bluuebunny/crossref_metadata_2025 huggingface dataset:
Fibroblast Growth Factor-1 Activates Neurons in the Arcuate Nucleus and Dorsal Vagal Complex
Authors: Roberts Brandon L. , Kim Eric J. , Lindsley Sarah R. , Tennant Katherine G. , Kievit Paul
Published: December 2021

Central administration of fibroblast growth factor-1 (FGF1) results in long-lasting resolution of hyperglycemia in various rodent models, but the pre- and postsynaptic mechanisms mediating the central effects of FGF1 are unknown. Here we utilize electrophysiology recordings from neuronal populations in the arcuate nucleus of the hypothalamus (ARH), nucleus of the solitary tract (NTS), and area postrema (AP) to investigate the mechanisms underlying FGF1 actions. While FGF1 did not alter membrane potential in ARH-NPY-GFP neurons, it reversibly depolarized 83% of ARH-POMC-EGFP neurons and decreased the frequency of inhibitory inputs onto ARH-POMC-EGFP neurons. This depolarizing effect persisted in the presence of FGF receptor (R) blocker FIIN1, but was blocked by pretreatment with the voltage-gated sodium channel (VGSC) blocker tetrodotoxin (TTX). Non-FGF1 subfamilies can activate vascular endothelial growth factor receptors (VEGFR). Surprisingly, the VEGFR inhibitors axitinib and BMS605541 blocked FGF1 effects on ARH-POMC-EGFP neurons. We also demonstrate that FGF1 induces c-Fos in the dorsal vagal complex, activates NTS-NPY-GFP neurons through a FGFR mediated pathway, and requires VGSCs to activate AP neurons. We conclude that FGF1 acts in multiple brain regions independent of FGFRs. These studies present anatomical and mechanistic pathways for the future investigation of the pharmacological and physiological role of FGF1 in metabolic processes.
The Differential Effects of Propylthiouracil and Methimazole as Graves’ Disease Treatment on Vascular Atherosclerosis Markers: A Randomized Clinical Trial
Authors: Wisnu Wismandari , Alwi Idrus , Nafrialdi Nafrialdi , Harimurti Kuntjoro , Pemayun Tjokorda Gede D. , Jusman Sri Widia A. , Santoso Dewi Irawati S. , Harahap Alida R. , Suwarto Suhendro , Subekti Imam
Published: December 2021

Background

Hyperthyroidism is related to vascular atherosclerosis. Propylthiouracil (PTU) and methimazole, other than their antithyroid effects, may have different mechanisms in preventing atherogenesis in Graves’ disease.

Objective

This study aimed to investigate the effect of antithyroid drugs on markers of vascular atherosclerosis in Graves’ hyperthyroidism.

Methods

This study was a single-blind, randomized clinical trial conducted on 36 patients with Graves’ disease in Cipto Mangunkusumo General Hospital, Jakarta, Indonesia, from June 2019 until July 2020. Graves’ disease was diagnosed from clinical manifestation of hyperthyroidism with diffuse goiter and then confirmed by thyroid stimulation hormone (TSH), free T4 (fT4), and TSH-receptor antibody (TRAb) measurements. Participants were randomly assigned to either a PTU or a methimazole treatment group and followed up for 3 months. Markers of vascular atherosclerosis were represented by adhesion molecules [intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin], carotid artery stiffness [pulse wave velocity (PWV)], and thickness [carotid intima media thickness (cIMT)].

Results

By the end of the study, 24 participants reached euthyroid condition (13 from the PTU group and 11 from the methimazole group). After 3 months of follow-up, in the PTU group, we noticed an improvement of ICAM-1 [pretreatment: 204.1 (61.3) vs. posttreatment: 141.6 (58.4) ng/ml; p = 0.001], VCAM-1 [837 (707–977) vs. 510 (402–630) ng/ml; p < 0.001] and E-selectin [32.1 (24.1–42.7) vs. 28.2 (21.6–36.8) ng/ml; p = 0.045] in the PTU group. In the methimazole group, only VCAM-1 improvement [725 (565–904) vs. 472 (367–590); p = 0.001] was observed. Meanwhile, we found no significant changes in PWV or cIMT in either group.

Conclusion

Antithyroid treatment in Graves’ disease leads to improvement in adhesion molecules, with a lesser effect on methimazole, whereas there were no significant changes in PWV or cIMT. PTU may have a better mechanism compared with methimazole in terms of improving adhesion molecules.
Research on Energy-Related CO2 Emissions Characteristics, Decoupling Relationship and LMDI Factor Decomposition in Qinghai
Authors: Huang Can , Zhou Yin-Jun , Cheng Jin-Hua
Published: December 2021

Based on the statistical data from 1997 to 2017, with the utilization of the IPCC carbon accounting method, Tapio decoupling model, and Logarithmic Mean Divisia Index (LMDI), the temporal evolution characteristics of Qinghai’s energy-related carbon emissions, the decoupling relationship, and its driving factors were analyzed. The results indicated that 1) The carbon emissions of Qinghai showed a trend of first slowly increasing, then rapidly increasing, and finally fluctuating and decreasing. It increased from 3.85 million tons in 1997 to 14.33 million tons in 2017, with an average annual growth rate of 6.79%. The carbon emission intensity revealed a steady downward trend, from 189.82 tons/million CNY in 1997 to 54.6 tons/million CNY in 2017, with an average annual growth rate of –6.04%. 2) The relationship between carbon emissions and economic growth was represented by four types: weak decoupling, strong decoupling, expansion negative decoupling, and expansion coupling. Among them, a strong decoupling was achieved only in the five periods of 1997–1998, 1999–2000, 2001–2002, 2013–2015, and 2016–2017. 3) The structural effect of energy consumption was the paramount factor in restraining carbon emissions, followed by the energy intensity effect, while economic growth, and population size were important factors facilitating the increase in carbon emissions. To this end, Qinghai should continuously optimize its energy structure and improve energy utilization efficiency, thus achieving economic green and high-quality development.
Impact of Sex Hormones on Macrophage Responses to Coxiella burnetii
Authors: Gay Laetitia , Melenotte Cléa , Lopez Alexandre , Desnues Benoit , Raoult Didier , Leone Marc , Mezouar Soraya , Mege Jean-Louis
Published: December 2021

Introduction

Q fever, a zoonosis caused by Coxiella burnetii, affects more males than females despite a similar level of exposure. A protective role of estradiol has been reported in mice, suggesting that sex hormones are involved in C. burnetii infection. We wondered whether the responses of monocytes and monocyte-derived macrophages (MDMs) to C. burnetii are influenced by sex hormones.

Materials and Methods

The bacterial intracellular fate in monocytes was studied using quantitative PCR, and monocyte cytokine production in response to C. burnetii was assessed using qRT-PCR and immunoassays. Before infection, MDMs from males and females were incubated with testosterone and estradiol, respectively.

Results

Bacterial uptake and persistence were similar in monocytes from males and females but were slightly increased in male MDMs. The expression of inflammatory genes, including those encoding TNF and CXCL10, was higher in MDMs from females than in MDMs from males infected by C. burnetii. Adding testosterone to male MDMs amplified their immunoregulatory properties, including increased expression of IL10 and TGFB genes and TGF-β production in response to C. burnetii. In contrast, adding estradiol to MDMs from females had no effect on their inflammatory profile.

Conclusion

The stronger inflammatory profile of macrophages from females may have a protective role, likely under estrogen control, while testosterone may affect disease progression by promoting an anti-inflammatory response. This finding may have consequences for personalized management of patients with Q fever.
Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue
Authors: Fevang Børre , Wyller Vegard Bruun Bratholm , Mollnes Tom Eirik , Pedersen Maria , Asprusten Tarjei Tørre , Michelsen Annika , Ueland Thor , Otterdal Kari
Published: December 2021

Background

Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) that can lead to chronic fatigue syndrome. The CEBA-project (Chronic fatigue following acute EBV infection in Adolescents) has followed 200 patients with IM and here we present an immunological profiling of adolescents with IM related to clinical characteristics.

Methods

Patients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated in vitro (n=68), and supernatants analyzed for cytokine release. Plasma was analyzed for inflammatory markers (n=200). The Chalder Fatigue Questionnaire diagnosed patients with and without chronic fatigue at 6 months (CF+ and CF- group, respectively) (n=32 and n=91, in vitro and plasma cohorts, respectively.

Results

Broad activation of PBMC at baseline, with high levels of RANTES (Regulated on activation, normal T-cell expressed and secreted) in the CF+ group, and broad inflammatory response in plasma with high levels of T-cell markers was obeserved. At 6 months, there was an increased β-agonist response and RANTES was still elevated in cultures from the CF+ group. Plasma showed decrease of inflammatory markers except for CRP which was consistently elevated in the CF+ group.

Conclusion

Patients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months.

Clinical Trial Registration

https://clinicaltrials.gov/, identifier NCT02335437.
Detection of Antibody Responses Against SARS-CoV-2 in Plasma and Saliva From Vaccinated and Infected Individuals
Authors: Klingler Jéromine , Lambert Gregory S. , Itri Vincenza , Liu Sean , Bandres Juan C. , Enyindah-Asonye Gospel , Liu Xiaomei , Simon Viviana , Gleason Charles R. , Kleiner Giulio , Chiu Hsin-Ping , Hung Chuan-Tien , Kowdle Shreyas , Amanat Fatima , Lee Benhur , Zolla-Pazner Susan , Upadhyay Chitra , Hioe Catarina E.
Published: December 2021

Antibodies (Abs) are essential for the host immune response against SARS-CoV-2, and all the vaccines developed so far have been designed to induce Abs targeting the SARS-CoV-2 spike. Many studies have examined Ab responses in the blood from vaccinated and infected individuals. However, since SARS-CoV-2 is a respiratory virus, it is also critical to understand the mucosal Ab responses at the sites of initial virus exposure. Here, we examined plasma versus saliva Ab responses in vaccinated and convalescent patients. Although saliva levels were significantly lower, a strong correlation was observed between plasma and saliva total Ig levels against all SARS-CoV-2 antigens tested. Virus-specific IgG1 responses predominated in both saliva and plasma, while a lower prevalence of IgM and IgA1 Abs was observed in saliva. Antiviral activities of plasma Abs were also studied. Neutralization titers against the initial WA1 (D614G), B.1.1.7 (alpha) and B.1.617.2 (delta) strains were similar but lower against the B.1.351 (beta) strain. Spike-specific antibody-dependent cellular phagocytosis (ADCP) activities were also detected and the levels correlated with spike-binding Ig titers. Interestingly, while neutralization and ADCP potencies of vaccinated and convalescent groups were comparable, enhanced complement deposition to spike-specific Abs was noted in vaccinated versus convalescent groups and corresponded with higher levels of IgG1 plus IgG3 among the vaccinated individuals. Altogether, this study demonstrates the detection of Ab responses after vaccination or infection in plasma and saliva that correlate significantly, although Ig isotypic differences were noted. The induced plasma Abs displayed Fab-mediated and Fc-dependent functions with comparable neutralization and ADCP potencies, but a greater capacity to activate complement was elicited upon vaccination.
Case Report: A New Gain-of-Function Mutation of STAT1 Identified in a Patient With Chronic Mucocutaneous Candidiasis and Rosacea-Like Demodicosis: An Emerging Association
Authors: Martinot Martin , Korganow Anne Sophie , Wald Mathieu , Second Julie , Birckel Elodie , Mahé Antoine , Souply Laurent , Mohseni-Zadeh Mahsa , Droy Laure , Tarabeux Julien , Okada Satoshi , Migaud Mélanie , Puel Anne , Guffroy Aurelien
Published: December 2021

Purpose

Heterozygous missense STAT1 mutations leading to a gain of function (GOF) are the most frequent genetic cause of chronic mucocutaneous candidiasis (CMC). We describe the case of a patient presenting a new GOF mutation of STAT1 with the clinical symptoms of CMC, recurrent pneumonia, and persistent central erythema with papulopustules with ocular involvement related to rosacea-like demodicosis.

Methods

Genetic analysis via targeted next-generation sequencing (NGS; NGS panel DIPAI v.1) exploring the 98 genes most frequently involved in primary immunodeficiencies, including STAT1, was performed to identify an underlying genetic defect.

Results

NGS identified a novel variant of STAT1, c.884C>A (exon 10), p.T295Y, not previously described. This variant was found to be gain of function using an in vitro luciferase reporter assay. Rosacea-like demodicosis was confirmed by substantial Demodex proliferation observed via the microscopic examination of a cutaneous sample. A review of literature retrieved 20 other cases of STAT1 GOF mutations associated with early-onset rosacea-like demodicosis, most with ocular involvement.

Conclusion

We describe a new STAT1 GOF mutation associated with a phenotype of CMC and rosacea-like demodicosis. Rosacea-like demodicosis appears as a novel and important clinical phenotype among patients with STAT1 GOF mutation.
Intracellular NAD+ Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation
Authors: Shim Do-Wan , Cho Hyo-Joung , Hwang Inhwa , Jung Taek-Yeol , Kim Hyun-Seok , Ryu Ju Hee , Yu Je-Wook
Published: December 2021

Nicotinamide adenine dinucleotide (NAD+) is an important cofactor in many redox and non-redox NAD+-consuming enzyme reactions. Intracellular NAD+ level steadily declines with age, but its role in the innate immune potential of myeloid cells remains elusive. In this study, we explored whether NAD+ depletion by FK866, a highly specific inhibitor of the NAD salvage pathway, can affect pattern recognition receptor-mediated responses in macrophages. NAD+-depleted mouse bone marrow-derived macrophages (BMDMs) exhibited similar levels of proinflammatory cytokine production in response to LPS or poly (I:C) stimulation compared with untreated cells. Instead, FK866 facilitated robust caspase-1 activation in BMDMs in the presence of NLRP3-activating signals such as ATP and nigericin, a potassium ionophore. However, this FK866-mediated caspase-1 activation was completely abolished in Nlrp3-deficient macrophages. FK866 plus nigericin stimulation caused an NLRP3-dependent assembly of inflammasome complex. In contrast, restoration of NAD+ level by supplementation with nicotinamide mononucleotide abrogated the FK866-mediated caspase-1 cleavage. FK866 did not induce or increase the expression levels of NLRP3 and interleukin (IL)-1β but drove mitochondrial retrograde transport into the perinuclear region. FK866-nigericin-induced mitochondrial transport is critical for caspase-1 cleavage in macrophages. Consistent with the in vitro experiments, intradermal coinjection of FK866 and ATP resulted in robust IL-1β expression and caspase-1 activation in the skin of wild-type, but not Nlrp3-deficient mice. Collectively, our data suggest that NAD+ depletion provides a non-transcriptional priming signal for NLRP3 activation via mitochondrial perinuclear clustering, and aging-associated NAD+ decline can trigger NLRP3 inflammasome activation in ATP-rich environments.
Characterization of Definitive Regulatory B Cell Subsets by Cell Surface Phenotype, Function and Context
Authors: Neu Savannah D. , Dittel Bonnie N.
Published: December 2021

Regulatory B cell or “Breg” is a broad term that represents the anti-inflammatory activity of B cells, but does not describe their individual phenotypes, specific mechanisms of regulation or relevant disease contexts. Thus, given the variety of B cell regulatory mechanisms reported in human disease and their animal models, a more thorough and comprehensive identification strategy is needed for tracking and comparing B cell subsets between research groups and in clinical settings. This review summarizes the discovery process and mechanism of action for well-defined regulatory B cell subsets with an emphasis on the mouse model of multiple sclerosis experimental autoimmune encephalomyelitis. We discuss the importance of conducting thorough B cell phenotyping along with mechanistic studies prior to defining a particular subset of B cells as Breg. Since virtually all B cell subsets can exert regulatory activity, it is timely for their definitive identification across studies.
Thromboxane Mobilizes Insect Blood Cells to Infection Foci
Authors: Roy Miltan Chandra , Nam Kiwoong , Kim Jaesu , Stanley David , Kim Yonggyun
Published: December 2021

Innate immune responses are effective for insect survival to defend against entomopathogens including a fungal pathogen, Metarhizium rileyi, that infects a lepidopteran Spodoptera exigua. In particular, the fungal virulence was attenuated by cellular immune responses, in which the conidia were phagocytosed by hemocytes (insect blood cells) and hyphal growth was inhibited by hemocyte encapsulation. However, the chemokine signal to drive hemocytes to the infection foci was little understood. The hemocyte behaviors appeared to be guided by a Ca2+ signal stimulating cell aggregation to the infection foci. The induction of the Ca2+ signal was significantly inhibited by the cyclooxygenase (COX) inhibitor. Under the inhibitory condition, the addition of thromboxane A2 or B2 (TXA2 or TXB2) among COX products was the most effective to recover the Ca2+ signal and hemocyte aggregation. TXB2 alone induced a microaggregation behavior of hemocytes under in vitro conditions. Indeed, TXB2 titer was significantly increased in the plasma of the infected larvae. The elevated TXB2 level was further supported by the induction of phospholipase A2 (PLA2) activity in the hemocytes and subsequent up-regulation of COX-like peroxinectins (SePOX-F and SePOX-H) in response to the fungal infection. Finally, the expression of a thromboxane synthase (Se-TXAS) gene was highly expressed in the hemocytes. RNA interference (RNAi) of Se-TXAS expression inhibited the Ca2+ signal and hemocyte aggregation around fungal hyphae, which were rescued by the addition of TXB2. Without any ortholog to mammalian thromboxane receptors, a prostaglandin receptor was essential to mediate TXB2 signal to elevate the Ca2+ signal and mediate hemocyte aggregation behavior. Specific inhibitor assays suggest that the downstream signal after binding TXB2 to the receptor follows the Ca2+-induced Ca2+ release pathway from the endoplasmic reticulum of the hemocytes. These results suggest that hemocyte aggregation induced by the fungal infection is triggered by TXB2via a Ca2+ signal through a PG receptor.
Improvement of PD-1 Blockade Efficacy and Elimination of Immune-Related Gastrointestinal Adverse Effect by mTOR Inhibitor
Authors: Bai Xin , Wang Xueyan , Ma Guozhen , Song Jinen , Liu Xiaowei , Wu Xi , Zhao Yujie , Liu Xu , Liu Zhihui , Zhang Wei , Zhao Xin , Zheng Zirui , Jing Jing , Shi Hubing
Published: December 2021

During the past decades, immunotherapy, especially the antibody-mediated immune checkpoint blockade (ICB) has shown durable tumor inhibition and changed the paradigm of cancer treatment. However, a growing body of evidence suggests that ICB treatment induces severe immune-related adverse events (irAEs), and the side effect even leads to the discontinuation of lifesaving treatment. Here, we found that ICB treatment induces colitis in melanoma patients and promotes the infiltration of CD8+ effector T cells into colitic lesions. Further transcriptomic dissection indicated the PI3K-AKT-mTOR pathway was highly activated in CD8+ effector T cells of colitic lesions. Moreover, we developed a mouse melanoma model to recapitulate the gastrointestinal toxicity of anti-PD-1 treatment in clinical settings. Anti-PD-1 treatment significantly contributed to the infiltration of CD8+ T cells, and correspondingly induced severe enteritis. Immunohistochemistry experiments showed that the PI3K-AKT-mTOR pathway of T cells was activated by anti-PD-1 treatment. Blockade of the pathway with mTOR inhibitor sirolimus not only inhibits tumor growth but also suppresses the T cell infiltration in colitic lesions. More importantly, combination with sirolimus and anti-PD-1 synergistically inhibits tumor growth via inducing the immunogenic cell death of tumor cells in vivo. In summary, our research demonstrated the principle of mTOR inhibitor and anti-PD-1 combinatorial therapeutic regimen, which provided a novel therapeutic strategy for irAEs in clinics.
The Tumor Immune Landscape and Architecture of Tertiary Lymphoid Structures in Urothelial Cancer
Authors: Dijk Nick van , Gil-Jimenez Alberto , Silina Karina , Montfoort Maurits L. van , Einerhand Sarah , Jonkman Lars , Voskuilen Charlotte S. , Peters Dennis , Sanders Joyce , Lubeck Yoni , Broeks Annegien , Hooijberg Erik , Vis Daniel J. , Broek Maries van den , Wessels Lodewyk F. A. , Rhijn Bas W. G. van , Heijden Michiel S. van der
Published: December 2021

Candidate immune biomarkers have been proposed for predicting response to immunotherapy in urothelial cancer (UC). Yet, these biomarkers are imperfect and lack predictive power. A comprehensive overview of the tumor immune contexture, including Tertiary Lymphoid structures (TLS), is needed to better understand the immunotherapy response in UC. We analyzed tumor sections by quantitative multiplex immunofluorescence to characterize immune cell subsets in various tumor compartments in tumors without pretreatment and tumors exposed to preoperative anti-PD1/CTLA-4 checkpoint inhibitors (NABUCCO trial). Pronounced immune cell presence was found in UC invasive margins compared to tumor and stroma regions. CD8+PD1+ T-cells were present in UC, particularly following immunotherapy. The cellular composition of TLS was assessed by multiplex immunofluorescence (CD3, CD8, FoxP3, CD68, CD20, PanCK, DAPI) to explore specific TLS clusters based on varying immune subset densities. Using a k-means clustering algorithm, we found five distinct cellular composition clusters. Tumors unresponsive to anti-PD-1/CTLA-4 immunotherapy showed enrichment of a FoxP3+ T-cell-low TLS cluster after treatment. Additionally, cluster 5 (macrophage low) TLS were significantly higher after pre-operative immunotherapy, compared to untreated tumors. We also compared the immune cell composition and maturation stages between superficial (submucosal) and deeper TLS, revealing that superficial TLS had more pronounced T-helper cells and enrichment of early TLS than TLS located in deeper tissue. Furthermore, superficial TLS displayed a lower fraction of secondary follicle like TLS than deeper TLS. Taken together, our results provide a detailed quantitative overview of the tumor immune landscape in UC, which can provide a basis for further studies.
Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity
Authors: Perelygina Ludmila , Faisthalab Raeesa , Abernathy Emily , Chen Min-hsin , Hao LiJuan , Bercovitch Lionel , Bayer Diana K. , Noroski Lenora M. , Lam Michael T. , Cicalese Maria Pia , Al-Herz Waleed , Nanda Arti , Hajjar Joud , Vanden Driessche Koen , Schroven Shari , Leysen Julie , Rosenbach Misha , Peters Philipp , Raedler Johannes , Albert Michael H. , Abraham Roshini S. , Rangarjan Hemalatha G. , Buchbinder David , Kobrynski Lisa , Pham-Huy Anne , Dhossche Julie , Cunningham Rundles Charlotte , Meyer Anna K. , Theos Amy , Atkinson T. Prescott , Musiek Amy , Adeli Mehdi , Derichs Ute , Walz Christoph , Krüger Renate , von Bernuth Horst , Klein Christoph , Icenogle Joseph , Hauck Fabian , Sullivan Kathleen E.
Published: December 2021

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.
Vascular Microenvironment, Tumor Immunity and Immunotherapy
Authors: Lamplugh Zachary , Fan Yi
Published: December 2021

Immunotherapy holds great promise for treating cancer. Nonetheless, T cell-based immunotherapy of solid tumors has remained challenging, largely due to the lack of universal tumor-specific antigens and an immunosuppressive tumor microenvironment (TME) that inhibits lymphocyte infiltration and activation. Aberrant vascularity characterizes malignant solid tumors, which fuels the formation of an immune-hostile microenvironment and induces tumor resistance to immunotherapy, emerging as a crucial target for adjuvant treatment in cancer immunotherapy. In this review, we discuss the molecular and cellular basis of vascular microenvironment-mediated tumor evasion of immune responses and resistance to immunotherapy, with a focus on vessel abnormality, dysfunctional adhesion, immunosuppressive niche, and microenvironmental stress in tumor vasculature. We provide an overview of opportunities and challenges related to these mechanisms. We also propose genetic programming of tumor endothelial cells as an alternative approach to recondition the vascular microenvironment and to overcome tumor resistance to immunotherapy.
Mechanical and Self-Healing Performances of Crumb Rubber Modified High-Strength Engineered Cementitious Composites
Authors: Jiangtao Yu , Fangming Jiang , Qiong Xing , Qi Yang , Mi Li
Published: December 2021

High-strength engineered cementitious composite (HS-ECC) reinforced with polyethylene (PE) fiber characterizes wider crack widths than the conventional polyvinyl alcohol fiber-reinforced ECC (PVA-ECC), weakening the self-healing potential of HS-ECC. The properties of HS-ECC are tailored by introducing crumb rubber (CR), as artificial flaws can lower the matrix toughness and the crack width, leading to an enhanced self-healing potential of HS-ECC. In this study, CR is used to entirely replace silica sand (SS) with three equivalent aggregate-to-binder ratios of 0.2, 0.4, and 0.6, and two CR particle sizes (i.e., CR1 and CR2) are also considered to investigate the effects on density, compressive properties, and tensile performances of HS-ECC. Although CR substitution of SS influences adversely the mechanical strengths of HS-ECC, it can reduce the HS-ECC matrix fracture toughness, activate more microcracks, and reduce the crack width. Moreover, CR-modified HS-ECC specimens featuring the smallest crack width were preloaded to three specific strain levels, including 0.5%, 1.0%, and 2.0%, and then experienced wet–dry conditioning to exhibit effective mechanical and non-mechanical property recovery. The further hydration of binder materials enhances the interfacial bond stress and thus retains the mechanical performances of self-healed HS-ECC, which is expected to improve the practical application and benefit the sustainability of HS-ECC.
Pediatric Nuclear Medicine Examinations and Subsequent Risk of Neoplasm: A Nationwide Population-Based Cohort Study
Authors: Yuan Mei-Kang , Chang Shih-Chieh , Yuan Mei-Chun , Foo Ning-Ping , Chan Shan-Ho , Wang Shyh-Yau , Lin Cheng-Li , Hsu Chung-Y. , Kao Chia-Hung
Published: December 2021

Objective: To evaluate the association between radiation exposure from repeated nuclear medicine (NM) examinations and the subsequent risk of neoplasm in pediatric patients.

Methods: From 2000 to 2017, participants under 18 years of age who underwent NM scanning were identified using the Health and Welfare Data Science Center (HWDC) dataset, which was extracted from the Taiwan National Health Insurance Research Database (NHIRD). Both the exposed cohort and unexposed subjects were followed up with until the presence of any malignancy arose, including malignant brain, lymphoid and hematopoietic tumors and benign brain or other central nervous tumors.

Results: There were 35,292 patients in the exposed cohort and 141,152 matched subjects in the non-exposed group. The exposed cohort had an overall higher IR (IR: incidence rate, per 100,000 person-years) of any malignancy and benign central nervous tumor than the non-exposed group [IR, 16.9 vs. 1.54; adjusted hazard ratio (HR), 10.9; 95% CI, 6.53–18.2]. Further stratifying the number of NM examinations into 1-2, 3-4, and 5 or more times revealed that the IR of pediatric neoplasms increased gradually with the increased frequency of NM examinations (IR, 11.5; adjusted HR, 7.5; 95% CI, 4.29–13.1; IR, 25.8; adjusted HR, 15.9; 95% CI, 7.00–36.1; IR, 93.8; adjusted HR, 56.4; 95% CI, 28.8–110.3).

Conclusion: NM examination is significantly associated with a higher risk of pediatric neoplasms, according to our population-based data. Thorough radiation protection and dose reduction in pediatric NM procedures should be an issue of concern.
Veno-Arterial Extracorporeal Membrane Oxygenation for Patients Undergoing Heart Transplantation: A 7-Year Experience
Authors: Hou Jun-yi , Li Xin , Yang Shou-guo , Zheng Ji-li , Ma Jie-fei , Su Ying , Zhang Yi-jie , Guo Ke-fang , Tu Guo-wei , Luo Zhe
Published: December 2021

Objective: Primary graft dysfunction (PGD) is the leading cause of early death after heart transplantation. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can provide temporary mechanical circulatory support and time for functional recovery of the transplanted heart. The purpose of this study was to analyze the timing and prognoses of VA-ECMO in patients with severe PGD after heart transplantation.

Methods: A total of 130 patients underwent heart transplantation at the Zhongshan Hospital Affiliated with Fudan University between January 2014 and December 2020. All patients received basiliximab immunoinduction and a classic double vena cava anastomosis orthotopic heart transplantation. Among them, 29 patients (22.3%) developed severe PGD in the early postoperative period. VA-ECMO was performed in patients with difficulty weaning from cardiopulmonary bypass (CPB) or postoperative refractory cardiogenic shock. Patients were divided into two groups according to whether or not they were successfully weaned from VA-ECMO (patients who survived for 48 h after weaning and did not need VA-ECMO assistance again). The perioperative clinical data were recorded, and all patients were followed up until discharge. Early outcomes were compared between groups.

Results: A total of 29 patients with VA-ECMO support after heart transplantation were included in this study. The proportion of patients receiving VA-ECMO was 22.3% (29/130). Nineteen patients (65.5%) needed VA-ECMO due to difficulty with weaning from CPB, and 10 patients required VA-ECMO for postoperative cardiogenic shock. Nineteen patients (65.5%) were successfully weaned from VA-ECMO. Overall, in-hospital mortality of VA-ECMO support patients was 55.2%. The main causes of death were ventricular fibrillation (four cases), major bleeding (three cases), infection (four cases), and graft failure (five cases).

Conclusion: Despite advances in heart transplantation, severe PGD remains a lethal complication after heart transplantation. At present, the treatment for severe PGD after heart transplantation is a challenge. VA-ECMO provides an effective treatment for severe PGD after heart transplantation, which can promote graft function recovery.
Influence of Timing of Postoperative Weight-Bearing on Implant Failure Rate Among Older Patients With Intertrochanteric Hip Fractures: A Propensity Score Matching Cohort Study
Authors: Jia Xiaoyang , Qiang Minfei , Zhang Kun , Han Qinghui , Wu Ying , Chen Yanxi
Published: December 2021

Introduction: The purpose of this study was to determine whether immediate weight-bearing as tolerated increased the risk of implant failure and decreased functional outcomes compared with restricted weight-bearing.

Methods: From January 2010 to December 2018, 1,125 consecutive patients (≥65 years) with intertrochanteric fractures were identified. Of them, 130 patients were excluded, resulting in 995 patients in final cohort (563 receiving immediate weight-bearing and 432 receiving restricted weight-bearing). Propensity score (PS) matching yielded 403 patient pairs. Primary outcome was implant failure at 12 months. Secondary outcomes were implant failure at 3 months, functional outcomes at 12 months, and time to full weight-bearing.

Results: Among 806 patients who were matched by PS, the mean age was 77.8 years (SD, 7.6), and 603 patients (74.8%) were women. After matching, there was no significant difference between immediate (10.0% [39/389]) and restricted (9.1%, [35/385]) weight-bearing for implant failure at 12 months (absolute risk difference, 0.93% [95% CI, −3.26 to 5.13%]; RR, 1.11 [95% CI, 0.69 to 1.80]; p = 0.66). Additionally, no significant difference was seen for implant failure at 3 months and functional outcomes at 12 months. Patients with immediate weight-bearing had shorter time to full weight-bearing (mean [SD], 87.6 days [7.5] vs. 121.3 days [11.0]; mean difference, −33.7 [95% CI, −35.0 to −32.3]; p < 0.001).

Conclusions: Among older patients with intertrochanteric fractures, receipt of immediate weight-bearing as tolerated did not increase risks of implant failure or worsen functional outcomes compared with receipt of restricted weight-bearing. However, patients receiving immediate weight-bearing had a shorter time to full weight-bearing.
Whole Genome Sequencing of Staphylococci Isolated From Bovine Milk Samples
Authors: Fergestad Marte Ekeland , Touzain Fabrice , De Vliegher Sarne , De Visscher Anneleen , Thiry Damien , Ngassam Tchamba Cyrille , Mainil Jacques G. , L’Abee-Lund Trine , Blanchard Yannick , Wasteson Yngvild
Published: December 2021

Staphylococci are among the commonly isolated bacteria from intramammary infections in bovines, where Staphylococcus aureus is the most studied species. This species carries a variety of virulence genes, contributing to bacterial survival and spread. Less is known about non-aureus staphylococci (NAS) and their range of virulence genes and mechanisms, but they are the most frequently isolated bacteria from bovine milk. Staphylococci can also carry a range of antimicrobial resistance genes, complicating treatment of the infections they cause. We used Illumina sequencing to whole genome sequence 93 staphylococcal isolates selected from a collection of staphylococcal isolates; 45 S. aureus isolates and 48 NAS isolates from 16 different species, determining their content of antimicrobial resistance genes and virulence genes. Antimicrobial resistance genes were frequently observed in the NAS species as a group compared to S. aureus. However, the lincosamide resistance gene lnuA and penicillin resistance gene blaZ were frequently identified in NAS, as well as a small number of S. aureus. The erm genes conferring macrolide resistance were also identified in several NAS isolates and in a small number of S. aureus isolates. In most S. aureus isolates, no antimicrobial resistance genes were detected, but in five S. aureus isolates three to six resistance genes were identified and all five of these carried the mecA gene. Virulence genes were more frequently identified in S. aureus, which contained on average five times more virulence genes compared to NAS. Among the NAS species there were also differences in content of virulence genes, such as S. chromogenes with a higher average number of virulence genes. By determining the content of a large selection of virulence genes and antimicrobial resistance genes in S. aureus and 16 different NAS species our results contribute with knowledge regarding the genetic basis for virulence and antimicrobial resistance in bovine staphylococci, especially the less studied NAS. The results can create a broader basis for further research into the virulence mechanisms of this important group of bacteria in bovine intramammary infections.
Turnover of Lecanoroid Mycobionts and Their Trebouxia Photobionts Along an Elevation Gradient in Bolivia Highlights the Role of Environment in Structuring the Lichen Symbiosis
Authors: Medeiros Ian D. , Mazur Edyta , Miadlikowska Jolanta , Flakus Adam , Rodriguez-Flakus Pamela , Pardo-De la Hoz Carlos J. , Cieślak Elżbieta , Śliwa Lucyna , Lutzoni François
Published: December 2021

Shifts in climate along elevation gradients structure mycobiont–photobiont associations in lichens. We obtained mycobiont (lecanoroid Lecanoraceae) and photobiont (Trebouxia alga) DNA sequences from 89 lichen thalli collected in Bolivia from a ca. 4,700 m elevation gradient encompassing diverse natural communities and environmental conditions. The molecular dataset included six mycobiont loci (ITS, nrLSU, mtSSU, RPB1, RPB2, and MCM7) and two photobiont loci (ITS, rbcL); we designed new primers to amplify Lecanoraceae RPB1 and RPB2 with a nested PCR approach. Mycobionts belonged to Lecanora s.lat., Bryonora, Myriolecis, Protoparmeliopsis, the “Lecanora” polytropa group, and the “L.” saligna group. All of these clades except for Lecanora s.lat. occurred only at high elevation. No single species of Lecanoraceae was present along the entire elevation gradient, and individual clades were restricted to a subset of the gradient. Most Lecanoraceae samples represent species which have not previously been sequenced. Trebouxia clade C, which has not previously been recorded in association with species of Lecanoraceae, predominates at low- to mid-elevation sites. Photobionts from Trebouxia clade I occur at the upper extent of mid-elevation forest and at some open, high-elevation sites, while Trebouxia clades A and S dominate open habitats at high elevation. We did not find Trebouxia clade D. Several putative new species were found in Trebouxia clades A, C, and I. These included one putative species in clade A associated with Myriolecis species growing on limestone at high elevation and a novel lineage sister to the rest of clade C associated with Lecanora on bark in low-elevation grassland. Three different kinds of photobiont switching were observed, with certain mycobiont species associating with Trebouxia from different major clades, species within a major clade, or haplotypes within a species. Lecanoraceae mycobionts and Trebouxia photobionts exhibit species turnover along the elevation gradient, but with each partner having a different elevation threshold at which the community shifts completely. A phylogenetically defined sampling of a single diverse family of lichen-forming fungi may be sufficient to document regional patterns of Trebouxia diversity and distribution.
Microbial Systems Ecology to Understand Cross-Feeding in Microbiomes
Authors: Mataigne Victor , Vannier Nathan , Vandenkoornhuyse Philippe , Hacquard Stéphane
Published: December 2021

Understanding how microorganism-microorganism interactions shape microbial assemblages is a key to deciphering the evolution of dependencies and co-existence in complex microbiomes. Metabolic dependencies in cross-feeding exist in microbial communities and can at least partially determine microbial community composition. To parry the complexity and experimental limitations caused by the large number of possible interactions, new concepts from systems biology aim to decipher how the components of a system interact with each other. The idea that cross-feeding does impact microbiome assemblages has developed both theoretically and empirically, following a systems biology framework applied to microbial communities, formalized as microbial systems ecology (MSE) and relying on integrated-omics data. This framework merges cellular and community scales and offers new avenues to untangle microbial coexistence primarily by metabolic modeling, one of the main approaches used for mechanistic studies. In this mini-review, we first give a concise explanation of microbial cross-feeding. We then discuss how MSE can enable progress in microbial research. Finally, we provide an overview of a MSE framework mostly based on genome-scale metabolic-network reconstruction that combines top-down and bottom-up approaches to assess the molecular mechanisms of deterministic processes of microbial community assembly that is particularly suitable for use in synthetic biology and microbiome engineering.
The Expansion of Lignocellulose Biomass Conversion Into Bioenergy via Nanobiotechnology
Authors: Sankaran Revathy , Markandan Kalaimani , Khoo Kuan Shiong , Cheng Chin Kui , Ashokkumar Veeramuthu , Deepanraj B. , Show Pau Loke
Published: December 2021

Lignocellulosic biomass has arisen as a solution to our energy and environmental challenges because it is rich in feedstock that can be converted to biofuels. Converting lignocellulosic biomass to sugar is a complicated system involved in the bioconversion process. There are indeed a variety of techniques that have been utilized in the bioconversion process consisting of physical, chemical, and biological approaches. However, most of them have drawbacks when used on a large scale, which include the high cost of processing, the development of harmful inhibitors, and the detoxification of the inhibitors that have been produced. These constraints, taken together, hinder the effectiveness of current solutions and demand for the invention of a new, productive, cost-effective, and environmentally sustainable technique for LB processing. In this context, the approach of nanotechnology utilizing various nanomaterials and nanoparticles in treating lignocellulose biomass and bioenergy conversion has achieved increased interest and has been explored greatly in recent times. This mini review delves into the application of nanotechnological techniques in the bioconversion of lignocellulose biomass into bioenergy. This review on nanotechnological application in biomass conversion provides insights and development tools for the expansion of new sectors, resulting in excellent value and productivity, contributing to the long-term economic progress.
Application of Deep Convolutional Neural Networks for Discriminating Benign, Borderline, and Malignant Serous Ovarian Tumors From Ultrasound Images
Authors: Wang Huiquan , Liu Chunli , Zhao Zhe , Zhang Chao , Wang Xin , Li Huiyang , Wu Haixiao , Liu Xiaofeng , Li Chunxiang , Qi Lisha , Ma Wenjuan
Published: December 2021

Objective

This study aimed to evaluate the performance of the deep convolutional neural network (DCNN) to discriminate between benign, borderline, and malignant serous ovarian tumors (SOTs) on ultrasound(US) images.

Material and Methods

This retrospective study included 279 pathology-confirmed SOTs US images from 265 patients from March 2013 to December 2016. Two- and three-class classification task based on US images were proposed to classify benign, borderline, and malignant SOTs using a DCNN. The 2-class classification task was divided into two subtasks: benign vs. borderline & malignant (task A), borderline vs. malignant (task B). Five DCNN architectures, namely VGG16, GoogLeNet, ResNet34, MobileNet, and DenseNet, were trained and model performance before and after transfer learning was tested. Model performance was analyzed using accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC).

Results

The best overall performance was for the ResNet34 model, which also achieved the better performance after transfer learning. When classifying benign and non-benign tumors, the AUC was 0.96, the sensitivity was 0.91, and the specificity was 0.91. When predicting malignancy and borderline tumors, the AUC was 0.91, the sensitivity was 0.98, and the specificity was 0.74. The model had an overall accuracy of 0.75 for in directly classifying the three categories of benign, malignant and borderline SOTs, and a sensitivity of 0.89 for malignant, which was better than the overall diagnostic accuracy of 0.67 and sensitivity of 0.75 for malignant of the senior ultrasonographer.

Conclusion

DCNN model analysis of US images can provide complementary clinical diagnostic information and is thus a promising technique for effective differentiation of benign, borderline, and malignant SOTs.
Comparative Analysis of Two Surgical Treatment Options for Giant Cell Tumor of the Proximal Femur: Extended Curettage and Segmental Resection
Authors: Yuan Yuhao , Liu Qing , Liu Yupeng , Wu Ziyi , Zhong Wei , He Hongbo , Luo Wei
Published: December 2021

Aim

As a locally destructive intermediate bone tumor with low incidence, high recurrence rate, and difficulty in reconstruction, giant cell tumor of bone (GCTB) in the proximal femur has no unified surgical treatment standard. This study aimed to compare the differences in local recurrence, reconstruction durability, and postoperative function after treatment with either extended curettage (EC) or segmental resection (SR) for GCTB in the proximal femur so as to provide constructive suggestions for the rational selection of EC or SR operation scheme.

Patients and Methods

29 patients (15 men and 14 women) were included in this retrospective study, with a mean age of 32.1 years. According to the division method of proximal femur of International Society Of Limb Salvage (ISOLS), there was 1 case in the H1 area, 17 cases in the H2 area, 10 cases in the H1+H2 area, and 1 case in the H1+H2+H3 area. Among them were 11 cases of Campanacci grade II GCTB, 18 cases of Campanacci grade III GCTB, and 7 cases with pathological fractures. All patients underwent either EC or SR surgery. The Musculoskeletal Tumor Society (MSTS) score was used for patient evaluation. The operation effectiveness was analyzed according to the Mankin evaluation standard. Regular follow-up was performed to evaluate the recurrence rate, limb function, and long-term complications of the two surgical methods.

Results

All patients were followed up for a mean of 60.4 months. Local recurrence occurred in one of 19 patients treated with EC (5.3%) and one of 10 patients treated with SR (10%). The MSTS score of lower limb function in patients in the EC group was better compared to patients in the SR group (P = 0.002). Complications occurred in 2 cases (10.5%) and 5 cases (50%) in the EC group (osteoarthritis, osteonecrosis) and SR group (joint stiffness, infection, prosthesis loosening), respectively, with significant differences between the two groups (P = 0.03). The operation effectiveness was analyzed according to the Mankin evaluation standard. The EC group showed an optimal rate of 94.7% (18/19) as opposed to 80% (8/10) in the SR group.

Conclusions

For GCTB in the proximal femur, when the tumor does not extensively involves the surrounding soft tissues, the articular surface was not damaged, and there is no pathological fracture with apparent displacement, EC surgery should be fully considered.