bluuebunny/crossref_metadata_2025 huggingface dataset:
Tectonomagmatic evolution of southwestern Laurentia: Insights from zircon U-Pb geochronology and hafnium isotopic composition of the Red Bluff Granite Suite, west Texas, USA
Authors: Mahar Munazzam Ali , Goodell Philip C. , Ricketts Jason W. , Kappus Eric J. , Crowley James L. , Alvarez Anthony M.
Published: February 2023

We provide laser ablation–multicollector–inductively coupled plasma–mass spectrometry (LA-MC-ICP-MS) and high-precision chemical abrasion–isotope dilution–thermal ionization mass spectrometry (CA-ID-TIMS) U-Pb ages and Hf isotopic compositions of zircons from the Red Bluff Granite Suite and mafic dikes in the Franklin Mountains of El Paso, Texas, USA. Granitoids exposed in the Franklin Mountains were previously divided into five magmatic stages based on cross-cutting relationships. Major and trace element compositions showed that these granitoids are ferroan, alkaline, and A2 type. Homogeneity in the whole-rock geochemistry suggests that the granite stages are genetically related and share similar petrogenetic histories. Weighted mean zircon 206Pb/238U dates from the older magmatic stage 1 alkali-feldspar quartz syenite and stage 2 alkali-feldspar granite are 1112.36 ± 0.35 and 1112.46 ± 0.37 Ma, respectively. The weighted mean εHf(t) values varying from +5.3 to +7.2 are similar to those of other regional ca. 1.1 Ga magmatic rocks throughout southwestern Laurentia. Geochemical characteristics, petrological modeling, and enriched Hf isotopic composition suggest fractional crystallization of a basaltic magma that was produced by melting of an enriched mantle reservoir. However, zircon inheritance ages of ca. 1.3 Ga and 1.26–1.15 Ga are consistent with a minor contribution from felsic crustal basement. Our data and regional geology are consistent with a post-collisional slab break-off that facilitated asthenospheric upwelling and partial melting of the enriched mantle, possibly subcontinental lithospheric mantle, extending from Llano Uplift, Texas, in the southeast to California to the northwest. Magma thus generated upon differentiation produced ferroan and A-type granitoids.
Missed or delayed diagnosis of anorectal malformations: a review of the literature, current training and practice in the UK in relation to detection via the NIPE programme
Authors: Murthi Govind V S , McEwan Thomas , Walker Gregor M , Bustani Porus
Published: February 2023

Anorectal malformations (ARMs) are a spectrum of congenital anomalies where there is abnormal development of the anus and rectum. With an incidence of 1:5000 live births and affecting both males and females, these anomalies vary in their appearance and presentation, lack features enabling antenatal detection and should be detected at birth by the examining midwife or within 72 hours through the newborn and infant physical examination (NIPE) screening programme. However, it is recognised that the diagnosis of ARMs can be missed or delayed leading to morbidity and mortality. In the UK, despite the existence of the NIPE screening programme and NICE guidelines, published literature shows that nearly a quarter of ARMs are not diagnosed at birth. This review takes a critical look at the frequency of missed/delayed diagnosis of ARMs at birth, the implications of delayed diagnosis, and the possible reasons for this related to education and training of healthcare professionals involved in newborn examination, focusing on the UK national screening programme for NIPE. We propose a strategy for enhancing detection of ARMs in a timely manner through the existing framework of the NIPE screening programme.
Long-term survivor of giant pancreatic solid pseudopapillary neoplasm with splenic infiltration and lymph node metastasis
Authors: Ogawa Daisuke , Okabe Hirohisa , Masuda Toshiro , Sugita Hiroki
Published: February 2023

A man in his 70s with a 10 cm abdominal mass in the tail of the pancreas was diagnosed with pancreatic tail cancer. Distal pancreatectomy with curative intent was performed. Since tumour invasion of the spleen and transverse colon was suspected, pancreatectomy with splenectomy, left adrenalectomy and partial transverse colectomy was performed. Pathological examination of the resected specimen showed a giant pancreatic tumour, and a diagnosis of locally invasive solid pseudopapillary neoplasm (SPN) of the pancreas was made. The patient achieved 8-year survival without any recurrences. We herein report a very rare case of a giant pancreatic SPN with splenic infiltration and lymph node metastasis that was cured by resection.
Aspetar clinical practice guideline on rehabilitation after anterior cruciate ligament reconstruction
Authors: Kotsifaki Roula , Korakakis Vasileios , King Enda , Barbosa Olivia , Maree Dustin , Pantouveris Michail , Bjerregaard Andreas , Luomajoki Julius , Wilhelmsen Jan , Whiteley Rodney
Published: February 2023

This guideline was developed to inform clinical practice on rehabilitation after anterior cruciate ligament reconstruction (ACLR) and was performed in accordance with the Appraisal of Guidelines for REsearch & Evaluation II (AGREE II) instrument and used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. A Guideline Development Group systematically searched and reviewed evidence using randomised clinical trials and systematic reviews to evaluate the effectiveness of rehabilitation interventions and guide clinicians and patients on the content of the optimal rehabilitation protocol after ACLR.

The guideline targets patients during rehabilitation after ACLR and investigates the effectiveness of the available interventions to the physiotherapist, alone or in combination (eg, exercise, modalities, objective progression criteria). Exercise interventions should be considered the mainstay of ACLR rehabilitation. However, there is little evidence on the dose–response relationship between volume and/or intensity of exercise and outcomes. Physical therapy modalities can be helpful as an adjunct in the early phase of rehabilitation when pain, swelling and limitations in range of motion are present. Adding modalities in the early phase may allow earlier pain-free commencement of exercise rehabilitation. Return to running and return to training/activity are key milestones for rehabilitation after ACLR. However, there is no evidence on which progression or discharge criteria should be used.

While there is a very low level of certainty for most components of rehabilitation, most of the recommendations provided in this guideline were agreed to by expert clinicians. This guideline also highlights several new elements of ACLR management not reported previously.
Socioecological factors linked with pharmaceutical incentive-driven prescribing in Pakistan
Authors: Noor Muhammad Naveed , Rahman-Shepherd Afifah , Siddiqui Amna Rehana , Aftab Wafa , Shakoor Sadia , Hasan Rumina , Khan Mishal
Published: February 2023

Pharmaceutical marketing through financial incentivisation to general practitioners (GPs) is a poorly studied health system problem in Pakistan. Pharmaceutical incentivisation is seen to be distorting GPs prescribing behaviour that can compromise the health and well-being of patients. We draw on a conceptual framework outlined in the ecological system theory to identify multiple factors linked with pharmaceutical incentivisation to GPs in Pakistan. We conducted qualitative interviews with 28 policy actors to seek their views on the health system dynamics, how they sustain pharmaceutical incentivisation and their effect on the quality of care. Our analysis revealed four interlinked factors operating at different levels and how they collectively contribute to pharmaceutical incentivisation. In addition to influences such as the increasing family needs and peers’ financial success, sometimes GPs may naturally be inclined to maximise incomes by engaging in pharmaceutical incentivisation. On other hand, the pharmaceutical market dynamics that involve that competition underpinned by a profit-maximisation mindset enable pharmaceutical companies to meet GPs’ desires/needs in return for prescribing their products. Inadequate monitoring and health regulations may further permit the pharmaceutical industry and GPs to sustain the incentive-driven relationship. Our findings have important implications for potential health reforms such as introducing regulatory controls, and appropriate monitoring and regulation of the private health sector, required to address pharmaceutical incentivisation to GPs.
Trauma and syncope: looking beyond the injury
Authors: Kavi Kieran S , Gall Nicholas P
Published: February 2023

Background

42% of the population experience syncope by the age of 70, accounting for up to 6% of hospital admissions that frequently present as falls. The etiologies of some falls are benign, and others, such as cardiac syncope, are associated with a greater mortality and must be identified.

Methods

This review article aims to bridge the literature gap by providing a comprehensive practice review and critical summary of the current syncope guidance relating to the trauma patient.

Results

The National Institute for Health and Care Excellence, the American College of Cardiology, and European Society of Cardiology published syncope risk stratification guidance. The inclusion of certain high-risk features represented in all three guidelines suggests their significance to identify cardiac syncope including heart failure, abnormal vital signs, syncope during exercise with little to no prodrome, family history of sudden cardiac death, and ECG abnormalities. Of 11 syncope risk stratification scoring systems based on these guidelines, only 2 are externally validated in the emergency department, neither of which are validated for major trauma use. Adherence to thorough history-taking, examination, orthostatic blood pressure recording, and an ECG can diagnose the cause of syncope in up to 50% of patients. ECG findings are 95% to 98% sensitive in the detection of serious adverse outcomes after cardiac syncope and should form part of a standardized syncope trauma assessment. Routine blood testing in trauma is often performed despite evidence that it is neither useful nor cost effective, where the screening of cardiac enzymes and D-dimer rarely influences management.

Discussion

In the absence of a gold-standard clinical test to identify the cause of a syncopal episode, standardized syncope guidelines as described in this review could be incorporated into trauma protocols to analyze high-risk etiologies, improve diagnostic accuracy, reduce unnecessary investigations, and develop an effective and safer management strategy.
Shoreline change rates and land to sea sediment and soil organic carbon transfer in eastern Parry Peninsula from 1965 to 2020 (Amundsen Gulf, Canada)
Authors: Tanguy Rodrigue , Whalen Dustin , Prates Gonçalo , Vieira Gonçalo
Published: February 2023

As the Arctic warms, permafrost coasts are eroding faster, threatening coastal communities, habitats, and altering sediment and nutrient budgets. The western Canadian Arctic is eroding at a rapid pace, however little is known on changes occurring in the Amundsen Gulf area. This study was conducted in the eastern coast of Parry Peninsula, a neglected rock-dominated coastal area. We used orthorectified aerial photos of 1965 and 1993 and very-high resolution satellite imagery of 2020 to manually delineate the shoreline according to backshore and foreshore centered approaches. Shoreline change rates were calculated and sediment and Organic Carbon transfer from land to sea estimated using digital elevation model, the Northern Circumpolar Soil Carbon Database and ground-ice content. The results show a mean erosion rate of 0.12 m/yr for the backshore zone and 0.16 m/yr for the foreshore zone, with increasing erosion in the Paulatuk Peninsula in recent decades. The average sediment transfer from land to sea was 20 m3/m/yr and the SOC flux was 7 kg C/m/yr. We highlight the importance of using the cliff-top as shoreline reference to accurately estimate sediment and SOC transfers, an approach neglected in automatic shoreline delineation techniques based on remote sensing imagery using the waterline.
An existing pile efficiency method for the design of lateral new pile behavior in sites with existing piles
Authors: Li Hongjiang , Tamura Shuji
Published: February 2023

Foundation reuse is the development trend of sustainable engineering construction. However, the reuse of existing piles as rigid inclusions and their contribution to newly constructed piles (new piles) under different new and existing pile spacings are still insufficiently understood. In this paper, a series of numerical investigations were conducted based on centrifuge tests to examine the effect of existing piles on the lateral behavior of new piles under different pile spacings. The existing pile efficiency that reflects the contribution of existing piles to the lateral capacity of new piles was analyzed, and it was shown that the impact of existing piles decays exponentially with the pile spacing between new and existing piles. Beyond the spacing of 6 D ( D: the diameter of new piles), the lateral new pile–soil–existing pile interaction can be neglected. A parametric study was subsequently performed to quantify the existing pile efficiency under different variables, including the new pile-head restraint, loading displacement, bending stiffness, load eccentricity, embedded depth, and soil properties. Finally, an existing pile efficiency-based method for the estimation of the lateral capacity of new piles was proposed, which provides an efficient way to design laterally loaded new piles in sites with existing piles.
Carbonate-rock aquifers in arid environments (central Tunisia, Western Mediterranean province): gravity and time domain electromagnetic methods investigations
Authors: Hamrouni Mohamed , Gabtni Hakim
Published: February 2023

Gravity and time domain electromagnetic (TDEM) methods were used in this study to investigate the subsurface hydrogeology of the carbonate-rock aquifer in arid environments (central Tunisia, Western Mediterranean province). The El Houdh basin can be considered an appropriate case for evaluating the vulnerability of groundwater resources under present-day climate change. The identification of structural context and the discontinuities affecting the Eocene or Campanian to Maastrichtian carbonates is an important key to recognize water recharge and discharge pathways and to develop effective and long-term groundwater exploration strategies. First, we have produced an available residual gravity field using a specific Gaussian filter. Then, we generated derivative maps, Euler deconvolution solutions map and a 3D gravity model to delineate different anomalies and to estimate the depth-to-basement parameter and the subsurface density contrasts. Positive and negative anomalies mapping and 3D gravity modelling showed that the El Houdh basin is associated with an asymmetric ‘perched syncline’ with a segmentation into NE–SW sub-basins (local negative residual anomalies) separated by NW–SE lineaments. The TDEM survey was calibrated using boreholes to image the karst saturated and unsaturated zone and to deduce the epikarst and endokarst relationship. Finally, the proposed method provides a fast and valuable approach for better management of hydrogeological exploitation.

Thematic collection:
This article is part of the Climate change and resilience in Engineering Geology and Hydrogeology collection available at:
https://www.lyellcollection.org/cc/climate-change-and-resilience-in-engineering-geology-and-hydrogeology
Improved Fuel Cell Chemical Durability of an Heteropoly Acid Functionalized Perfluorinated Terpolymer-Perfluorosulfonic Acid Composite Membrane
Authors: Kim ChulOong , Wu Ivy , Kuo Mei-Chen , Carmosino Dominic J. , Bloom Ethan W. , Seifert Soenke , Cullen David A. , Ha Phuc , Lindell Matthew J. , Jiang Ruichun , Gittleman Craig S. , Yandrasits Michael A. , Herring Andrew M.
Published: February 2023

Commercial proton exchange membrane heavy-duty fuel cell vehicles will require a five-fold increase in durability compared to current state-of-the art light-duty fuel cell vehicles. We describe a new composite membrane that incorporates silicotungstic heteroply acid (HPA), α-K8SiW11O40▪13H2O, a radical decomposition catalyst and when acid-exchanged can potentially conduct protons. The HPA was covalently bound to a terpolymer of tetrafluoroethylene, vinylidene fluoride, and sulfonyl fluoride containing monomer (1,1,2,2,3,3,4,4-octafluoro-4-((1,2,2-trifluorovinyl)oxy)butane-1-sulfonyl fluoride) by dehydrofluorination followed by addition of diethyl (4-hydroxyphenyl) phosphonate, giving a perfluorosulfonic acid-vinylidene fluoride-heteropoly acid (PFSA-VDF-HPA). A composite membrane was fabricated using a blend of the PFSA-VDF-HPA and the 800EW 3M perfluoro sulfonic acid polymer. The bottom liner-side of the membrane tended to have a higher proportion of HPA moieties compared to the air-side as gravity caused the higher mass density PFSA-VDF-HPA to settle. The composite membrane was shown to have less swelling, more hydrophobic properties, and higher crystallinity than the pure PFSA membrane. The proton conductivity of the membrane was 0.130 ± 0.03 S cm−1 at 80 °C and 95% RH. Impressively, when the membrane with HPA-rich side was facing the anode, the membrane survived more than 800 h under accelerated stress test conditions of open-circuit voltage, 90 °C and 30% RH.
Highly Efficient Sensing of Hydrogen Peroxide Based on Atomically Dispersed Iron- and Nitrogen-Doped Carbon
Authors: Chen Jingchao , Yang Jie , Ding Ruimin , Liu Shanshan , Chen Lifang , Shi Wenwen , Yin Xi
Published: February 2023

Electrochemical hydrogen peroxide (H2O2) sensors are valuable tools in biological research and industrial applications for in situ monitoring H2O2 levels with the advantages of simplicity, portability, rapid response, and low cost. Herein, we demonstrate a novel electrochemical sensing platform based on Fe- and N-doped C composite (Fe–N–C) modified electrodes for sensitive detection of H2O2. This platform showed an excellent response to H2O2 reduction in near-neutral pH solutions with a low reduction potential and high sensitivities. The results of site-poisoning experiments suggest that the atomically dispersed Fe–Nx sites, which resemble the peroxidase-type enzymes, contribute to the high activity of the Fe-N-C catalyst for the H2O2 reduction reaction. Further, we developed a screen-printed electrode (SPE) modified with Fe–N–C with excellent electrocatalytic performances, including a favorable sensitivity (24.95 ± 0.77 μA μM−1 cm−2) and a low detection reagent (40 μl solution). Moreover, the as-prepared Fe–N–C/SPE was successfully applied to H2O2 sensing in an actual milk sample, with good recovery (between 98% and 102%). The as-prepared Fe–N–C/SPE sensor also exhibits superior selectivity, stability, and reproducibility, making it a promising candidate as a portable platform for H2O2 analytes, further improving its practical H2O2 sensing applications.
Rapid Synthesis of C60-MoC Nanocomposites by Molten Salt Electrolysis for Hydrogen Evolution
Authors: Zhou Zhaoyu , Wang Qiang , Yao Heliang , Wang Min , Wu Ping , Wang Heng , Zhang Lingxia , Guo Limin
Published: February 2023

Molybdenum carbide is a promising alternative of Pt/C in H2 evolution reaction (HER). However, its synthesis is time-consuming and energy-intensive. In this work, we propose a rapid one-pot strategy to fabricate C60-MoC nanocomposites in Li2CO3-K2CO3 molten salt using CO2 and ammonium molybdate as carbon and Mo sources, respectively. The as-obtained C60-MoC-600 sample at 600 °C shows high HER activity in both acid and alkaline electrolytes. Especially in 1 M KOH, the η
10 (overpotential at 10 mA cm−2) of C60-MoC-600 is 142 mV. Under an industrial current density of 220 mA cm−2, its activity with an overpotential of 250 mV is close to that of commercial Pt/C and exhibits excellent constant current stability during 10 h. This strategy not only implements the simple synthesis of MoC-based catalysts but also paves a highly efficient way for the rapid abatement and high-value-added utilization of CO2.
Review—Role of Nanomaterials in Screenprinted Electrochemical Biosensors for Detection of Covid-19 and for Post-Covid Syndromes
Authors: Sundeep Dola , Varadharaj Eswaramoorthy K. , Umadevi Kovuri , Jhansi Ragala
Published: February 2023

Covid-19 still remains as global pandemic surging with different variants like alpha, beta, gamma, delta and most omicronin various countries resulted into SARS-CoV-2. An escalation in random testing for Covid-19 is considered as golden standard by World Health Organization (WHO) to control the spread of Corona virus. RT-PCR and nucleic acid hybridization strategies are the two highly sensitive outstanding tests used for the detection of SARS-CoV-2 in the DNA by the former and RNA/DNA by the later. Apart from the test for virus, antigen and antibodies other alternative hematological tests like CRP, Ferritine, IL-6, Blood Platelets and WBC and plasma became essential for the detection and management of Covid-19. Overcoming the limitations a rapid, efficient, low-cost and easy-to-implement test kits are in imperative need to meet the requirement. Electrochemical sensors are considered as potential, ultra-fast and point-of-care sensors used as self-testing kits. In this work, a meta review of various modified electrodes with different nanomaterials such as graphene, CNTs, and nano-dopants used as electrochemical sensors in association with testing various different parameters for detection of Covid-19. A detailed discussion on the merits and demerits of present testing patterns and scope of screen-printed electrochemical sensors modified with different nanomaterials and their advantages are presented.
The effect of single bout and prolonged aerobic exercise on tumor hypoxia in mice
Authors: Elming Pernille Byrialsen , Busk Morten , Wittenborn Thomas Rea , Bussink Johan , Horsman Michael R. , Lønbro Simon
Published: February 2023

This study provides novel information on the effects of acute and chronic exercise on tumor hypoxia in mice. In contrast to the few related existing studies, diverging findings on tumor hypoxia after acute exercise were observed, suggesting that tumor model and location should be considered in future studies. Highly significant reductions in tumor hypoxia following chronic high-intensity exercise propose a future clinical potential but this should be investigated in patients.
PTGIS May Be a Predictive Marker for Ovarian Cancer by Regulating Fatty Acid Metabolism
Authors: Wu Xiaoqing , Lu Wenping , Xu Chaojie , Jiang Cuihong , Zhang Weixuan , Zhang Dongni , Cui Shasha , Zhuo Zhili , Cui Yongjia , Mei Heting , Wang Ya’nan , Li Chen
Published: February 2023

Background. Ovarian cancer tends to metastasize to the omentum, which is an organ mainly composed of adipose tissue. Many studies have found that fatty acid metabolism is related to the occurrence and metastasis of cancers. Therefore, it is possible that fatty acid metabolism‐related genes (FAMRG) affect the prognosis of ovarian cancer patients. Methods. First, profiles of ovarian cancer and normal ovarian tissue transcriptomes were acquired from The Cancer Genome Atlas (TCGA) and the Genotype‐Tissue Expression (GTEx) databases. A LASSO regression predictive model was developed via the “glmnet” R package. The nomogram was created via the “regplot.” Gene Set Variation Analysis (GSVA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) analyses were conducted to determine the FAMRGs’ roles. The percentage of immunocyte infiltration was calculated via CIBERSORT. Using “pRRophetic,” the sensitivity of eight regularly used medications and immunotherapy was anticipated. Results. 125 genes were determined as different expression genes (DEGs). Based on RXRA, ECI2, PTGIS, and ACACB, a prognostic model is created and the risk score is calculated. Analyses of univariate and multivariate regressions revealed that the risk score was a distinct prognostic factor (univariate: HR: 2.855, 95% CI: 1.756‐4.739, P < 0.001; multivariate: HR: 2.943, 95% CI: 1.800‐4.812, P < 0.001). The nomogram demonstrated that it properly predicted the 1‐year survival rate. The expression of memory B molecular units, follicular helper T molecular units, regulatory T molecular units, and M1 macrophages differed remarkably between the groups at high and low risk (P < 0.05). Adipocytokine signaling pathways, cancer pathways, and degradation of valine, leucine, and isoleucine vary between high‐ and low‐risk populations. The findings of the GO enrichment revealed that the extracellular matrix and cellular structure were the two most enriched pathways. PTGIS, which is an important gene in fatty acid metabolism, was identified as the hub gene. This result was verified in ovarian cancer and ovarian tissues. The connection between the gene and survival was statistically remarkable (P = 0.015). The pRRophetic algorithm revealed that the low‐risk group was more adaptable to cisplatin, doxorubicin, 5‐fluorouracil, and etoposide (P < 0.001). Conclusion. PTGIS may be an indicator of prognosis and a possible therapeutic target for the therapy of ovarian cancer patients. The fatty acid metabolism of immune cells may be controlled, which has an indirect effect on cancer cell growth.
A Potential Objective Sign of Central Sensitization: Referred Pain Elicited by Manual Gluteus Minimus Muscle Exploration is Coincident with Pathological Autonomic Response Provoked by Noxious Stimulation
Authors: Skorupska Elzbieta , Dybek Tomasz , Rychlik Michał , Jokiel Marta , Dobrakowski Paweł , Szczerba Anna , Wotzka Daria , Jankowska Anna
Published: February 2023

Referred pain/sensation provoked by trigger points suits the nociplastic pain criteria. There is a debate over whether trigger points are related to a peripheral phenomenon or central sensitization (CS) processes. Referred pain is considered a possible sign of CS, which occurs probably mainly due to the abnormal activity of the immune and autonomic nervous systems. To confirm abnormal autonomic reactivity within the referred pain zone of active trigger points, a new diagnostic tool, the Skorupska Protocol® (the SP test®), was applied. The test uses noxious stimulation (10 minutes of dry needling under infrared camera control) as a diagnostic tool to confirm abnormal autonomic nervous system activity. A response to the SP test® of healthy subjects with referred pain sensations provoked by latent trigger points (LTrPs) stimulation was not explored before. The study aims at examining if LTrPs can develop an autonomic response. Methods. Two groups of healthy subjects, (i) gluteus minimus LTrPs with referred pain (n = 20) and (ii) control (n = 27), were examined using the SP test®. Results. Abnormal autonomic activity within the referred pain zone was confirmed for all analyzed LTrPs subjects. 70% of control subjects had no feature of vasodilatation and others presented minor vasomotor fluctuations. The size of vasomotor reactivity within the referred pain zone was LTrPs 11.1 + 10.96% vs. control 0.8 + 0.6%

p
<
0.05

. Conclusions. Noxious stimulation of latent TrPs induces abnormal autonomic nervous system activity within the referred pain zone. The observed phenomenon supports the concept of central nervous system involvement in the referred pain patomechanizm.
Research on the Targeted Treatment of Squamous Cell Carcinoma by Nanographene Drug Delivery System
Authors: Zhang Xiangyu , Guo Liwei , Sun Zhenbang , Han Deming , Zhao Lihui
Published: February 2023

In order to find an effective cure for squamous cell carcinoma, we innovatively used nano-graphene oxide as a pharmaceutical delivery system, overcoming resistance to cisplatin-targeted anti-squamous carcinoma. For this purpose, we prepared a nano-graphene oxide using an oxidation method, functionally modified with polyethylene glycol (PEG) and branched polyethyleneimine (BPEI) and loaded with the antitumor drug cisplatin (CDDP), a compound with preliminary anticancer efficacy. Then, anti-human squamous cell carcinoma monoclonal antibody was combined to construct a target graphene nanopharmaceutical system. The administration system was applied to nude mice carrying human squamous cell carcinoma. Through the detection of frozen tissue slices, the anti-squamous cell carcinoma effect and targeting of the graphene nanoloaded system were analyzed. The safety of the pharmaceutical system was confirmed through further experiments. Results showed that the NGO-PEG-BPEI-CDDP-Antibody complex had a significant antitumor effect and was able to enter the nude mice and targeted squamous cell carcinoma cell and effectively kill squamous cell carcinoma cells, thus reducing the use of clinical chemotherapeutic drugs, improving the efficacy and providing a new answer for the treatment of squamous cell carcinoma.
Do Temporomandibular Disorder Patients with Joint Pain Exhibit Forward Head Posture? A Cephalometric Study
Authors: Xiao Chu-Qiao , Wan Yi-Dan , Li Ya-Qi , Yan Zhe-Bin , Cheng Qiao-Yu , Fan Pei-Di , Huang Yi , Wang Xiao-Yi , Xiong Xin
Published: February 2023

Purpose. To evaluate head and cervical posture in individuals with or without temporomandibular disorders (TMDs) and to assess the correlations between pain, severity of symptoms, and posture. Methods. A total of 384 patients (129 males and 255 females) was included. The Fonseca Anamnestic Index (FAI) was used to assess the severity and prevalence of TMD and the presence of temporomandibular joint (TMJ) pain. Patients were divided into three groups: the TMD-free group, TMD without TMJ pain group, and TMD with TMJ pain group. Subsequently, the patients with TMJ pain were further divided into mild TMD and moderate/severe TMD groups. Nine parameters were traced on cephalograms to characterize the head and cervical posture. Results. TMD patients with TMJ pain showed increased forward head posture (FHP) than patients without TMJ pain and TMD-free subjects. No significant difference was observed between the TMD patients without TMJ pain and TMD-free subjects. In the TMD patients with the TMJ pain group, the moderate/severe TMD patients demonstrated increased FHP compared to mild TMD patients. TMD patients with joint pain had greater CVT/RL (B = 3.099), OPT/RL (B = 2.117), and NSL/C2’ (B = 4.646) than the patients without joint pain after adjusting for confounding variables (

P
<
0.05

). Conclusion. TMD patients with TMJ pain showed increased FHP compared to other groups, and FHP became more significant as TMD severity increased in male patients, indicating the FHP might play an important role in the development of TMJ pain. In the clinical assessment of TMD, the patients’ abnormal head and cervical posture might be considered.
Biomarker Data from the Phase III KATHERINE Study of Adjuvant T-DM1 versus Trastuzumab for Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer
Authors: Denkert Carsten , Lambertini Chiara , Fasching Peter A. , Pogue-Geile Katherine L. , Mano Max S. , Untch Michael , Wolmark Norman , Huang Chiun-Sheng , Loibl Sibylle , Mamounas Eleftherios P. , Geyer Charles E. , Lucas Peter C. , Boulet Thomas , Song Chunyan , Lewis Gail D. , Nowicka Malgorzata , de Haas Sanne , Basik Mark
Published: February 2023

Purpose:

In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzumab in patients with residual invasive breast cancer after neoadjuvant therapy (NAT) comprised of HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT.

Experimental Design:

Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molecular Subtyping. HER2 expression on paired pre- and post-NAT samples was examined.

Results:

T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab [HR, 2.02; 95% confidence interval (CI), 1.32–3.11], but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56–1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44–1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59–1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples.

Conclusions:

T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.
Anticoagulants Enhance Molecular and Cellular Immunotherapy of Cancer by Improving Tumor Microcirculation Structure and Function and Redistributing Tumor Infiltrates
Authors: Wei Fang , Su Yuling , Quan Yibo , Li Xiaojia , Zou Qi , Zhang Liuxi , Li Shu , Jiang Mengmeng , Lin Guohuan , Liang Ping , He Jie , Xie Keping
Published: February 2023

Purpose:

Pancreatic ductal adenocarcinoma (PDA) resists immunotherapy of adoptive cell transfer (ACT) and immune checkpoint inhibitors. Understanding the mechanisms underlying this resistance will improve PDA immunotherapy. This study investigated therapeutic effects and underlying mechanisms of anticoagulants on immunotherapy in PDA.

Experimental Design:

The antitumor activity of immunotherapy was evaluated in mouse models of desert, excluded, and inflamed tumors. The underlying mechanisms were investigated by analyzing immune cell infiltration by immunofluorescence imaging and tumor microcirculation by interstitial fluid pressure and coagulation status measurement.

Results:

Combined use of heparin and ACT inhibited tumor growth and metastasis, whereas neither heparin nor ACT had any therapeutic effect. The combination of heparin and ACT significantly increased the intratumor infiltration of CD8+ T cells and M1 macrophages and reduced the infiltration of immunosuppressive M2 macrophages and FOXP3+/CD4+ regulatory T cells (Treg). Assessments of tumor microenvironment revealed that heparin promoted tumor vascular regression and normalized the remaining blood vessels, facilitating the extravasation and perivascular accumulation of activated CD8+ T cells in tumors. Mechanistically, tumor microvessel hemodynamic properties were significantly improved by heparin, which is consistent with its inhibitory effects on tumor angiogenesis. Similarly, the combination of heparin and anti-PD1 also produced a pronounced antitumor activity, whereas neither heparin nor anti-PD1 treatment had appreciable antitumor activity.

Conclusions:

Combined treatment of heparin and ACT or anti-PD1 produced synergistic antitumor effects, which were at least in part through tumor vascular normalization, hence increased antitumor T-cell responses due to reduced Treg infiltration and increased M1 macrophage polarization. This synergistic combination therapy warrants clinical evaluation.

See related commentary by Korc, p. 2348
Anabolic Androgenic Steroid Use Patterns and Steroid Use Disorders in a Sample of Male Gym Visitors
Authors: de Zeeuw Tjeerd Idger , Brunt Tibor Markus , van Amsterdam Jan , van de Ven Katinka , van den Brink Wim
Published: February 2023

Introduction: The use of anabolic androgenic steroids (AAS) and other image- and performance-enhancing drugs is a growing public health concern. AAS use is associated with various physical and mental harms, including cardiovascular risks, cognitive deficiencies, and dependence. The aim of this study was to determine whether patterns of AAS use and other variables are associated with the presence of an AAS use disorder (AASUD). Methods: An online survey was completed by 103 male AAS consumers visiting gyms. The association of different patterns of AAS consumption (cycling vs. continuous forms of AAS use), psychoactive substance use, mental health disorders, and sociodemographic variables with moderate-severe AASUD (fifth edition of the Diagnostic and Statistical Manual of Mental Disorders ≥4 criteria) was investigated. The associations between duration of AAS use and the AAS dose with moderate-severe AASUD were investigated using logistic regression analysis with moderate-severe AASUD as the dependent variable. Results: Moderate-severe AASUD was present in 25 (24.3%) of the participants. AAS consumers meeting criteria for moderate-severe AASUD, compared to those that did not, in the last 12 months reported a longer duration of AAS use (in weeks), a higher average AAS dose (mg/week), and a greater number of AAS side effects. Duration of AAS use and the AAS dose were the only independent predictors, with an increase of 3.4% in the probability of moderate-severe AASUD with every week increase of the duration of AAS use in the last year (p < 0.05) and an increase in moderate-severe AASUD of 0.1% with every 10 mg increase in the average AAS dose per week (p < 0.05), respectively. Conclusion: Our findings show that moderate-severe AASUD is relatively frequent among male AAS consumers and is positively associated with the duration and average dose of AAS use in the last 12 months.
Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets
Authors: Sawicki Konrad Teodor , De Jesus Adam , Ardehali Hossein
Published: February 2023

The cardiovascular system requires iron to maintain its high energy demands and metabolic activity. Iron plays a critical role in oxygen transport and storage, mitochondrial function, and enzyme activity. However, excess iron is also cardiotoxic due to its ability to catalyze the formation of reactive oxygen species and promote oxidative damage. While mammalian cells have several redundant iron import mechanisms, they are equipped with a single iron-exporting protein, which makes the cardiovascular system particularly sensitive to iron overload. As a result, iron levels are tightly regulated at many levels to maintain homeostasis. Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich’s ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives.
Integrin-Dependent Cell–Matrix Adhesion in Endothelial Health and Disease
Authors: Aman Jurjan , Margadant Coert
Published: February 2023

The endothelium is a dynamic, semipermeable layer lining all blood vessels, regulating blood vessel formation and barrier function. Proper composition and function of the endothelial barrier are required for fluid homeostasis, and clinical conditions characterized by barrier disruption are associated with severe morbidity and high mortality rates. Endothelial barrier properties are regulated by cell–cell junctions and intracellular signaling pathways governing the cytoskeleton, but recent insights indicate an increasingly important role for integrin-mediated cell–matrix adhesion and signaling in endothelial barrier regulation. Here, we discuss diseases characterized by endothelial barrier disruption, and provide an overview of the composition of endothelial cell–matrix adhesion complexes and associated signaling pathways, their crosstalk with cell–cell junctions, and with other receptors. We further present recent insights into the role of cell–matrix adhesions in the developing and mature/adult endothelium of various vascular beds, and discuss how the dynamic regulation and turnover of cell–matrix adhesions regulates endothelial barrier function in (patho)physiological conditions like angiogenesis, inflammation and in response to hemodynamic stress. Finally, as clinical conditions associated with vascular leak still lack direct treatment, we focus on how understanding of endothelial cell–matrix adhesion may provide novel targets for treatment, and discuss current translational challenges and future perspectives.
Abstract 111: Cerebrovascular Effects Of Pre/post-losartan Treatment In Humanized ACE2 Knock-in Mice After SARS-CoV-2 Spike Protein Injection
Authors: Foster Kaleigh , Moore Joshua , Burnett Faith , Bolduc Deanna , Hafez Sherif S , Coucha Maha , Abdelsaid Mohammed A
Published: February 2023

SARS-CoV-2 has killed millions of people globally and has left many with devastating health problems, including neurological deficits. SARS-CoV-2 invades endothelial cells via binding its Spike-protein with angiotensin-converting enzyme 2 (ACE2) receptors. Losartan, an angiotensin receptor blocker, upregulates ACE2 expression. We hypothesize that pre-treatment with losartan could increase the cerebrovascular dysfunction associated with SARS-CoV-2 spike-protein, while post-SARS-CoV-2 losartan would provide potential protective effects.

Methods:
Recombinant SARS-CoV-2 spike-protein was injected intravenously in transgenic hACE2 mice, humanized ACE2 receptors knock-in mice. Treatment with losartan was started either two weeks before or right after spike-protein injection. Cognitive function was assessed using Y-Maze. Vascular density and cerebral blood flow were evaluated in the hACE2 mice with/out spike protein injection. Western blot and RT-PCR analysis were used to measure protein/gene expression.

Results:
Spike-protein injection decreased cerebral vascular density and cerebral blood flow in hACE2 brains compared to control (*P<0.05), which was associated with increased cognitive dysfunction in
h
ACE2 mice (*P<0.05). Pre-losartan treatment exacerbated spike protein-induced cognitive dysfunction, while post-losartan treatment helped restore cognitive function (*P<0.05). Spike-protein decreased ACE2 expression and increased endothelial cell inflammation and apoptosis, as shown by the increased expression of TNF-
α
; and caspase-3 (*P<0.05), which were prevented by post-losartan treatment.

Conclusion:
Spike-protein decreased vascular density, cerebral blood flow, and cognitive function via increasing brain endothelial cell apoptosis. Pre-losartan treatment exacerbated the detrimental effects of spike-protein, while post-losartan treatment restored ACE2 expression and decreased SARS-CoV-2 spike-protein damaging effects.
Abstract 113: Detection Of Patent Foramen Ovale In Patients With Ischemic Stroke On Prospective ECG-gated Cardiac CT Compared To Transthoracic Echocardiography
Authors: Rinkel Leon A , Bouma Berto , Boekholdt S Matthijs , Beemsterboer Chiel , Lobé Nick H , Beenen Ludo , Marquering Henk , Roos Yvo , Majoie Charles B , van Randen Adrienne , Planken Nils , Coutinho Jonathan
Published: February 2023

Background:
Cardiac CT acquired during the acute stroke imaging protocol is an emerging alternative to transthoracic echocardiography (TTE) to screen for sources of cardioembolism, but its diagnostic accuracy to detect patent foramen ovale (PFO) is unclear.

Methods:
This was a substudy of Mind the Heart, a prospective single-center cohort study in which consecutive adult patients with acute ischemic stroke underwent prospective ECG-gated cardiac CT during the initial stroke imaging protocol. Patients also underwent routine work-up, including TTE. We included patients <60 years who underwent TTE with agitated saline contrast (cTTE). Presence of a PFO on CT and cTTE was scored according to predefined criteria by a cardioradiologist and cardiologist, respectively, who were blinded to each other’s scoring. On CT, PFO was defined as a crypt shaped contrast jet from the left atrium to the right atrium towards the vena cava or an atrium septum discontinuity. On cTTE, a PFO was defined as the appearance of microbubbles in the left atrium within 3-6 cardiac beats after opacification of the right atrium. We assessed the sensitivity and specificity of cardiac CT for the detection of PFO using cTTE as the reference standard.

Results:
Of 452 patients in Mind the Heart, 92 were younger than 60 years. Of these, 56 (61%) patients underwent both cardiac CT and cTTE and were included. Median age was 55 (interquartile range [IQR] 49-57) years and 38 (68%) were male. In total, 32/56 (57%) patients had cryptogenic stroke and their median Risk of Paradoxical Embolism score was 6 (IQR 6-7). Cardiac CT detected a PFO in 5/56 (9%) patients, 3 of which were confirmed on cTTE. cTTE detected a PFO in 12/56 (21%) patients. The sensitivity and specificity of cardiac CT were 25% (95%CI: 5-57%) and 95% (95%CI: 85-99%), respectively. Positive and negative predictive value were 59% (95%CI: 22-87) and 83% (95%CI: 77-87), respectively

Conclusion:
Due to its low sensitivity, prospective ECG-gated cardiac CT does not appear to be a suitable screening method for PFO. If cardiac CT is used to screen for cardioembolism, additional echocardiography remains indicated in patients with cryptogenic stroke in whom PFO detection would have therapeutic consequences.
Abstract 130: History Of Pregnancy Induced Hypertension Is Associated With Markers Of Cerebral Small Vessel Disease: The Northern Manhattan Study And Washington Heights-Hamilton Heights-Inwood Columbia Aging Project
Authors: Miller Eliza C , Bello Natalie A , Booker Whitney A , Sanchez Danurys , Brickman Adam M , Manly Jennifer J , Gutierrez Jose
Published: February 2023

Background:
A history of pregnancy-induced hypertension (PIH) is associated with higher risk of developing cerebrovascular disease. Data are lacking on the relationship between PIH, chronic hypertension, and MRI markers of cerebral small vessel disease (CSVD) in older people.

Methods:
We recruited parous individuals without dementia from the Northern Manhattan Study and the Washington Heights-Inwood Washington Heights-Hamilton Heights-Inwood Columbia Aging Project, two long-running prospective cohort studies in New York City. Detailed obstetric and medical histories were obtained by interview. We defined history of PIH as self-report of at least one pregnancy complicated by gestational hypertension, preeclampsia or eclampsia. We categorized participants as having no hypertension, current hypertension without history of PIH, or current hypertension with history of PIH. Number and location of infarcts and white matter hyperintensity (WMH) volume was assessed by MRI. We used generalized linear models to compare imaging outcomes between groups, adjusting for demographics and cardiovascular risk factors. To account for the effects of early onset hypertension, we performed a sensitivity analysis in NOMAS participants only, adjusting for hypertension as a time varying covariate.

Results:
A total of 221 participants were interviewed (mean age 69 years [SD 7.5]; 22% white, 28% non-Hispanic Black, 48% Hispanic) of whom 128 (58%) had current hypertension without history of PIH, and 16 (7%) had current hypertension with history of PIH. Adjusting for covariates, hypertensive participants with a history of PIH had higher WMH volume, but no difference in deep silent brain infarcts (Table).

Conclusions:
In a multiethnic cohort of older parous individuals, those with hypertension and a history of PIH had the highest volume of WMH, suggesting a higher burden of CSVD.