bluuebunny/crossref_metadata_2025 huggingface dataset:
S2P intramembrane protease RseP degrades small membrane proteins and suppresses the cytotoxicity of intrinsic toxin HokB
Authors: Yokoyama Tatsuhiko , Yamagata Yutaro , Honna Saisei , Mizuno Shinya , Katagiri Shizuka , Oi Rika , Nogi Terukazu , Hizukuri Yohei , Akiyama Yoshinori
Published: July 2023

The site2
-
protease (S2P) family of intramembrane proteases (IMPs) is conserved in all kingdoms of life and cleaves transmembrane proteins within the membrane to regulate and maintain various cellular activities. RseP, an
Escherichia coli
S2P peptidase, is involved in the regulation of gene expression through the regulated cleavage of the two target membrane proteins (RseA and FecR) and in membrane quality control through the proteolytic elimination of remnant signal peptides. RseP is expected to have additional substrates and to be involved in other cellular processes. Recent studies have shown that cells express small membrane proteins (SMPs; single-spanning membrane proteins of approximately 50–100 amino acid residues) with crucial cellular functions. However, little is known about their metabolism, which affects their functions. This study investigated the possible RseP-catalyzed cleavage of
E. coli
SMPs based on the apparent similarity of the sizes and structures of SMPs to those of remnant signal peptides. We screened SMPs cleaved by RseP
in vivo
and
in vitro
and identified 14 SMPs, including HokB, an endogenous toxin that induces persister formation, as potential substrates. We demonstrated that RseP suppresses the cytotoxicity and biological functions of HokB. The identification of several SMPs as novel potential substrates of RseP provides a clue to a comprehensive understanding of the cellular roles of RseP and other S2P peptidases and highlights a novel aspect of the regulation of SMPs.

IMPORTANCE

Membrane proteins play an important role in cell activity and survival. Thus, understanding their dynamics, including proteolytic degradation, is crucial.
E. coli
RseP, an S2P family intramembrane protease, cleaves membrane proteins to regulate gene expression in response to environmental changes and to maintain membrane quality. To identify novel substrates of RseP, we screened small membrane proteins (SMPs), a group of proteins that have recently been shown to have diverse cellular functions, and identified 14 potential substrates. We also showed that RseP suppresses the cytotoxicity of the intrinsic toxin, HokB, an SMP that has been reported to induce persister cell formation, by degrading it. These findings provide new insights into the cellular roles of S2P peptidases and the functional regulation of SMPs.
Longevity of Fungal Mycelia and Nuclear Quality Checks: a New Hypothesis for the Role of Clamp Connections in Dikaryons
Authors: Aanen Duur K. , van ’t Padje Anouk , Auxier Benjamin
Published: July 2023

This paper addresses the stability of mycelial growth in fungi and differences between ascomycetes and basidiomycetes. Starting with general evolutionary theories of multicellularity and the role of sex, we then discuss individuality in fungi.
Growth Transformation of B Cells by Epstein-Barr Virus Requires
IMPDH2
Induction and Nucleolar Hypertrophy
Authors: Sugimoto Atsuko , Watanabe Takahiro , Matsuoka Kazuhiro , Okuno Yusuke , Yanagi Yusuke , Narita Yohei , Mabuchi Seiyo , Nobusue Hiroyuki , Sugihara Eiji , Hirayama Masaya , Ide Tomihiko , Onouchi Takanori , Sato Yoshitaka , Kanda Teru , Saya Hideyuki , Iwatani Yasumasa , Kimura Hiroshi , Murata Takayuki
Published: July 2023

EBV infections cause nucleolar enlargement via the induction of IMPDH2, which are essential for B cell growth transformation by EBV. Although the significance of IMPDH2 induction and nuclear hypertrophy in the tumorigenesis of glioblastoma has been reported, EBV infection brings about the change quickly by using its transcriptional cofactor, EBNA2, and MYC. Moreover, we present here, for the novel, basic evidence that an IMPDH2 inhibitor, namely, MPA or MMF, can be used for EBV-positive posttransplant lymphoproliferative disorder (PTLD).
The Existing Drug Nifuroxazide as an Antischistosomal Agent:
In Vitro
,
In Vivo
, and
In Silico
Studies of Macromolecular Targets
Authors: Roquini Vinícius , Mengarda Ana C. , Cajas Rayssa A. , Martins-da-Silva Milene F. , Godoy-Silva Julia , Santos Gustavo A. , Espírito-Santo Maria Cristina C. , Pavani Thais F. A. , Melo Vanusa A. , Salvadori Maria C. , Teixeira Fernanda S. , Rando Daniela G. G. , de Moraes Josué
Published: July 2023

The increasing recognition of the burden imposed by helminthiasis, associated with the limited therapeutic arsenal, has led to initiatives and strategies to research and develop new drugs for the treatment of schistosomiasis. One of these strategies is drug repurposing, which considers low-risk compounds with potentially reduced costs and shorter time for development.
Host Factor Nucleophosmin 1 (NPM1/B23) Exerts Antiviral Effects against Chikungunya Virus by Its Interaction with Viral Nonstructural Protein 3
Authors: Pradeep Parvanendhu , Sivakumar Krishnankutty Chandrika , Sreekumar Easwaran
Published: July 2023

Chikungunya, a recently reemerged mosquito-borne infection caused by a positive-sense, single-stranded RNA virus, has caused explosive epidemics in tropical regions. Unlike the classical symptoms of acute fever and debilitating arthralgia, incidences of neurological complications and mortality were reported.
Predictors and outcomes of pacemaker implantation in patients with cardiac amyloidosis
Authors: Saturi Giulia , De Frutos Fernando , Sguazzotti Maurizio , Gonzalez-Lopez Esther , Nardi Elena , Domínguez Fernando , Ponziani Alberto , Cabrera Eva , Caponetti Angelo Giuseppe , Lozano Sara , Massa Paolo , Cobo-Marcos Marta , Accietto Antonella , Castro-Urda Victor , Giovannetti Alessandro , Toquero Jorge , Gagliardi Christian , Gómez-Bueno Manuel , Rios-Tamayo Rafael , Biagini Elena , Segovia Javier , Galiè Nazzareno , García-Pavía Pablo , Longhi Simone
Published: July 2023

Objective

We sought to investigate prevalence, incidence and prognostic implications of permanent pacemaker (PPM) implantation in patients with cardiac amyloidosis (CA), thereby identifying the predictors of time to PPM implantation.

Methods

Seven hundred eighty-seven patients with CA (602 men, median age 74 years, 571 transthyretin amyloidosis (ATTR), 216 light-chain amyloidosis (AL)) evaluated at two European referral centres were retrospectively included. Clinical, laboratory and instrumental data were analysed. The associations between PPM implantation and mortality, heart failure (HF) or a composite endpoint of mortality, cardiac transplantation and HF were analysed.

Results

81 (10.3%) patients had a PPM before initial evaluation. Over a median follow-up time of 21.7 months (IQR 9.6–45.2), 81 (10.3%) additional patients (18 with AL (22.2%) and 63 with ATTR (77.8%)) underwent PPM implantation with a median time to implantation of 15.6 months (IQR 4.2–40), complete atrioventricular block was the most common indication (49.4%). Independent predictors of PPM implantation were QRS duration (HR 1.03, 95% CI 1.02 to 1.03, p<0.001) and interventricular septum (IVS) thickness (HR 1.1, 95% CI 1.03 to 1.17, p=0.003). The model to estimate the probability of PPM at 12 months and containing both factors showed a C-statistic of 0.71 and a calibration of slope of 0.98.

Conclusions

Conduction system disease requiring PPM is a common complication in CA that affects up to 20.6% of patients. QRS duration and IVS thickness are independently associated with PPM implantation. A PPM implantation at 12 months model was devised and validated to identify patients with CA at higher risk of requiring a PPM and who require closer follow-up.
Can CANVAS due toRFC1biallelic expansions present with pure ataxia?
Authors: Hadjivassiliou Marios , Currò Riccardo , Beauchamp Nick , Dominik Natalia , Grunewald Richard A , Shanmugarajah Priya , Zis Panayiotis , Hoggard Nigel , Cortese Andrea
Published: July 2023

Background

Biallelic expansion of AAGGG in the replication factor complex subunit 1 (RFC1) was identified as a major cause of cerebellar ataxia, neuropathy (sensory ganglionopathy, or SG) and vestibular areflexia syndrome (CANVAS). We wanted to clarify ifRFC1expansions can present with pure ataxia and if such expansions could be responsible for some cases where an alternative diagnosis had been made.

Methods

We identified patients with a combination of ataxia and SG and no other cause found, patients where an alternative diagnosis had been made, and patients with pure ataxia. Testing forRFC1expansions was done using established methodology.

Results

Among 54 patients with otherwise idiopathic sporadic ataxia without SG, none was found to haveRFC1expansions. Among 38 patients with cerebellar ataxia and SG in which all other causes were excluded, 71% hadRFC1expansions. Among 27 patients with cerebellar ataxia and SG diagnosed with coeliac disease or gluten sensitivity, 15% hadRFC1expansions.

Conclusions

Isolated cerebellar ataxia without SG makes the diagnosis of CANVAS due toRFC1expansions highly improbable, but CANVAS is frequently the cause of the combination of idiopathic cerebellar ataxia with SG. It is important to screen patients diagnosed with other causes of acquired ataxia and SG as a small percentage were found to haveRFC1expansions.
Risk of secondary progressive multiple sclerosis after early worsening of disability
Authors: Dzau Winston , Sharmin Sifat , Patti Francesco , Izquierdo Guillermo , Eichau Sara , Prat Alexandre , Girard Marc , Duquette Pierre , Onofrj Marco , Lugaresi Alessandra , Ozakbas Serkan , Gerlach Oliver , Boz Cavit , Grammond Pierre , Terzi Murat , Amato Maria Pia , La Spitaleri Daniele , Ramo-Tello Cristina , Maimone Davide , Cartechini Elisabetta , Buzzard Katherine , Skibina Olga , van der Walt Anneke , Butzkueven Helmut , Iuliano Gerardo , Soysal Aysun , Kalincik Tomas
Published: July 2023

Background

Whether progression independent of relapse activity (PIRA) heralds earlier onset of secondary progressive multiple sclerosis (SPMS) and more rapid accumulation of disability during SPMS remains to be determined. We investigated the association between early PIRA, relapse-associated worsening (RAW) of disability and time to SPMS, subsequent disability progression and their response to therapy.

Methods

This observational cohort study included patients with relapsing-remitting multiple sclerosis (RRMS) from the MSBase international registry across 146 centres and 39 countries. Associations between the number of PIRA and RAW during early multiple sclerosis (MS) (the initial 5 years of MS onset) were analysed with respect to: time to SPMS using Cox proportional hazards models adjusted for disease characteristics; and disability progression during SPMS, calculated as the change of Multiple Sclerosis Severity Scores over time, using multivariable linear regression.

Results

10 692 patients met the inclusion criteria: 3125 (29%) were men and the mean MS onset age was 32.2 years. A higher number of early PIRA (HR=1.50, 95% CI 1.28 to 1.76, p<0.001) and RAW (HR=2.53, 95% CI 2.25 to 2.85, p<0.001) signalled a higher risk of SPMS. A higher proportion of early disease-modifying therapy exposure (per 10%) reduced the effect of early RAW (HR=0.94, 95% CI 0.89 to 1.00, p=0.041) but not PIRA (HR=0.97, 95% CI 0.91 to 1.05, p=0.49) on SPMS risk. No association between early PIRA/RAW and disability progression during SPMS was found.

Conclusions

Early disability increase during RRMS is associated with a greater risk of SPMS but not the rate of disability progression during SPMS. The deterioration associated with early relapses represents a potentially treatable risk factor of SPMS.

Trial registration number

Australian New Zealand Clinical Trials Registry (ACTRN12605000455662).
Photoelectric properties of monolayer NbS2 and NbSe2 under three types of strain: A first-principles study
Authors: Jie Ni Jun , Yang Lu
Published: July 2023

Based on the first principles, the crystal structure, photoelectric properties, and structural stability of two transition metal dichalcogenides (TMDCs) under different strain treatments are systematically calculated. The properties of NbX2 under tensile and compressive strains are discussed for the first time. Recently, a single-layer 1T structure with X atoms surrounding the transition metal atoms was synthesized in experiments. The 1T multi-forms were octahedral coordination structures, and some of the systems showed excellent semiconductor properties and stability. The results show that NbS2 has an indirect band gap under different strains and tends to transition to semiconductors which can effectively improve the material activity. NbSe2 has more excellent properties in the optical field and can be used to manufacture infrared lenses, anti-reflection coatings, and UV reflectors. This study provides a new understanding of the unconventional structure of NbX2 and provides theoretical guidance for the work in the field of TMDCs.
IgG4-Related Disease: A Concise Review
Authors: Lee Carolyn , To Chi Hung
Published: July 2023

IgG4-related disease (IgG4-RD) is a multi-organ fibroinflammatory disorder that may result in organ dysfunction and complications. Glucocorticoids remain the primary treatment for inducing remission, while recently reported disease phenotypes might inform personalized therapeutic strategies. Progress in understanding the pathophysiology of IgG4-RD has led to the identification of novel treatment targets. Ongoing research will further refine the optimal treatment for IgG4-RD. This review offers an update on the latest evidence on the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of IgG4-RD.
Monazite–xenotime thermometry: a review of best practices and an example from the Caledonides of northern Scotland
Authors: Mako Calvin A. , Caddick Mark J. , Law Richard D. , Thigpen J. Ryan
Published: July 2023

Monazite–xenotime thermometry is a potentially powerful technique for understanding the evolution of Earth systems. While a rich set of experimental and empirical datasets are available for monazite–xenotime equilibria, five different thermometric calibrations yield significantly different results, making this technique difficult to apply in practice. To clarify best practices for monazite–xenotime thermometry, a compilation of published compositional data for monazite and xenotime with independently determined pressure–temperature conditions is evaluated. For each existing thermometer, we examine how closely estimated temperatures match independent empirical temperatures and consider how best to calculate monazite end-members for each thermometer. Monazite–xenotime thermometry is applied to samples from the Northern Highlands Terrane of northern Scotland, which experienced amphibolite–upper greenschist facies metamorphism and penetrative deformation during the Scandian orogeny. Thermometry data in conjunction with U–Pb dating define relatively slow regional cooling across the Scandian thrust nappes. Thermometry data closely match quartz
c
-axis fabric-based deformation thermometry across the structurally lower nappes, suggesting that monazite and xenotime record the timing and temperature of penetrative deformation and shearing. The data suggest that ductile deformation in the hinterland nappes of the Scandian orogen in Scotland occurred as late as 415–410 Ma.
Li-Ni Metal Oxides Processed with Rapid Atmospheric-Pressure-Plasma Jet for Flexible Gel-Electrolyte Li-Ion Hybrid Supercapacitors
Authors: Wu Chia-Ling , Ni I-Chih , Wu Chih-I , Cheng I-Chun , Chen Chien-Fu , Chen Jian-Zhang
Published: July 2023

We use screen printing to deposit LiCl + Ni(NO3)2·6H2O pastes on a flexible carbon cloth substrate and then calcine it using a nitrogen atmospheric-pressure-plasma jet (APPJ). Through the high-temperature treatment by APPJ, pastes can be rapidly converted into Li-Ni oxides (LNOs). The LNOs on carbon cloth are then used as the electrodes of flexible gel-electrolyte Li-ion hybrid supercapacitors (Li-ion HSCs). The best areal capacity of 21.076 mC cm−2, as measured by cyclic voltammetry, is achieved by APPJ treatment at 620 °C for 480 s. To demonstrate the flexibility of the Li-ion HSCs, the Li-ion HSCs were bent at different curvatures to measure its performance. After bending test, the capacity remains >93% under bending with a curvature of up to 2 cm−1.
Interactive classroom: from motoneuron activity to skeletal muscle contraction and relaxation
Authors: Todini Luca , Menchetti Laura
Published: July 2023

We set up an interactive practical classroom, engaging all the attending students of the year ( n = 47). Each student was assigned a physiological role marked on a cardboard sign, starting from motoneuron stimulation up to skeletal muscle contraction and relaxation. Students were asked to actively reproduce physiological events, positioning themselves and moving around and onto drawings on the ground (motoneuron, synapsis, sarcoplasmic reticulum, etc.). Finally, a complete, dynamic, and fluid representation was performed.
Unique miRNome and transcriptome profiles underlie microvascular heterogeneity in mouse kidney
Authors: Luxen Matthijs , Zwiers Peter J. , Meester Femke , Jongman Rianne M. , Kuiper Timara , Moser Jill , Pultar Marianne , Skalicky Susanna , Diendorfer Andreas B. , Hackl Matthias , van Meurs Matijs , Molema Grietje
Published: July 2023

Renal endothelial cells display a high level of heterogeneity depending on the (micro)vascular bed they reside in. The molecular basis contributing to these differences is poorly understood yet of high importance to increase understanding of microvascular engagement in the kidney in health and disease. This report describes m(icro)RNA expression profiles of microvascular beds in the mouse renal cortex and uncovers microvascular compartment-specific m(icro)RNAs and miRNA-mRNA pairs, thereby revealing important molecular mechanisms underlying renal microvascular heterogeneity.
The importance of serial sarcomere addition for muscle function and the impact of aging
Authors: Hinks Avery , Hawke Thomas J. , Franchi Martino V. , Power Geoffrey A.
Published: July 2023

During natural aging, skeletal muscle experiences impairments in mechanical performance due, in part, to changes in muscle architecture and size, notably with a loss of muscle cross-sectional area (CSA). Another important factor that has received less attention is the shortening of fascicle length (FL), potentially reflective of a decrease in serial sarcomere number (SSN). Interventions that promote the growth of new serial sarcomeres, such as chronic stretching and eccentric-biased resistance training, have been suggested as potential ways to mitigate age-related impairments in muscle function. Although current research suggests it is possible to stimulate serial sarcomerogenesis in muscle in old age, the magnitude of sarcomerogenesis may be less than in young muscle. This blunted effect may be partly due to age-related impairments in the pathways regulating mechanotransduction, muscle gene expression, and protein synthesis, as some have been implicated in SSN adaptation. The purpose of this review was to investigate the impact of aging on the ability for serial sarcomerogenesis and elucidate the molecular pathways that may limit serial sarcomerogenesis in old age. Age-related changes in mechanistic target of rapamycin (mTOR), insulin-like growth factor 1 (IGF-1), myostatin, and serum response factor signaling, muscle ring finger protein (MuRFs), and satellite cells may hinder serial sarcomerogenesis. In addition, our current understanding of SSN in older humans is limited by assumptions based on ultrasound-derived fascicle length. Future research should explore the effects of age-related changes in the identified pathways on the ability to stimulate serial sarcomerogenesis, and better estimate SSN adaptations to gain a deeper understanding of the adaptability of muscle in old age.
Age alters the thermoregulatory responses to extreme heat exposure with accompanying activities of daily living
Authors: McKenna Zachary J. , Foster Josh , Atkins Whitley C. , Belval Luke N. , Watso Joseph C. , Jarrard Caitlin P. , Orth Bonnie D. , Crandall Craig G.
Published: July 2023

Using an experimental model of extreme heat exposure that incorporates brief periods of light physical activity to simulate activities of daily living, the extent of thermal strain reported herein more accurately represents what would occur during actual heatwave conditions. Despite matching metabolic heat generation and environmental conditions, we show that older adults have augmented core temperature responses, likely due to age-related reductions in heat dissipating mechanisms.
Aldolase A Promotes Colorectal Cancer Progression through Targeting COPS6 and Regulating MAPK Signaling Pathway
Authors: Lu Ya , Zhang Yuan , Wang Xinyue , Zhang Hui , Zhu Yue , Zhang Junying , Sha Huanhuan , Zou Renrui , Gan Yujie , Sui Ying , Wang Juan , Du Tongde , Wu Jianzhong , Feng Jifeng
Published: July 2023

Colorectal cancer (CRC) is a serious threat to human health, and its underlying mechanisms remain to be further explored. Aldolase A (ALDOA) has received increasing attention for its reported association with multiple cancers, but the role and mechanisms of ALDOA in CRC are still unclear. In the current study, high expression levels and enzymatic activity of ALDOA were detected in CRC tissues and cell lines, indicating the clinical significance of ALDOA in human CRC. In addition, silencing ALDOA significantly impaired the proliferation and metastasis of CRC cells in vitro and in vivo. Mechanistically, immunoprecipitation assays and mass spectrometry analysis identified the binding protein COPS6 of ALDOA. Furthermore, the promoting effects of upregulated ALDOA on CRC cell proliferation and metastasis were inhibited by COPS6 depletion, demonstrating COPS6 was required for ALDOA in mediating CRC progress. Moreover, the epithelial-mesenchymal transition (EMT) program and MAPK signaling pathway were found to be activated by ALDOA overexpression as well. In summary, our findings suggested that ALDOA facilitated the proliferation and metastasis of CRC by binding and regulating COPS6, inducing EMT, and activating the mitogen-activated protein kinase (MAPK) signaling pathway. The present study provided evidence for ALDOA as a promising potential biomarker for CRC.
The Deformation Behavior and Failure Modes of Surrounding Rock after Excavation: A Experimental Study
Authors: Liang Jinping , Jing Haoyong , Li Xiaorui , Hou Gongyu
Published: July 2023

The deformation and failure of the surrounding rock during roadway excavation often determine the choice of supporting methods. To study the deformation behavior and failure modes of the surrounding rock after excavation under unloading stress, structural model tests were carried out with a novel experimental device. The present structural model test using partial hollow thick-walled cylinder cement mortar specimen φ200 mm × 280 mm with a horizontal central circular hole of 60 mm diameter and the hollow height of 160 mm was conducted to investigate the deformation, failure characteristics, and AE response of a whole testing process from excavation to postunloading state. Experimental results revealed that the amount of deformation behind the surface is significantly higher than that in front of the surface, and the radial strain increases with the increase of the distance from the surface within the range affected by unloading. Furthermore, the unloading rate has a little effect on the radial deformation of the surrounding rock in front of the surface, but has a substantial effect on the radial deformation behind the excavation surface. The peak value of the strain rate at the unloading rate of 2 MPa/s is much higher than that at the unloading rate of 0.1 MPa/s. According to AE results and the failure of opening the boundary, the increase of unloading rate triggers and exacerbates the damage of the specimen under high in situ stress conditions. The surrounding rock expanded to the inner hollow, accompanied by large dilation and volume changes, and it resulted in the shrinkage of the hole diameter. A large number of rock slices are generated at the opening curved free surface and then fell off, whose morphology is similar to the rock blocks that fell off after caving failure and rock burst in situ field. The results show that the system can accurately simulate the mechanical response and acoustic emission response of the excavated surrounding rock, which provides a new experimental method for further study of the unloading response of the surrounding rock.
Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment
Authors: Nambiar Dhanya K. , Viswanathan Vignesh , Cao Hongbin , Zhang Weiruo , Guan Li , Chamoli Manish , Holmes Brittany , Kong Christina , Hildebrand Rachel , Koong Amanda Jeanette , von Eyben Rie , Plevritis Sylvia , Li Lingyin , Giaccia Amato , Engleman Edgar , Le Quynh Thu
Published: July 2023

The immune system plays a crucial role in the regulation of metastasis. Tumor cells systemically change immune functions to facilitate metastatic progression. Through this study, we deciphered how tumoral galectin-1 (Gal1) expression shapes the systemic immune environment to promote metastasis in head and neck cancer (HNC). In multiple preclinical models of HNC and lung cancer in immunogenic mice, Gal1 fostered the establishment of a premetastatic niche through polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), which altered the local microenvironment to support metastatic spread. RNA sequencing of MDSCs from premetastatic lungs in these models demonstrated the role of PMN-MDSCs in collagen and extracellular matrix remodeling in the premetastatic compartment. Gal1 promoted MDSC accumulation in the premetastatic niche through the NF-κB signaling axis, triggering enhanced CXCL2-mediated MDSC migration. Mechanistically, Gal1 sustained NF-κB activation in tumor cells by enhancing stimulator of interferon gene (STING) protein stability, leading to prolonged inflammation-driven MDSC expansion. These findings suggest an unexpected protumoral role of STING activation in metastatic progression and establish Gal1 as an endogenous-positive regulator of STING in advanced-stage cancers.

Significance:

Galectin-1 increases STING stability in cancer cells that activates NF-κB signaling and CXCL2 expression to promote MDSC trafficking, which stimulates the generation of a premetastatic niche and facilitates metastatic progression.
CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression
Authors: Kohlmeyer Jordan L. , Lingo Joshua J. , Kaemmer Courtney A. , Scherer Amanda , Warrier Akshaya , Voigt Ellen , Raygoza Garay Juan A. , McGivney Gavin R. , Brockman Qierra R. , Tang Amy , Calizo Ana , Pollard Kai , Zhang Xiaochun , Hirbe Angela C. , Pratilas Christine A. , Leidinger Mariah , Breheny Patrick , Chimenti Michael S. , Sieren Jessica C. , Monga Varun , Tanas Munir R. , Meyerholz David K. , Darbro Benjamin W. , Dodd Rebecca D. , Quelle Dawn E.
Published: July 2023

Purpose:

Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models.

Experimental Design:

Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti–PD-L1 response.

Results:

Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti–PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression.

Conclusions:

CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti–PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.
LncRNA-Encoded Micropeptide ACLY-BP Drives Lipid Deposition and Cell Proliferation in Clear Cell Renal Cell Carcinoma via Maintenance of ACLY Acetylation
Authors: Zhang Shenghua , Zhang Zheng , Liu Xiaolong , Deng Yibin , Zheng Jian , Deng Jieqiong , Wang Yirong , Guo Binbin , Li Fanrong , Chen Xiaoyue , Pan Yacheng , Wang Jieyu , Lu Jiachun , Wu Siqi , Guo Qiang , Zhou Yifeng
Published: July 2023

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of lethal kidney cancer. Reprogramming of fatty acid and glucose metabolism resulting in the accumulation of lipids and glycogen in the cytoplasm is a hallmark of ccRCC. Here, we identified a micropeptide ACLY-BP encoded by the GATA3-suppressed LINC00887, which regulated lipid metabolism and promoted cell proliferation and tumor growth in ccRCC. Mechanistically, the ACLY-BP stabilizes the ATP citrate lyase (ACLY) by maintaining ACLY acetylation and preventing ACLY from ubiquitylation and degradation, thereby leading to lipid deposition in ccRCC and promoting cell proliferation. Our results may offer a new clue for the therapeutic approaches and the diagnostic assessment for ccRCC.

Implications:

This study identifies ACLY-BP encoded by LINC00887 as a lipid-related micropeptide that stabilizes ACLY to generate acetyl-CoA, driving lipid deposition and promoting cell proliferation in ccRCC.
TRIM50 Inhibits Gastric Cancer Progression by Regulating the Ubiquitination and Nuclear Translocation of JUP
Authors: Hu Jiajia , Huang Runjie , Liang Chengcai , Wang Yingnan , Wang Min , Chen Yanxing , Wu Chenyi , Zhang Jinling , Liu Zekun , Zhao Qi , Liu Zexian , Wang Feng , Yuan Shuqiang
Published: July 2023

Gastric cancer is one of the most frequent cancers in the world. Emerging clinical data show that ubiquitination system disruptions are likely involved in carcinoma genesis and progression. However, the precise role of ubiquitin (Ub)-mediated control of oncogene products or tumor suppressors in gastric cancer is unknown. Tripartite motif-containing 50 (TRIM50), an E3 ligase, was discovered by high-output screening of ubiquitination-related genes in tissues from patients with gastric cancer to be among the ubiquitination-related enzymes whose expression was most downregulated in gastric cancer. With two different databases, we verified that TRIM50 expression was lower in tumor tissues relative to normal tissues. TRIM50 also suppressed gastric cancer cell growth and migration in vitro and in vivo. JUP, a transcription factor, was identified as a new TRIM50 ubiquitination target by MS and coimmunoprecipitation experiments. TRIM50 increases JUP K63-linked polyubiquitination mostly at the K57 site. We discovered that the K57 site is critical for JUP nuclear translocation by prediction with the iNuLoC website and further studies. Furthermore, ubiquitination of the K57 site limits JUP nuclear translocation, consequently inhibiting the MYC signaling pathway. These findings identify TRIM50 as a novel coordinator in gastric cancer cells, providing a potential target for the development of new gastric cancer treatment strategies.

Implications:

TRIM50 regulates gastric cancer tumor progression, and these study suggest TRIM50 as a new cancer target.
Updating the Definition of Cancer
Authors: Brown Joel S. , Amend Sarah R. , Austin Robert H. , Gatenby Robert A. , Hammarlund Emma U. , Pienta Kenneth J.
Published: July 2023

Most definitions of cancer broadly conform to the current NCI definition: “Cancer is a disease in which some of the body's cells grow uncontrollably and spread to other parts of the body.” These definitions tend to describe what cancer “looks like” or “does” but do not describe what cancer “is” or “has become.” While reflecting past insights, current definitions have not kept pace with the understanding that the cancer cell is itself transformed and evolving. We propose a revised definition of cancer: Cancer is a disease of uncontrolled proliferation by transformed cells subject to evolution by natural selection. We believe this definition captures the essence of the majority of previous and current definitions. To the simplest definition of cancer as a disease of uncontrolled proliferation of cells, our definition adds in the adjective “transformed” to capture the many tumorigenic processes that cancer cells adopt to metastasize. To the concept of uncontrolled proliferation of transformed cells, our proposed definition then adds “subject to evolution by natural selection.” The subject to evolution by natural selection modernizes the definition to include the genetic and epigenetic changes that accumulate within a population of cancer cells that lead to the lethal phenotype. Cancer is a disease of uncontrolled proliferation by transformed cells subject to evolution by natural selection.
Table S3 from Proteogenomic approaches for the identification of NF1/neurofibromin-depleted estrogen receptor positive breast cancers for targeted treatment
Authors: Kim Beom-Jun , Zheng Ze-Yi , Lei Jonathan T. , Holt Matthew V. , Chen Anran , Peng Jianheng , Fandino Diana , Singh Purba , Kennedy Hilda , Dou Yongchao , Chica-Parrado María del Rosario , Bikorimana Emmanuel , Ye Dan , Wang Yunguan , Hanker Ariella B. , Mohamed Nada , Hilsenbeck Susan G. , Lim Bora , Asirvatham Jaya Ruth , Sreekumar Arun , Zhang Bing , Miles George , Anurag Meenakshi , Ellis Matthew J. , Chang Eric C
Published: July 2023

Table S3. H-scores of NF1 protein levels in patient and PDX tumors as determined by IHC.
Figure S5 from Proteogenomic approaches for the identification of NF1/neurofibromin-depleted estrogen receptor positive breast cancers for targeted treatment
Authors: Kim Beom-Jun , Zheng Ze-Yi , Lei Jonathan T. , Holt Matthew V. , Chen Anran , Peng Jianheng , Fandino Diana , Singh Purba , Kennedy Hilda , Dou Yongchao , Chica-Parrado María del Rosario , Bikorimana Emmanuel , Ye Dan , Wang Yunguan , Hanker Ariella B. , Mohamed Nada , Hilsenbeck Susan G. , Lim Bora , Asirvatham Jaya Ruth , Sreekumar Arun , Zhang Bing , Miles George , Anurag Meenakshi , Ellis Matthew J. , Chang Eric C
Published: July 2023

Figure S5. IHC analysis on NF1 in baseline biopsies from the POL cohort.
Supplementary Figure 6 from Immuno-PET Imaging of CD69 Visualizes T-Cell Activation and Predicts Survival Following Immunotherapy in Murine Glioblastoma
Authors: Nisnboym Michal , Vincze Sarah R. , Xiong Zujian , Sneiderman Chaim T. , Raphael Rebecca A. , Li Bo , Jaswal Ambika P. , Sever ReidAnn E. , Day Kathryn E. , LaToche Joseph D. , Foley Lesley M. , Karimi Hanieh , Hitchens T. Kevin , Agnihotri Sameer , Hu Baoli , Rajasundaram Dhivyaa , Anderson Carolyn J. , Blumenthal Deborah T. , Pearce Thomas M. , Uttam Shikhar , Nedrow Jessie R. , Panigrahy Ashok , Pollack Ian F. , Lieberman Frank S. , Drappatz Jan , Raphael Itay , Edwards Wilson B. , Kohanbash Gary
Published: July 2023

SUV analysis and BioD data of CD69 immuno-PET.
Supplementary Figure 10 from Immuno-PET Imaging of CD69 Visualizes T-Cell Activation and Predicts Survival Following Immunotherapy in Murine Glioblastoma
Authors: Nisnboym Michal , Vincze Sarah R. , Xiong Zujian , Sneiderman Chaim T. , Raphael Rebecca A. , Li Bo , Jaswal Ambika P. , Sever ReidAnn E. , Day Kathryn E. , LaToche Joseph D. , Foley Lesley M. , Karimi Hanieh , Hitchens T. Kevin , Agnihotri Sameer , Hu Baoli , Rajasundaram Dhivyaa , Anderson Carolyn J. , Blumenthal Deborah T. , Pearce Thomas M. , Uttam Shikhar , Nedrow Jessie R. , Panigrahy Ashok , Pollack Ian F. , Lieberman Frank S. , Drappatz Jan , Raphael Itay , Edwards Wilson B. , Kohanbash Gary
Published: July 2023

MRI analysis of tumor volume before and after treatment.
Supplementary Figure 1 from Immuno-PET Imaging of CD69 Visualizes T-Cell Activation and Predicts Survival Following Immunotherapy in Murine Glioblastoma
Authors: Nisnboym Michal , Vincze Sarah R. , Xiong Zujian , Sneiderman Chaim T. , Raphael Rebecca A. , Li Bo , Jaswal Ambika P. , Sever ReidAnn E. , Day Kathryn E. , LaToche Joseph D. , Foley Lesley M. , Karimi Hanieh , Hitchens T. Kevin , Agnihotri Sameer , Hu Baoli , Rajasundaram Dhivyaa , Anderson Carolyn J. , Blumenthal Deborah T. , Pearce Thomas M. , Uttam Shikhar , Nedrow Jessie R. , Panigrahy Ashok , Pollack Ian F. , Lieberman Frank S. , Drappatz Jan , Raphael Itay , Edwards Wilson B. , Kohanbash Gary
Published: July 2023

CD69 is upregulated upon T-cell activation.
Data from Immuno-PET Imaging of CD69 Visualizes T-Cell Activation and Predicts Survival Following Immunotherapy in Murine Glioblastoma
Authors: Nisnboym Michal , Vincze Sarah R. , Xiong Zujian , Sneiderman Chaim T. , Raphael Rebecca A. , Li Bo , Jaswal Ambika P. , Sever ReidAnn E. , Day Kathryn E. , LaToche Joseph D. , Foley Lesley M. , Karimi Hanieh , Hitchens T. Kevin , Agnihotri Sameer , Hu Baoli , Rajasundaram Dhivyaa , Anderson Carolyn J. , Blumenthal Deborah T. , Pearce Thomas M. , Uttam Shikhar , Nedrow Jessie R. , Panigrahy Ashok , Pollack Ian F. , Lieberman Frank S. , Drappatz Jan , Raphael Itay , Edwards Wilson B. , Kohanbash Gary
Published: July 2023

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Immunotherapy may be promising for the treatment of some patients with GBM; however, there is a need for noninvasive neuroimaging techniques to predict immunotherapeutic responses. The effectiveness of most immunotherapeutic strategies requires T-cell activation. Therefore, we aimed to evaluate an early marker of T-cell activation, CD69, for its use as an imaging biomarker of response to immunotherapy for GBM. Herein, we performed CD69 immunostaining on human and mouse T cells following in vitro activation and post immune checkpoint inhibitors (ICI) in an orthotopic syngeneic mouse glioma model. CD69 expression on tumor-infiltrating leukocytes was assessed using single-cell RNA sequencing (scRNA-seq) data from patients with recurrent GBM receiving ICI. Radiolabeled CD69 Ab PET/CT imaging (CD69 immuno-PET) was performed on GBM-bearing mice longitudinally to quantify CD69 and its association with survival following immunotherapy. We show CD69 expression is upregulated upon T-cell activation and on tumor-infiltrating lymphocytes (TIL) in response to immunotherapy. Similarly, scRNA-seq data demonstrated elevated CD69 on TILs from patients with ICI-treated recurrent GBM as compared with TILs from control cohorts. CD69 immuno-PET studies showed a significantly higher tracer uptake in the tumors of ICI-treated mice compared with controls. Importantly, we observed a positive correlation between survival and CD69 immuno-PET signals in immunotherapy-treated animals and established a trajectory of T-cell activation by virtue of CD69-immuno-PET measurements. Our study supports the potential use of CD69 immuno-PET as an immunotherapy response assessment imaging tool for patients with GBM.
Significance:
Immunotherapy may hold promise for the treatment of some patients with GBM. There is a need to assess therapy responsiveness to allow the continuation of effective treatment in responders and to avoid ineffective treatment with potential adverse effects in the nonresponders. We demonstrate that noninvasive PET/CT imaging of CD69 may allow early detection of immunotherapy responsiveness in patients with GBM.
Data from Proteogenomic approaches for the identification of NF1/neurofibromin-depleted estrogen receptor positive breast cancers for targeted treatment
Authors: Kim Beom-Jun , Zheng Ze-Yi , Lei Jonathan T. , Holt Matthew V. , Chen Anran , Peng Jianheng , Fandino Diana , Singh Purba , Kennedy Hilda , Dou Yongchao , Chica-Parrado María del Rosario , Bikorimana Emmanuel , Ye Dan , Wang Yunguan , Hanker Ariella B. , Mohamed Nada , Hilsenbeck Susan G. , Lim Bora , Asirvatham Jaya Ruth , Sreekumar Arun , Zhang Bing , Miles George , Anurag Meenakshi , Ellis Matthew J. , Chang Eric C
Published: July 2023

Abstract
NF1 is a key tumor suppressor that represses both RAS and estrogen receptor-α (ER) signaling in breast cancer. Blocking both pathways by fulvestrant (F), a selective ER degrader (SERD), together with binimetinib (B), a MEK inhibitor, promotes tumor regression in NF1-depleted ER+ models. We aimed to establish approaches to determine how NF1 protein levels impact B+F treatment response to improve our ability to identify B+F sensitive tumors. We examined a panel of ER+ PDX models by DNA and mRNA sequencing and found that more than half of these models carried an NF1 shallow deletion and generally have low mRNA levels. Consistent with RAS and ER activation, RET and MEK levels in NF1-depleted tumors were elevated when profiled by mass spectrometry (MS) after kinase inhibitor bead pull-down. MS showed that NF1 can also directly and selectively bind to palbociclib-conjugated beads, aiding quantification. An immunohistochemistry (IHC) assay was also established to measure NF1, but the MS-based approach was more quantitative. Combined IHC and MS analysis defined a threshold of NF1 protein loss in ER+ breast PDX, below which tumors regressed upon treatment with B+F. These results suggest that we now have a MS-verified NF1 IHC assay that can be used for patient selection as a complement to somatic genomic analysis.
Avanços diagnósticos em violência sexual: aspectos forenses
Authors: Miziara Carmen Silvia Molleis Galego , Oliveira Beatriz Mariana Silva de , Silva Nicoly Ogeda da , Frederico Mayara da Matta , Paula Larissa Fagundes de , Gabriel Julia Corrêa , Miziara Ivan Dieb
Published: July 2023

INTRODUÇÃO: a violência sexual é problema de saúde pública, cujos dados são, provavelmente, subnotificados em serviços de saúde em decorrência da falha na identificação das vítimas, ou de notificações compulsórias ao sistema de saúde e à autoridade policial. Essa problemática apresenta variações de acordo com idade e sexo das vítimas.OBJETIVO: mostrar as principais técnicas de identificação criminológica de vítimas de violência sexual, com adequação às faixas etárias e ao sexo. MÉTODO: revisão narrativa de literatura na base de dados PubMed com os descritores “Violência Sexual; Medicina Forense, Prova Pericial”, sem limite de tempos de busca. Foram incluídos artigos em português, inglês e espanhol e obtidos na íntegra. RESULTADOS e DISCUSSÃO: a identificação do abuso em crianças varia de múltiplos fatores (idade, sexo, modus operandi do agressor etc.). Muitos crimes sexuais não deixam vestígios físicos nas vítimas, ou os vestígios deixados necessitam de técnicas aperfeiçoadas para a análise. A prática médico-legal convencional nem sempre consegue oferecer ao juízo a prova técnica irrefutável. Avanços na área de identificação do agressor por meio de material biológico deixado na vítima têm mostrado resultados promissores, muitos deles ainda inacessíveis na nossa prática. A atualização, quanto aos novos métodos, deve abrir discussão quanto à sua aplicabilidade e assim incluir novos métodos na rotina médico-pericial forense em busca de vestígios e de resultados. CONCLUSÃO: os testes para a identificação criminológica das vítimas possibilitam oferecer segurança e conforto, mesmo em casos tardios, e estabelecer medidas de proteção a fim de reduzir a reincidência do abuso.
Antagonistic Roles of Human Platelet Integrin αIIbβ3 and Chemokines in Regulating Neutrophil Activation and Fate on Arterial Thrombi Under Flow
Authors: Schönichen Claudia , Montague Samantha J. , Brouns Sanne L.N. , Burston James J. , Cosemans Judith M.E.M. , Jurk Kerstin , Kehrel Beate E. , Koenen Rory R. , Ní Áinle Fionnuala , O’Donnell Valerie B. , Soehnlein Oliver , Watson Steve P. , Kuijpers Marijke J.E. , Heemskerk Johan W.M. , Nagy Magdolna
Published: July 2023

Background:

Platelets and neutrophils are the first blood cells accumulating at sites of arterial thrombus formation, and both cell types contribute to the pathology of thrombotic events. We aimed to identify key interaction mechanisms between these cells using microfluidic approaches.

Methods:

Whole-blood perfusion was performed over a collagen surface at arterial shear rate. Platelet and leukocyte (in majority neutrophil) activation were microscopically visualized using fluorescent markers. The contributions of platelet-adhesive receptors (integrin, P-selectin, CD40L) and chemokines were studied by using inhibitors or antibodies and using blood from patients with GT (Glanzmann thrombasthenia) lacking platelet-expressed αIIbβ3.

Results:

We observed (1) an unknown role of activated platelet integrin αIIbß3 preventing leukocyte adhesion, which was overcome by short-term flow disturbance provoking massive adhesion; (2) that platelet-expressed CD40L controls the crawling pattern and thrombus fidelity of the cells on a thrombus; (3) that continued secretion of platelet substances promotes activation of identified neutrophils, as assessed by (fMLP [
N
-formylmethionyl-leucyl-phenylalanine, a potent chemotactic agent and leukocyte activator] induced) [Ca
2+
]
i
rises and antigen expression; (4) and that platelet-released chemokines activate the adhered cells in the order of CXCL7>CCL5>CXCL4. Furthermore, postsilencing of the platelets in a thrombus suppressed the leukocyte activation. However, the leukocytes on thrombi did no more than limitedly form neutrophil extracellular traps, unless stimulated with phorbol ester or lipopolysaccharide.

Conclusions:

Together, these findings reveal a multifaceted regulation of adhesion and activation of neutrophils by platelets in a thrombus, with a balanced role of several platelet-adhesive receptors and a promoting role of platelet-released substances. This multivalent nature of neutrophil-thrombus interactions offers novel prospects for pharmacological intervention.
THE CONCEPTUALIZATION OF COUNTRY IMAGE: A QUALITATIVE APPROACH
Authors: İZMİR Onur , EROGLU-HALL Elif , SEVİM Nurdan
Published: July 2023

Although country of origin studies go back to 1960’s, there is still no consensus on the conceptualization and measurement of country image. Country image has been studied from a cognitive dominant perspective and most of the scales measuring this construct has failed to capture affective aspects of it. This study intents to provide a more accurate conceptual framework for the country image construct and provide some insights into the measurement of this concept for future studies. In this study, it is identified that country image consists of cognitive and affective elements in which fifteen sub-dimensions of this concept have been reached. It is determined that cognitive oriented development of the literature causes a major threat to the validity of the studies because studies have mostly applied cognitive dominant perspectives/scales and attributed the results to general country image. As a result of this study, new definition of country image is proposed, and it is thought that this concept has been placed on a more concrete and valid theoretical ground. As a result of the content analysis of the qualitative data and literature review, an item pool composed of 85 items were proposed. Future studies with an intention to measure country image with its cognitive and affective aspects can benefit the findings of this study.