia J. , Jhingran Anuja , Lin Lilie , Ramondetta Lois M. , Futreal Andrew P. , Jazaeri Amir A. , Schmeler Kathleen M. , Yue Jingyan , Mitra Aparna , Yoshida-Court Kyoko , Wargo Jennifer A. , Solley Travis N. , Hegde Venkatesh , Nookala Sita S. , Yanamandra Ananta V. , Dorta-Estremera Stephanie , Mathew Geena , Kavukuntla Rohit , Papso Cassidy , Ahmed-Kaddar Mustapha , Kim Minsoo , Zhang Jianhua , Reuben Alexandre , Holliday Emma B. , Minsky Bruce D. , Koong Albert C. , Koay Eugene J. , Das Prajnan , Taniguchi Cullen M. , Klopp Ann 
Published: January 2022

AbstractHuman papillomavirus (HPV) infection causes 600,000 new cancers worldwide each year. HPV-related cancers express the oncogenic proteins E6 and E7, which could serve as tumor-specific antigens. It is not known whether immunity to E6 and E7 evolves during chemoradiotherapy or affects survival. Using T cells from 2 HPV16+ patients, we conducted functional T-cell assays to identify candidate HPV-specific T cells and common T-cell receptor motifs, which we then analyzed across 86 patients with HPV-related cancers. The HPV-specific clones and E7-related T-cell receptor motifs expanded in the tumor microenvironment over the course of treatment, whereas non–HPV-specific T cells did not. In HPV16+ patients, improved recurrence-free survival was associated with HPV-responsive T-cell expansion during chemoradiotherapy.
Impact of Body Mass Index on Postoperative Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy Undergoing Septal Myectomy
Authors: Zhang Jian , Zhu Changsheng , Nie Changrong , Song Changpeng , Zhang Yang , Huang Manyun , Zheng Xinxin , Lu Jie , Wang Shuiyun , Huang Xiaohong 
Published: January 2022

Background
Obesity is an established cardiovascular risk factor in patients with hypertrophic cardiomyopathy. Postoperative atrial fibrillation (POAF) is one of the most common complications after surgery in patients with obstructive hypertrophic cardiomyopathy (OHCM). We aimed to determine the impact of body mass index (BMI) on the occurrence of POAF in patients with OHCM who underwent septal myectomy.

Methods and Results

In all, 712 OHCM patients without previous atrial fibrillation who underwent septal myectomy were identified. Patients were stratified into 3 groups based on BMI. Of these, 224 (31.5%) had normal weight (BMI<24 kg/m
2
), 339 (47.6%) were overweight (BMI, 24 to <28 kg/m
2
), and 149 (20.9%) were obese (BMI≥28 kg/m
2
). Overweight and obese patients had increased levels of left atrial diameter (
P
<0.001) and left ventricular end‐diastolic diameter (
P
<0.001), compared with patients with normal weight. Among 184 patients (25.8%) developing POAF, 32 cases (14.3%) occurred in the normal weight group, 100 cases (29.5%) occurred in the overweight group, and 52 cases (34.9%) occurred in the obese group (
P
<0.001). Logistic regression analysis indicated that overweight (odds ratio [OR]: 2.161, 95% CI, 1.333–3.503;
P
=0.002) or obesity (OR, 2.803; 95% CI, 1.589–4.944;
P
<0.001), age (OR, 1.037; 95% CI, 1.018–1.057;
P
<0.001), and left atrial diameter (OR, 1.060; 95% CI, 1.027–1.095;
P
<0.001) were independently associated with the occurrence of POAF in patients with OHCM.

Conclusions
Overweight and obesity are strong predictors of POAF in patients with OHCM. Strategies aimed at lowering BMI may be a potential way to prevent POAF.
Hyperglycemia, Risk of Subsequent Stroke, and Efficacy of Dual Antiplatelet Therapy: A Post Hoc Analysis of the POINT Trial
Authors: Mac Grory Brian , Piccini Jonathan P. , Yaghi Shadi , Poli Sven , De Havenon Adam , Rostanski Sara K. , Weiss Martin , Xian Ying , Johnston S. Claiborne , Feng Wuwei 
Published: January 2022

Background
One‐quarter of all strokes are subsequent events. It is not known whether higher levels of blood glucose are associated with an increased risk of subsequent stroke after high‐risk transient ischemic attack or minor ischemic stroke.

Methods and Results

We performed a secondary analysis of the POINT (Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial to evaluate the relationship between serum glucose hyperglycemia (≥180 mg/dL) versus normoglycemia (<180 mg/dL) before enrollment in the trial and outcomes at 90 days. The primary end point was subsequent ischemic stroke modeled by a multivariable Cox model with adjustment for age, sex, race, ethnicity, study treatment assignment, index event, and key comorbidities. Of 4878 patients included in this study, 267 had a recurrent stroke. There was a higher hazard of subsequent stroke in patients with hyperglycemia compared with normoglycemia (adjusted hazard ratio [HR], 1.50 [95% CI, 1.05–2.14]). Treatment with dual antiplatelet therapy was not associated with a reduced hazard of subsequent stroke in patients with hyperglycemia (HR, 1.18 [95% CI, 0.69–2.03]), though the wide confidence interval does not exclude a treatment effect. When modeled as a continuous variable, there was evidence of a nonlinear association between serum glucose and the hazard of subsequent stroke (
P
<0.001).

Conclusions
Hyperglycemia on presentation is associated with an increased risk of subsequent ischemic stroke after high‐risk transient ischemic attack or minor stroke. A rapid, simple assay of serum glucose may be a useful biomarker to identify patients at particularly high risk of subsequent ischemic stroke.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT0099102.
Prevalence and Patterns of Resuscitation‐Associated Injury Detected by Head‐to‐Pelvis Computed Tomography After Successful Out‐of‐Hospital Cardiac Arrest Resuscitation
Authors: Karatasakis Aris , Sarikaya Basar , Liu Linda , Gunn Martin L. , Kudenchuk Peter J. , Gatewood Medley O. , Maynard Charles , Sayre Michael R. , Counts Catherine R. , Carlbom David J. , Edwards Rachael M. , Branch Kelley R. H. 
Published: January 2022

Background
Patients resuscitated from out‐of‐hospital circulatory arrest (OHCA) frequently have cardiopulmonary resuscitation injuries identifiable by computed tomography, although the prevalence, types of injury, and effects on clinical outcomes are poorly characterized.

Methods and Results

We assessed the prevalence of resuscitation‐associated injuries in a prospective, observational study of a head‐to‐pelvis sudden‐death computed tomography scan within 6 hours of successful OHCA resuscitation. Primary outcomes included total injuries and time‐critical injuries (such as organ laceration). Exploratory outcomes were injury associations with mechanical cardiopulmonary resuscitation and survival to discharge. Among 104 patients with OHCA (age 56±15 years, 30% women), 58% had bystander cardiopulmonary resuscitation, and total cardiopulmonary resuscitation time was 15±11 minutes. The prevalence of resuscitation‐associated injury was high (81%), including 15 patients (14%) with time‐critical findings. Patients with resuscitation injury were older (58±15 versus 46±13 years;
P
<0.001), but had otherwise similar baseline characteristics and survival compared with those without. Mechanical chest compression systems (27%) had more frequent sternal fractures (36% versus 12%;
P
=0.009), including displaced fractures (18% versus 1%;
P
=0.005), but no difference in survival (46% versus 41%;
P
=0.66).

Conclusions
In patients resuscitated from OHCA, head‐to‐pelvis sudden‐death computed tomography identified resuscitation injuries in most patients, with nearly 1 in 7 with time‐critical complications, and one‐half with extensive rib‐cage injuries. These data suggest that sudden‐death computed tomography may have additional diagnostic utility and treatment implications beyond evaluating causes of OHCA. These important findings need to also be taken in context of the certain fatal outcome without resuscitation efforts.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03111043.