bluuebunny/crossref_metadata_2025 huggingface dataset:
CD169+ Subcapsular Macrophage Role in Antigen Adjuvant Activity
Authors: Lisk Christina , Yuen Rachel , Kuniholm Jeff , Antos Danielle , Reiser Michael L. , Wetzler Lee M.
Published: March 2021

Vaccines have played a pivotal role in improving public health, however, many infectious diseases lack an effective vaccine. Controlling the spread of infectious diseases requires continuing studies to develop new and improved vaccines. Our laboratory has been investigating the immune enhancing mechanisms of Toll-like receptor (TLR) ligand-based adjuvants, including the TLR2 ligand Neisseria meningitidis outer membrane protein, PorB. Adjuvant use of PorB increases costimulatory factors on antigen presenting cells (APC), increases antigen specific antibody production, and cytokine producing T cells. We have demonstrated that macrophage expression of MyD88 (required for TLR2 signaling) is an absolute requirement for the improved antibody response induced by PorB. Here-in, we specifically investigated the role of subcapsular CD169+ marginal zone macrophages in antibody production induced by the use of TLR-ligand based adjuvants (PorB and CpG) and non-TLR-ligand adjuvants (aluminum salts). CD169 knockout mice and mice treated with low dose clodronate treated animals (which only remove marginal zone macrophages), were used to investigate the role of these macrophages in adjuvant-dependent antibody production. In both sets of mice, total antigen specific immunoglobulins (IgGs) were diminished regardless of adjuvant used. However, the greatest reduction was seen with the use of TLR ligands as adjuvants. In addition, the effect of the absence of CD169+ macrophages on adjuvant induced antigen and antigen presenting cell trafficking to the lymph nodes was examined using immunofluorescence by determining the relative extent of antigen loading on dendritic cells (DCs) and antigen deposition on follicular dendritic cells (FDC). Interestingly, only vaccine preparations containing PorB had significant decreases in antigen deposition in lymphoid follicles and germinal centers in CD169 knockout mice or mice treated with low dose clodronate as compared to wildtype controls. Mice immunized with CpG containing preparations demonstrated decreased FDC networks in the mice treated with low dose clodronate. Conversely, alum containing preparations only demonstrated significant decreases in IgG in CD169 knockout mice. These studies stress that importance of subcapsular macrophages and their unique role in adjuvant-mediated antibody production, potentially due to an effect of these adjuvants on antigen trafficking to the lymph node and deposition on follicular dendritic cells.
The Integration of Human and Veterinary Studies for Better Understanding and Management of Crimean-Congo Haemorrhagic Fever
Authors: Gilbride Ciaran , Saunders Jack , Sharpe Hannah , Maze Emmanuel Atangana , Limon Georgina , Ludi Anna Barbara , Lambe Teresa , Belij-Rammerstorfer Sandra
Published: March 2021

Outbreaks that occur as a result of zoonotic spillover from an animal reservoir continue to highlight the importance of studying the disease interface between species. One Health approaches recognise the interdependence of human and animal health and the environmental interplay. Improving the understanding and prevention of zoonotic diseases may be achieved through greater consideration of these relationships, potentially leading to better health outcomes across species. In this review, special emphasis is given on the emerging and outbreak pathogen Crimean-Congo Haemorrhagic Fever virus (CCHFV) that can cause severe disease in humans. We discuss the efforts undertaken to better understand CCHF and the importance of integrating veterinary and human research for this pathogen. Furthermore, we consider the use of closely related nairoviruses to model human disease caused by CCHFV. We discuss intervention approaches with potential application for managing CCHFV spread, and how this concept may benefit both animal and human health.
Emerging Therapeutic Strategies to Restore Regulatory T Cell Control of Islet Autoimmunity in Type 1 Diabetes
Authors: Volfson-Sedletsky Victoria , Jones Albert , Hernandez-Escalante Jaileene , Dooms Hans
Published: March 2021

Despite many decades of investigation uncovering the autoimmune mechanisms underlying Type 1 Diabetes (T1D), translating these findings into effective therapeutics has proven extremely challenging. T1D is caused by autoreactive T cells that become inappropriately activated and kill the β cells in the pancreas, resulting in insulin insufficiency and hyperglycemia. A large body of evidence supports the idea that the unchecked activation and expansion of autoreactive T cells in T1D is due to defects in immunosuppressive regulatory T cells (Tregs) that are critical for maintaining peripheral tolerance to islet autoantigens. Hence, repairing these Treg deficiencies is a much sought-after strategy to treat the disease. To accomplish this goal in the most precise, effective and safest way possible, restored Treg functions will need to be targeted towards suppressing the autoantigen-specific immune responses only and/or be localized in the pancreas. Here we review the most recent developments in designing Treg therapies that go beyond broad activation or expansion of non-specific polyclonal Treg populations. We focus on two cutting-edge strategies namely ex vivo generation of optimized Tregs for re-introduction in T1D patients vs direct in situ stimulation and restoration of endogenous Treg function.
PKCα Is Recruited to Staphylococcus aureus-Containing Phagosomes and Impairs Bacterial Replication by Inhibition of Autophagy
Authors: Gauron Maria Celeste , Newton Alexandra C. , Colombo María Isabel
Published: March 2021

Hijacking the autophagic machinery is a key mechanism through which invasive pathogens such asStaphylococcus aureusreplicate in their host cells. We have previously demonstrated that the bacteria replicate in phagosomes labeled with the autophagic protein LC3, before escaping to the cytoplasm. Here, we show that the Ca2+-dependent PKCα binds toS. aureus-containing phagosomes and that α-hemolysin, secreted byS. aureus, promotes this recruitment of PKCα to phagosomal membranes. Interestingly, the presence of PKCα prevents the association of the autophagic protein LC3. Live cell imaging experiments using the PKC activity reporter CKAR reveal that treatment of cells withS. aureusculture supernatants containing staphylococcal secreted factors transiently activates PKC. Functional studies reveal that overexpression of PKCα causes a marked inhibition of bacterial replication. Taken together, our data identify enhancing PKCα activity as a potential approach to inhibitS. aureusreplication in mammalian cells.
Addressing Parental Vaccine Hesitancy and Other Barriers to Childhood/Adolescent Vaccination Uptake During the Coronavirus (COVID-19) Pandemic
Authors: Olusanya Olufunto A. , Bednarczyk Robert A. , Davis Robert L. , Shaban-Nejad Arash
Published: March 2021

Routine childhood immunizations are proven to be one of the most effective public health interventions at controlling numerous deadly diseases. Therefore, the CDC recommends routine immunizations for children and adolescent populations against vaccine-preventable diseases e.g., tetanus, pertussis, diphtheria, etc. This current review sought to examine barriers to pediatric vaccine uptake behaviors during the COVID-19 pandemic. We also explored the implications for parental vaccine hesitancy/delay during an ongoing health crisis and proposed recommendations for increasing vaccine confidence and compliance. Our review determined that the receipt for vaccinations steadily improved in the last decade for both the United States and Tennessee. However, this incremental progress has been forestalled by the COVID-19 pandemic and other barriers i.e. parental vaccine hesitancy, social determinants of health (SDoH) inequalities, etc. which further exacerbate vaccination disparities. Moreover, non-compliance to routine vaccinations could cause an outbreak of diseases, thereby, worsening the ongoing health crisis and already strained health care system. Healthcare providers are uniquely positioned to offer effective recommendations with presumptive languaging to increase vaccination rates, as well as, address parental vaccine hesitancy. Best practices that incorporate healthcare providers’ quality improvement coaching, vaccination reminder recall systems, adherence to standardized safety protocols (physical distancing, hand hygiene practices, etc.), as well as, offer telehealth and outdoor/drive-through/curbside vaccination services, etc. are warranted. Additionally, a concerted effort should be made to utilize public health surveillance systems to collect, analyze, and interpret data, thereby, ensuring the dissemination of timely, accurate health information for effective health policy decision-making e.g., vaccine distribution, etc.
Early Diagenesis in the Hypoxic and Acidified Zone of the Northern Gulf of Mexico: Is Organic Matter Recycling in Sediments Disconnected From the Water Column?
Authors: Rabouille Christophe , Lansard Bruno , Owings Shannon M. , Rabalais Nancy N. , Bombled Bruno , Metzger Edouard , Richirt Julien , Eitel Eryn M. , Boever Anthony D. , Beckler Jordon S. , Taillefert Martial
Published: March 2021

Hypoxia and associated acidification are growing concerns for ecosystems and biogeochemical cycles in the coastal zone. The northern Gulf of Mexico (nGoM) has experienced large seasonal hypoxia for decades linked to the eutrophication of the continental shelf fueled by the Mississippi River nutrient discharge. Sediments play a key role in maintaining hypoxic and acidified bottom waters, but this role is still not completely understood. In the summer 2017, when the surface area of the hypoxic zone in the nGoM was the largest ever recorded, we investigated four stations on the continental shelf differentially influenced by river inputs of the Mississippi-Atchafalaya River System and seasonal hypoxia. We investigated diagenetic processes under normoxic, hypoxic, and nearly anoxic bottom waters by coupling amperometric, potentiometric, and voltammetric microprofiling with high-resolution diffusive equilibrium in thin-films (DET) profiles and porewater analyses. In addition, we used a time-series of bottom-water dissolved oxygen from May to November 2017, which indicated intense O2 consumption in bottom waters related to organic carbon recycling. At the sediment-water interface (SWI), we found that oxygen consumption linked to organic matter recycling was large with diffusive oxygen uptake (DOU) of 8 and 14 mmol m–2 d–1, except when the oxygen concentration was near anoxia (5 mmol m–2 d–1). Except at the station located near the Mississippi river outlet, the downcore pore water sulfate concentration decrease was limited, with little increase in alkalinity, dissolved inorganic carbon (DIC), ammonium, and phosphate suggesting that low oxygen conditions did not promote anoxic diagenesis as anticipated. We attributed the low anoxic diagenesis intensity to a limitation in organic substrate supply, possibly linked to the reduction of bioturbation during the hypoxic spring and summer.
“If You Know the Enemy and Know Yourself”: Addressing the Problem of Biological Invasions in Ports Through a New NIS Invasion Threat Score, Routine Monitoring, and Preventive Action Plans
Authors: Miralles Laura , Ibabe Aitor , González Mónica , García-Vázquez Eva , Borrell Yaisel J.
Published: March 2021

Invasive alien species (IAS) are currently considered one of the greatest threats to global marine ecosystems. Thus, ships and maritime activity have been identified as the main factors responsible for the vast majority of accidental species translocations around the world, implying that prevention should be the core of environmental port policies. Preventive port strategies should include analyzing risks based on traffic origins and volumes, revising port policies for inspections, estimating probabilities of non-indigenous species (NIS) appearance, monitoring routine species within ports, and finally implementing management plans and focused actions. Here, we conducted a comprehensive NIS prediction analysis for the port of Gijon (northern Spain), one of the largest ports in the south Bay of Biscay, as a case study that can be extrapolated to other international seaports. An extensive bibliographic search (1953–2020) was conducted and we identified 380 species that have been transported through hull fouling and ballast water around the world. We evaluated their likelihood of arriving (from 14 years of traffic data) and becoming established (from habitat suitability and demonstrated impacts and invasion ability) within the Gijon port, creating a new NIS Invasion Threat Score (NIS-ITS). This new index could help to identify target species that are likely invaders for early detection and prevention policies within the port. The results showed that 15 NIS had >90% likelihood of becoming a biological invasion problem in Gijon Port. At the same time, we reported morphological and genetic analysis of biota found in two successive annual monitoring surveys of Gijon port and ships (n = 612 individuals) revealing 18 NIS, including 6 of the NIS predicted from high NIS-ITS. Actually, 80% (12 NIS) of those potentially most dangerous species (NIS-ITS > 90%) have already been detected in the Bay of Biscay area. We propose the use of this new tool for a risk-reduction strategy in ports, based on accurate predictions that help in promoting specific early detection tests and specific monitoring for NIS that have a high chance of establishment. All international seaports can adopt this strategy to address the problem of biological invasions and become “blueports” in line with EU policy.
Longitudinal Study of Total and Pathogenic Vibrio parahaemolyticus (tdh+ and/or trh+) in Two Natural Extraction Areas of Mytilus chilensis in Southern Chile
Authors: Bacian Cristina , Verdugo Cristobal , García Katherine , Perez-Larruscain Josu , de Blas Ignacio , Cachicas Viviana , Lopez-Joven Carmen
Published: March 2021

Vibrio parahaemolyticus is the leading cause of seafood-associated bacterial gastroenteritis worldwide. Although different studies have focused on its pattern of variation over time, knowledge about the environmental factors driving the dynamics of this pathogen, within the Chilean territory, is still lacking. This study determined the prevalence of total and pathogenic V. parahaemolyticus strains (tdh and/or trh genes) in mussels (Mytilus chilensis) collected from two natural growing areas between 2017 and 2018, using selective agar and PCR analysis. V. parahaemolyticus was detected in 45.6% (93/204) of pooled samples from the Valdivia River Estuary. The pathogenic strains carrying the tdh and/or trh gene were detected in 11.8% (24/204): tdh in 9.8% (20/204), trh in 0.5% (1/204), and 1.5% (3/204) presented both genes. In Reloncaví Fjord, V. parahaemolyticus was detected in 14.4% (30/209) of the samples, pathogenic V. parahaemolyticus carrying the trh gene was detected in 0.5% (1/209) of the samples, while the tdh gene was not detected in the samples from this area. The total count of mauve-purple colonies typical of V. parahaemolyticus on CHROMagar was positively associated by multivariate analysis with area, water temperature, and salinity. Similarly, V. parahaemolyticus detection rates by PCR had a positive correlation with the area and water temperature. The chances of detecting total V. parahaemolyticus in the Valdivia River Estuary are significantly higher than in the Reloncaví Fjord, but inversely, during spring-summer months, the interaction factor between the area and temperature indicated that the chances of detecting V. parahaemolyticus are higher in the Reloncaví Fjord. Interestingly, this period coincides with the season when commercial and natural-growing shellfish are harvested. On the other hand, pathogenic V. parahaemolyticus tdh+ was significantly correlated with an increase of water temperature. These environmental parameters could be used to trigger a warning on potential hazard, which would influence human health and economic losses in aquaculture systems.
Towards a Functional Cure of HIV-1: Insight Into the Chromatin Landscape of the Provirus
Authors: Janssens Julie , Bruggemans Anne , Christ Frauke , Debyser Zeger
Published: March 2021

Despite potent combination antiretroviral therapy, HIV-1 infection persists due to irreversible integration of the virus in long-living cells of the immune system. The main focus of HIV-1 cure strategies has been on HIV-1 eradication, yet without great success so far. Therefore, HIV-1 remission or a functional cure, whereby the virus is silenced rather than eradicated, is considered as an alternative strategy. Elite controllers, individuals who spontaneously control HIV-1, may point us the way toward a functional HIV-1 cure. In order to achieve such a cure, a profound understanding of the mechanisms controlling HIV-1 expression and silencing is needed. In recent years, evidence has grown that the site of integration as well as the chromatin landscape surrounding the integration site affects the transcriptional state of the provirus. Still, at present, the impact of integration site selection on the establishment and maintenance of the HIV-1 reservoirs remains poorly understood. The discovery of LEDGF/p75 as a binding partner of HIV-1 integrase has led to a better understanding of integration site selection. LEDGF/p75 is one of the important determinants of integration site selection and targets integration toward active genes. In this review, we will provide an overview of the most important determinants of integration site selection. Secondly, we will discuss the chromatin landscape at the integration site and its implications on HIV-1 gene expression and silencing. Finally, we will discuss how interventions that affect integration site selection or modifications of the chromatin could yield a functional cure of HIV-1 infection.
Aerobic Denitrification and Heterotrophic Sulfur Oxidation in the Genus Halomonas Revealed by Six Novel Species Characterizations and Genome-Based Analysis
Authors: Wang Liping , Shao Zongze
Published: March 2021

Bacteria of Halomonas are widely distributed in various environments and play a substantial role in the nutrient cycle. In this report, 14 strains capable of aerobic denitrification and heterotrophic sulfur oxidation were isolated from different habitats. Based on the phenotypic, genotypic, and chemotaxonomic analyses, these strains were considered to represent six novel species of the genus Halomonas, for which the names Halomonas zhangzhouensis sp. nov. type strain CXT3-11T ( = MCCC 1A11036T = KCTC 72087T), Halomonas aerodenitrificans sp. nov. CYD-9T ( = MCCC 1A11058T = KCTC 72088T), Halomonas sulfidoxydans sp. nov. CYN-1-2T ( = MCCC 1A11059T = KCTC 72089T), Halomonas ethanolica sp. nov. CYT3-1-1T ( = MCCC 1A11081T = KCTC 72090T), Halomonas sulfidivorans sp. nov. NLG_F1ET ( = MCCC 1A13718T = KCTC 72091T), and Halomonas tianxiuensis sp. nov. BC-M4-5T ( = MCCC 1A14433T = KCTC 72092T) are proposed. Intriguingly, they formed a unique group with 11 other species designated as the “H. desiderata group.” To better understand their featured metabolisms, genes involved in denitrification and sulfur oxidation were analyzed, along with 193 other available genomes of the whole genus. Consistently, complete denitrification pathways were confirmed in the “H. desiderata group,” in which napA, narG, nirS, norB, and nosZ genes coexist. Their nitrite reductase NirS formed a unique evolutionary lineage, distinguished from other denitrifiers in Halomonas. In addition, diverse occurrence patterns of denitrification genes were also observed in different phylogenetic clades of Halomonas. With respect to sulfur oxidation, fccAB genes involved in sulfide oxidation commonly exist in the “H. desiderata group,” while sqr genes are diverse and can be found in more species; sqr genes co-occurred with fccAB in eight strains of this study, contributing to more active sulfide oxidation. Besides, the tsdA gene, which encodes an enzyme that oxidizes thiosulfate to tetrathionate, is ubiquitous in the genus Halomonas. The widespread presence of sqr/fccAB, pdo, and tsdA in Halomonas suggests that many Halomonas spp. can act as heterotrophic sulfur oxidizers. These results provide comprehensive insights into the potential of denitrification and sulfur oxidation in the whole genus of Halomonas. With regard to the global distribution of Halomonas, this report implies their unneglectable role in the biogeochemical cycle.
Multiple Layered Control of the Conjugation Process of the Bacillus subtilis Plasmid pLS20
Authors: Meijer Wilfried J. J. , Boer D. Roeland , Ares Saúl , Alfonso Carlos , Rojo Fernando , Luque-Ortega Juan R. , Wu Ling Juan
Published: March 2021

Bacterial conjugation is the main horizontal gene transfer route responsible for the spread of antibiotic resistance, virulence and toxin genes. During conjugation, DNA is transferred from a donor to a recipient cell via a sophisticated channel connecting the two cells. Conjugation not only affects many different aspects of the plasmid and the host, ranging from the properties of the membrane and the cell surface of the donor, to other developmental processes such as competence, it probably also poses a burden on the donor cell due to the expression of the large number of genes involved in the conjugation process. Therefore, expression of the conjugation genes must be strictly controlled. Over the past decade, the regulation of the conjugation genes present on the conjugative Bacillus subtilis plasmid pLS20 has been studied using a variety of methods including genetic, biochemical, biophysical and structural approaches. This review focuses on the interplay between RcopLS20, RappLS20 and Phr*pLS20, the proteins that control the activity of the main conjugation promoter Pc located upstream of the conjugation operon. Proper expression of the conjugation genes requires the following two fundamental elements. First, conjugation is repressed by default and an intercellular quorum-signaling system is used to sense conditions favorable for conjugation. Second, different layers of regulation act together to repress the Pc promoter in a strict manner but allowing rapid activation. During conjugation, ssDNA is exported from the cell by a membrane-embedded DNA translocation machine. Another membrane-embedded DNA translocation machine imports ssDNA in competent cells. Evidences are reviewed indicating that conjugation and competence are probably mutually exclusive processes. Some of the questions that remain unanswered are discussed.
Silencing of the TRIM58 Gene by Aberrant Promoter Methylation is Associated with a Poor Patient Outcome and Promotes Cell Proliferation and Migration in Clear Cell Renal Cell Carcinoma
Authors: Gan Ying , Cao Congcong , Li Aolin , Song Haifeng , Kuang Guanyu , Ma Binglei , Zhang Quan , Zhang Qian
Published: March 2021

To investigate the underlying molecular mechanism of tripartite motif-containing 58 (TRIM58) in the development of clear cell renal cell carcinoma (ccRCC), we explored TRIM58 expression and methylation in tumor tissues and the association with clinicopathological features and prognosis of tissue samples; Moreover, we examined the direct gene transcription of TRIM58-specific DNA demethyltransferase (TRIM58-TET1) by the CRISPR-dCas9 fused with the catalytic domain of TET1 and the biological functions in RCC cells. In this study, we demonstrate that TRIM58 is frequently downregulated by promoter methylation in ccRCC tissues, associated significantly with tumor nuclear grade and poor patient survival. TRIM58-TET1 directly induces demethylation of TRIM58 CpG islands, and activates TRIM58 transcription in RCC cell lines. Besides, DNA demethylation of TRIM58 by TRIM58-TET1 significantly inhibits cell proliferation and migration Overall, our results demonstrate that TRIM58 is inactivated by promoter methylation, associates with tumor nuclear grade and poor survival, and TRIM58 DNA demethylation could directly activate TRIM58 transcription and inhibit cell proliferation and migration in RCC cell lines.
Thalamocortical Functional Connectivity in Patients With White Matter Hyperintensities
Authors: Chen Chen , Wang Xiaojing , Cao Shanshan , Zhang Jun , Wang Zhiqi , Pan Wen , Yang Jinying , Tian Yanghua , Qiu Bensheng , Wei Qiang , Wang Kai
Published: March 2021

Background: White matter hyperintensities (WMH)s is a very common neuroradiological manifestation in the elderly and is an increased risk of dementia and cognitive decline. As we all know, the thalamocortical circuit plays an important part in cognition regulation. However, the role of this circuit in WMHs and its related cognitive deficits is still unclear.

Method: Eighty WMH patients and 37 healthy controls (HCs) were enrolled in the current study. WMH patients were divided into a mild WMH group (n = 33) and moderate-severe WMH group (n = 47) according to Fazekas scores. Resting-state functional magnetic resonance imaging (rs-fMRI) data of all participants were collected for thalamocortical functional connectivity (FC) analysis. The analysis was performed in two steps. First, the whole cerebral cortex was divided into six regions of interest (ROIs), which were used as seeds to investigate the changes of FC with the thalamus. Then, the subregion of the thalamus generated in the previous step was used as the seed for FC analysis with the whole brain.

Results: In the first step of FC analysis, it was found that precentral gyrus (PrCG)-interthalamic adhesion (ITA) FC values in moderate-severe WMH group were higher than those in HC and mild WMH groups. However, when compared with the HC group, the increase of PrCG-ITA FC values in mild WMH group was not statistically significant. In the second step of FC analysis, the ITA was set as the seed, and compared with the HC group, the results showed that the FC values of the ITA-medial frontal gyrus (MFG) in mild group and moderate-severe WMH groups were significantly increased. In addition, the FC values in moderate-severe group were significantly higher than those in mild group. Finally, it was also found that FC values (PrCG-ITA and ITA-MFG) were significantly correlated with neuropsychological test results for multiple cognitive functions such as memory, execution and attention in WMH patients.

Conclusion: Abnormal thalamocortical FC was closely related with cognitive impairments in WMH patients.
Characteristic Alterations of Network in Patients With Intraoperative Stimulation-Induced Seizures During Awake Craniotomy
Authors: Fang Shengyu , Zhou Chunyao , Wang Lei , Fan Xing , Wang Yinyan , Zhang Zhong , Jiang Tao
Published: March 2021

Background: The use of electrocorticography (ECoG) to avoid intraoperative stimulation-induced seizure (ISS) during awake craniotomy is controversial. Although a standard direct cortical stimulating (DCS) protocol is used to identify the eloquent cortices and subcortical structures, ISS still occurs. Epilepsy is related to alterations in brain networks. In this study, we investigated specific alterations in brain networks in patients with ISS.

Methods: Twenty-seven patients with glioma were enrolled and categorized into the ISS and non-ISS groups based on their history of ISS occurrence. A standard DCS protocol was used during awake craniotomy without ECoG supervision. Graph theoretical measurement was used to analyze resting-state functional magnetic resonance imaging data to quantitatively reveal alterations in the functional networks.

Results: In the sensorimotor networks, the glioma significantly decreased the functional connectivity (FC) of four edges in the ISS group, which were conversely increased in the non-ISS group after multiple corrections (p < 0.001, threshold of p-value = 0.002). Regarding the topological properties, the sensorimotor network of all participants was classified as a small-world network. Glioma significantly increased global efficiency, nodal efficiency, and the sigma value, as well as decreased the shortest path length in the ISS group compared with the non-ISS group (p < 0.05).

Conclusions: The specific alterations indicating patient susceptibility to ISS during DCS increased global and nodal efficiencies and decreased the shortest path length and FC induced by gliomas. If the patient has these specific alterations, ECoG is recommended to monitor after-discharge current during DCS to avoid ISS.
Correlation of Lipid Ratios With the Severity of Pulmonary Alveolar Proteinosis: A Cross-Sectional Study
Authors: Yan Xin , Gao Yujuan , Zhao Qi , Qiu Xiaohua , Tian Mi , Dai Jinghong , Zhuang Yi
Published: March 2021

Background: Lipids are known to accumulate abnormally in the alveoli and circulate during pulmonary alveolar proteinosis (PAP). However, the relationship between lipid ratios and PAP is not clear. In this study, we investigated the lipid ratios in PAP patients and explored the relationships between lipid ratios and the severity of PAP.

Methods: A total of 122 PAP patients were diagnosed and divided the mild- moderate PAP group (n = 61) and the severe PAP group (n = 61) according to the value of disease severity score (DSS). One hundred thirty healthy volunteers were classified as the control group. Routine blood examination and pulmonary function tests were performed and lipid profile were measured.

Results: Compared with the control group, patients with PAP had significantly higher TG, TC/HDL-C, TG/HDL-C, and non-HDL-C, while lower HDL-C (all P < 0.05). Patients with the severe PAP had higher TC, TG, LDL-C, TC/HDL-C, and non-HDL-C, while lower HDL-C than patients with the mild- moderate PAP (all P < 0.05). Binary logistic regression analysis indicated that TC/HDL-C (OR = 2.322, 95% CI 1.621–3.713, P = 0.024) and non-HDL-C (OR = 1.797, 95% CI 1.239–3.109, P = 0.036) were all significantly correlated with the severity of PAP after adjustment for other risk factors. The AUC value of TC/HDL-C for predicting the severity of PAP was larger than that of non-HDL-C. The AUROC for TC/HDL-C was 0.741 (0.654–0.828), and the optimal cut-off point for TC/HDL-C was 5.05 (sensitivity: 73.6%, specificity: 68.1%).

Conclusions: Lipid ratios, including TC-HDL-C and non-HDL-C, were independent risk factors for the severity of PAP. TC/HDL-C is a promising biomarker for the severity of PAP.
Correlation Between Dual-Time-Point FDG PET and Tumor Microenvironment Immune Types in Non-Small Cell Lung Cancer
Authors: Zhou Jianyuan , Zou Sijuan , Cheng Siyuan , Kuang Dong , Li Dan , Chen Lixing , Liu Cong , Yan Jianhua , Zhu Xiaohua
Published: March 2021

Purpose

Dual-time-point 18F-fluorodeoxyglucose positron emission tomography (DTP 18F-FDG PET), which reflects the dynamics of tumor glucose metabolism, may also provide a novel approach to the characterization of both cancer cells and immune cells within the tumor immune microenvironment (TIME). We investigated the correlations between the metabolic parameters (MPs) of DTP 18F-FDG PET images and the tumor microenvironment immune types (TMITs) in patients with non-small cell lung cancer (NSCLC).

Methods

A retrospective analysis was performed in 91 patients with NSCLC who underwent preoperative DTP 18F-FDG PET/CT scans. MPs in the early scan (eSUVmax, eSUVmean, eMTV, eTLG) and delayed scan (dSUVmax, dSUVmean, dMTV, dTLG) were calculated, respectively. The change in MPs (ΔSUVmax, ΔSUVmean, ΔMTV, ΔTLG) between the two time points were calculated. Tumor specimens were analyzed by immunohistochemistry for PD-1/PD-L1 expression and CD8+ tumor-infiltrating lymphocytes (TILs). TIME was classified into four immune types (TMIT I ~ IV) according to the expression of PD-L1 and CD8+ TILs. Correlations between MPs with TMITs and the immune-related biomarkers were analyzed. A composite metabolic signature (Meta-Sig) and a combined model of Meta-Sig and clinical factors were constructed to predict patients with TMIT I tumors.

Results

eSUVmax, eSUVmean, dSUVmax, dSUVmean, ΔSUVmax, ΔSUVmean, and ΔTLG were significantly higher in PD-L1 positive patients (p = 0.0007, 0.0006, < 0.0001, < 0.0001, 0.0002, 0.0002, 0.0247, respectively), and in TMIT-I tumors (p = 0.0001, < 0.0001, < 0.0001, < 0.0001, 0.0009, 0.0009, 0.0144, respectively). Compared to stand-alone MP, the Meta-Sig and combined model displayed better performance for assessing TMIT-I tumors (Meta-sig: AUC = 0.818, sensitivity = 86.36%, specificity = 73.91%; Model: AUC = 0.869, sensitivity = 77.27%, specificity = 82.61%).

Conclusion

High glucose metabolism on DTP 18F-FDG PET correlated with the TMIT-I tumors, and the Meta-Sig and combined model based on clinical and metabolic information could improve the performance of identifying the patients who may respond to immunotherapy.
Differential Gene Expression Analysis Reveals Global LMTK2 Regulatory Network and Its Role in TGF-β1 Signaling
Authors: Cruz Daniel F. , Mitash Nilay , Mu Fangping , Farinha Carlos M. , Swiatecka-Urban Agnieszka
Published: March 2021

Lemur tyrosine kinase 2 (LMTK2) is a transmembrane Ser/Thr kinase whose role has been increasingly recognized; however, when compared to other kinases, understanding of the LMTK2 networks and biological functions is still limited. Recent data have shown that transforming growth factor (TGF)-β1 plays a role in modulating LMTK2 function by controlling its endocytic trafficking in human bronchial epithelial cells. Here, we aimed to unveil the LMTK2 regulatory network and elucidate how it affects cellular functions and disease pathways in either TGF-β1 dependent or independent manner. To understand how the LMTK2 and TGF-β1 pathways interconnect, we knocked down (KD) LMTK2 using small(si)RNA-mediated silencing in human bronchial epithelial CFBE41o- cells, treated cells with TGF-β1 or vehicle control, and performed differential gene expression analysis by RNA sequencing (RNAseq). In vehicle-treated cells, LMTK2 KD affected expression of 2,506 genes while it affected 4,162 genes after TGF-β1 stimulation. Bioinformatics analysis shows that LMTK2 is involved in diverse cellular functions and disease pathways, such as cell death and survival, cellular development, and cancer susceptibility. In summary, our study increases current knowledge about the LMTK2 network and its intersection with the TGF-β1 signaling pathway. These findings will serve as basis for future exploration of the predicted LMTK2 interactions and signaling pathways.
Comparative Efficacy and Safety of Immunotherapy Alone and in Combination With Chemotherapy for Advanced Non-small Cell Lung Cancer
Authors: Wang Xue , Niu Xiaomin , An Na , Sun Yile , Chen Zhiwei
Published: March 2021

There is a lack of direct cross-comparison studies in clinical trials between immunotherapy alone and combination treatment, especially in Non-Small Cell Lung Cancer (NSCLC) patients with high PD-L1 expression. To determine if anti-PD-(L)1 antibody combined with chemotherapy is more efficient than immune checkpoint inhibitor (ICI) monotherapy for advanced NSCLC patients in the real-world data. We retrospectively collected 325 patients with advanced NSCLC treated with ICI alone with or without chemotherapy from 11th July 2016 to 26th May 2020 to investigate which treatment scenario is the most efficient, and how clinical factors impact response. Patients with advanced NSCLC were treated with ICI monotherapy (178/325, 54.8%) or in combination with chemotherapy (147/325, 45.2%). The objective response rate and disease control rate were higher in the combination group than the monotherapy group. Patients (including those with distant metastasis) treated with chemo-immunotherapy were associated with a significantly longer median PFS and OS compared with the monotherapy group, irrespective of the PD-L1 expression level and previous treatment lines. No significant increase in the risk of immune-related adverse events (irAEs) was found after combination with chemotherapy (50.6 vs. 57.8%). IrAEs predicted better PFS of immunotherapy in the monotherapy group, especially for patients with late irAEs (after ≥4 cycles). Collectively, we demonstrated that ICI monotherapy plus chemotherapy might have better anti-tumor activity and an acceptable side-effect profile regardless of PD-L1 level or previous treatment lines. Both regimens were well-tolerated and cost-effective, the more efficient is usually recommended.
The Role of Macrophages in Oral Squamous Cell Carcinoma
Authors: Kalogirou Eleni Marina , Tosios Konstantinos I. , Christopoulos Panagiotis F.
Published: March 2021

Oral cancer is a common malignancy worldwide, with high disease-related death rates. Oral squamous cell carcinoma (OSCC) accounts for more than 90% of oral tumors, with surgical management remaining the treatment of choice. However, advanced and metastatic OSCC is still incurable. Thus, emphasis has been given lately in understanding the complex role of the oral tumor microenvironment (TME) in OSCC progression, in order to identify novel prognostic biomarkers and therapeutic targets. Tumor associated macrophages (TAMs) constitute a major population of the OSCC TME, with bipolar role in disease progression depending on their activation status (M1 vs. M2). Here, we provide an up to date review of the current literature on the role of macrophages during oral oncogenesis, as well as their prognostic significance in OSCC survival and response to standard treatment regimens. Finally, we discuss novel concepts regarding the potential use of macrophages as targets for OSCC immunotherapeutics and suggest future directions in the field.
Single-Cell RNA-seq Reveals Characteristics of Malignant Cells and Immune Microenvironment in Subcutaneous Panniculitis-Like T-Cell Lymphoma
Authors: Li Zifeng , Wang Hongsheng , Dong Rui , Man Jie , Sun Li , Qian Xiaowen , Zhu Xiaohua , Cao Ping , Yu Yi , Le Jun , Fu Yang , Wang Ping , Jiang Wenjin , Shen Chen , Ma Yangyang , Chen Lian , Xu Yaochen , Shi Jiantao , Zhang Hui , Qian Maoxiang , Zhai Xiaowen
Published: March 2021

Background

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a malignant primary T-cell lymphoma that is challenging to distinguish from autoimmune disorders and reactive panniculitides. Delay in diagnosis and a high misdiagnosis rate affect the prognosis and survival of patients. The difficulty of diagnosis is mainly due to an incomplete understanding of disease pathogenesis.

Methods

We performed single-cell RNA sequencing of matched subcutaneous lesion tissue, peripheral blood, and bone marrow from a patient with SPTCL, as well as peripheral blood, bone marrow, lymph node, and lung tissue samples from healthy donors as normal controls. We conducted cell clustering, gene expression program identification, gene differential expression analysis, and cell-cell interaction analysis to investigate the ecosystem of SPTCL.

Results

Based on gene expression profiles in a single-cell resolution, we identified and characterized the malignant cells and immune subsets from a patient with SPTCL. Our analysis showed that SPTCL malignant cells expressed a distinct gene signature, including chemokines families, cytotoxic proteins, T cell immune checkpoint molecules, and the immunoglobulin family. By comparing with normal T cells, we identified potential novel markers for SPTCL (e.g., CYTOR, CXCL13, VCAM1, and TIMD4) specifically differentially expressed in the malignant cells. We also found that macrophages and fibroblasts dominated the cell-cell communication landscape with the SPTCL malignant cells.

Conclusions

This work offers insight into the heterogeneity of subcutaneous panniculitis-like T-cell lymphoma, providing a better understanding of the transcription characteristics and immune microenvironment of this rare tumor.
Novel Molecular Hallmarks of Group 3 Medulloblastoma by Single-Cell Transcriptomics
Authors: Qin Chaoying , Pan Yimin , Li Yuzhe , Li Yue , Long Wenyong , Liu Qing
Published: March 2021

Medulloblastoma (MB) is a highly heterogeneous and one of the most malignant pediatric brain tumors, comprising four subgroups: Sonic Hedgehog, Wingless, Group 3, and Group 4. Group 3 MB has the worst prognosis of all MBs. However, the molecular and cellular mechanisms driving the maintenance of malignancy are poorly understood. Here, we employed high-throughput single-cell and bulk RNA sequencing to identify novel molecular features of Group 3 MB, and found that a specific cell cluster displayed a highly malignant phenotype. Then, we identified the glutamate receptor metabotropic 8 (GRM8), and AP-1 complex subunit sigma-2 (AP1S2) genes as two critical markers of Group 3 MB, corresponding to its poor prognosis. Information on 33 clinical cases was further utilized for validation. Meanwhile, a global map of the molecular cascade downstream of the MYC oncogene in Group 3 MB was also delineated using single-cell RNA sequencing. Our data yields new insights into Group 3 MB molecular characteristics and provides novel therapeutic targets for this relentless disease.
Permanent Interstitial Cesium-131 Brachytherapy in Treating High-Risk Recurrent Head and Neck Cancer: A Prospective Pilot Study
Authors: Kharouta Michael , Zender Chad , Podder Tarun , Rezaee Rod , Lavertu Pierre , Fowler Nicole , Thuener Jason , Li Shawn , Clancy Kate , Xu Zhengzheng , Yao Min
Published: March 2021

Purpose/Objectives

To establish the feasibility and safety of intraoperative placement of cesium-131 (Cs-131) seeds for re-irradiation in recurrent head and neck cancer (HNC).

Methods

Patients with resectable recurrent HNC who were deemed to have a high risk of second recurrence were eligible. Immediately after tumor extirpation, seeds were implanted in the surgical bed based on the preoperative treatment plan with intraoperative adjustment. The surgical bed and the seeds were covered with a regional flap or microvascular free flap. A CT of the neck was obtained on postoperative day 1 for evaluation of the postoperative dose distribution. Patients were followed 1 and 3 months after surgery, then every 3 months in the first 2 years.

Results

From November 2016 to September 2018, 15 patients were recruited and 12 patients received treatment per protocol. For the patients who had implants, the sites of initial recurrence included 10 neck alone, 1 neck and larynx, and 1 neck/peristomal. The median follow-up was 21.4 months. After surgery, patients remained hospitalized for a median of 6 days. There were no high-grade toxicities except two patients with wound complications requiring wound care. Eight patients had recurrences, three locoregional alone, three distant alone, and two with both locoregional and distant recurrences. Only one patient had an in-field failure. Five patients died, with 1- and 2-year overall survival of 75 and 58%.

Conclusions

Cs-131 implant after surgical resection in recurrent HNC is feasible and safe. There were no unexpected severe toxicities. Most failures were out-of-field or distant.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT02794675.
Patient-Derived Cancer Organoids as Predictors of Treatment Response
Authors: Verduin Maikel , Hoeben Ann , De Ruysscher Dirk , Vooijs Marc
Published: March 2021

Patient-derived cancer organoids have taken a prominent role in pre-clinical and translational research and have been generated for most common solid tumors. Cancer organoids have been shown to retain key genetic and phenotypic characteristics of their tissue of origin, tumor subtype and maintain intratumoral heterogeneity and therefore have the potential to be used as predictors for individualized treatment response. In this review, we highlight studies that have used cancer organoids to compare the efficacy of standard-of-care and targeted combination treatments with clinical patient response. Furthermore, we review studies using cancer organoids to identify new anti-cancer treatments using drug screening. Finally, we discuss the current limitations and improvements needed to understand the full potential of cancer organoids as avatars for clinical management of cancer therapy.
Status of Treatment and Prophylaxis for Radiation-Induced Oral Mucositis in Patients With Head and Neck Cancer
Authors: Liu Shiyu , Zhao Qin , Zheng Zhuangzhuang , Liu Zijing , Meng Lingbin , Dong Lihua , Jiang Xin
Published: March 2021

Radiation-induced oral mucositis (RIOM) is one of the most frequent complications in head and neck cancer (HNC) patients undergoing radiotherapy (RT). It is a type of mucosal injury associated with severe pain, dysphagia, and other symptoms, which leads to the interruption of RT and other treatments. Factors affecting RIOM include individual characteristics of HNC patients, concurrent chemoradiation therapy, and RT regimen, among others. The pathogenesis of RIOM is not yet fully understood; however, the release of inflammatory transmitters plays an important role in the occurrence and development of RIOM. The five biological stages, including initiation, primary damage response, signal amplification, ulceration, and healing, are widely used to describe the pathophysiology of RIOM. Moreover, RIOM has a dismal outcome with limited treatment options. This review will discuss the epidemiology, pathogenesis, clinical appearance, symptomatic treatments, and preventive measures related to this disease. We hope to provide a reference for the clinical treatment and prevention of RIOM in HNC patients after RT.
Case Report: A Novel Pathogenic Missense Mutation in FAS: A Multi-Generational Case Series of Autoimmune Lymphoproliferative Syndrome
Authors: Gaefke Claudia L. , Metts Jonathan , Imanirad Donya , Nieves Daime , Terranova Paola , Dell'Orso Gianluca , Gambineri Eleonora , Miano Maurizio , Lockey Richard F. , Walter Jolan Eszter , Westermann-Clark Emma
Published: March 2021

Autoimmune Lymphoproliferative Syndrome (ALPS), commonly caused by mutations in the FAS gene, is a disease with variable penetrance. Subjects may be asymptomatic, or they may present with lymphadenopathy, splenomegaly, cytopenias, or malignancy. Prompt recognition of ALPS is needed for optimal management. We describe a multi-generational cohort presenting with clinical manifestations of ALPS, and a previously unreported heterozygous missense variant of uncertain significance in FAS (c.758G >T, p.G253V), located in exon 9. Knowledge of the underlying genetic defect permitted prompt targeted therapy to treat acute episodes of cytopenia. This cohort underscores the importance of genetic testing in subjects with clinical features of ALPS and should facilitate the reclassification of this variant as pathogenic.
Opportunities to Target T Cell Trafficking in Pediatric Inflammatory Bowel Disease
Authors: Giannoudaki Eirini , Gargan Siobhan , Hussey Seamus , Long Aideen , Walsh Patrick T.
Published: March 2021

T cell subsets are considered central orchestrators of inflammation and homeostasis in the intestine and are established targets for the treatment of inflammatory bowel disease. While approaches aimed at the neutralization of T cell effector cytokines have provided significant benefits for pediatric and adult patients, more recent strategies aimed at inhibiting the infiltration of pathogenic T cell subsets have also emerged. In this review, we describe current knowledge surrounding the function of T cell subsets in pediatric inflammatory bowel disease and outline approaches aimed at targeting T cell trafficking to the intestine which may represent a new treatment option for pediatric inflammatory bowel disease.