bluuebunny/crossref_metadata_2025 huggingface dataset:
Remus: A Web Application for Prioritization of Regulatory Regions and Variants in Monogenic Diseases
Authors: Sztromwasser Paweł , Skrzypczak Damian , Michalak Arkadiusz , Fendler Wojciech
Published: March 2021

Background

Analysis of variants in distant regulatory elements could improve the current 25–50% yield of genetic testing for monogenic diseases. However, the vast size of the regulome, great number of variants, and the difficulty in predicting their phenotypic impact make searching for pathogenic variants in the regulatory genome challenging. New tools for the identification of regulatory variants based on their relevance to the phenotype are needed.

Methods

We used tissue-specific regulatory loci mapped by ENCODE and FANTOM, together with miRNA–gene interactions from miRTarBase and miRWalk, to develop Remus, a web application for the identification of tissue-specific regulatory regions. Remus searches for regulatory features linked to the known disease-associated genes and filters them using activity status in the target tissues relevant for the studied disorder. For user convenience, Remus provides a web interface and facilitates in-browser filtering of variant files suitable for sensitive patient data.

Results

To evaluate our approach, we used a set of 146 regulatory mutations reported causative for 68 distinct monogenic disorders and a manually curated a list of tissues affected by these disorders. In 89.7% of cases, Remus identified the regulator containing the pathogenic mutation. The tissue-specific search limited the number of considered variants by 82.5% as compared to a tissue-agnostic search.

Conclusion

Remus facilitates the identification of regulatory regions potentially associated with a monogenic disease and can supplement classical analysis of coding variations with the aim of improving the diagnostic yield in whole-genome sequencing experiments.
Differential Requirements for Mediator Complex Subunits in Drosophila melanogaster Host Defense Against Fungal and Bacterial Pathogens
Authors: Huang Chuqin , Xu Rui , Liégeois Samuel , Chen Di , Li Zi , Ferrandon Dominique
Published: March 2021

The humoral immune response to bacterial or fungal infections in Drosophila relies largely on a transcriptional response mediated by the Toll and Immune deficiency NF-κB pathways. Antimicrobial peptides are potent effectors of these pathways and allow the organism to attack invading pathogens. Dorsal-related Immune Factor (DIF), a transcription factor regulated by the Toll pathway, is required in the host defense against fungal and some Gram-positive bacterial infections. The Mediator complex is involved in the initiation of transcription of most RNA polymerase B (PolB)-dependent genes by forming a functional bridge between transcription factors bound to enhancer regions and the gene promoter region and then recruiting the PolB pre-initiation complex. Mediator is formed by several modules that each comprises several subunits. The Med17 subunit of the head module of Mediator has been shown to be required for the expression of Drosomycin, which encodes a potent antifungal peptide, by binding to DIF. Thus, Mediator is expected to mediate the host defense against pathogens controlled by the Toll pathway-dependent innate immune response. Here, we first focus on the Med31 subunit of the middle module of Mediator and find that it is required in host defense against Aspergillus fumigatus, Enterococcus faecalis, and injected but not topically-applied Metarhizium robertsii. Thus, host defense against M. robertsii requires Dif but not necessarily Med31 in the two distinct infection models. The induction of some Toll-pathway-dependent genes is decreased after a challenge of Med31 RNAi-silenced flies with either A. fumigatus or E. faecalis, while these flies exhibit normal phagocytosis and melanization. We have further tested most Mediator subunits using RNAi by monitoring their survival after challenges to several other microbial infections known to be fought off through DIF. We report that the host defense against specific pathogens involves a distinct set of Mediator subunits with only one subunit for C. glabrata or Erwinia carotovora carotovora, at least one for M. robertsii or a somewhat extended repertoire for A. fumigatus (at least eight subunits) and E. faecalis (eight subunits), with two subunits, Med6 and Med11 being required only against A. fumigatus. Med31 but not Med17 is required in fighting off injected M. robertsii conidia. Thus, the involvement of Mediator in Drosophila innate immunity is more complex than expected.
Detection of Alterations in the Gut Microbiota and Intestinal Permeability in Patients With Hashimoto Thyroiditis
Authors: Cayres Leonardo César de Freitas , de Salis Larissa Vedovato Vilela , Rodrigues Guilherme Siqueira Pardo , Lengert André van Helvoort , Biondi Ana Paula Custódio , Sargentini Larissa Donadel Barreto , Brisotti João Luiz , Gomes Eleni , de Oliveira Gislane Lelis Vilela
Published: March 2021

Hashimoto thyroiditis (HT) is the most common autoimmune disease worldwide, characterized by chronic inflammation and circulating autoantibodies against thyroid peroxidase and thyroglobulin. Patients require hormone replacement with oral levothyroxine, and if untreated, they can develop serious adverse health effects and ultimately death. There is a lot of evidence that the intestinal dysbiosis, bacterial overgrowth, and increased intestinal permeability favor the HT development, and a thyroid–gut axis has been proposed, which seems to impact our entire metabolism. Here, we evaluated alterations in the gut microbiota in Brazilian patients with HT and correlated this data with dietary habits, clinical data, and systemic cytokines and zonulin concentrations. Stool samples from 40 patients with HT and 53 controls were analyzed using real-time PCR, the serum cytokine levels were evaluated by flow cytometry, zonulin concentrations by ELISA, and the dietary habits were recorded by a food frequency questionnaire. We observed a significant increase (p < 0.05) in the Bacteroides species and a decrease in Bifidobacterium in samples of patients with HT. In addition, Lactobacillus species were higher in patients without thyroid hormone replacement, compared with those who use oral levothyroxine. Regarding dietary habits, we demonstrated that there are significant differences in the consumption of vegetables, fruits, animal-derived proteins, dairy products, saturated fats, and carbohydrates between patients and control group, and an inverse correlation between animal-derived protein and Bacteroides genus was detected. The microbiota modulation by diet directly influences the inflammatory profile due to the generated microbiota metabolites and their direct or indirect action on immune cells in the gut mucosa. Although there are no differences in systemic cytokines in our patients with HT, we detected increased zonulin concentrations, suggesting a leaky gut in patients with HT. These findings could help understand the development and progression of HT, while further investigations to clarify the underlying mechanisms of the diet–microbiota–immune system axis are still needed.
Understanding the Role of T-Cells in the Antimyeloma Effect of Immunomodulatory Drugs
Authors: D'Souza Criselle , Prince H. Miles , Neeson Paul J.
Published: March 2021

Immunomodulatory drugs (IMiDs) are effective treatments for patients with multiple myeloma. IMiDs have pleotropic effects including targeting the myeloma cells directly, and improving the anti-myeloma immune response. In the absence of myeloma cells, lenalidomide and pomalidomide induce CD4+T cell secretion of IL-2 and indirect activation of Natural Killer (NK) cells. In the context of T cell receptor ligation, IMiDs enhance T cell proliferation, cytokine release and Th1 responses, bothin vivoandin vitro. Furthermore, combination treatment of IMiDs and myeloma-targeting monoclonal antibodies eg. daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7), checkpoint inhibitors, or bispecific T cell engagers showed synergistic effects, mainly via enhanced T and NK cell dependent cellular toxicity and T cell proliferation. Conversely, the corticosteroid dexamethasone can impair the immune modulatory effects of IMiDs, indicating that careful choice of myeloma drugs in combination with IMiDs is key for the best anti-myeloma therapeutic efficacy. This review presents an overview of the role for T cells in the overall anti-myeloma effects of immunomodulatory drugs.
Transcriptomic Analysis of Inflammatory Cardiomyopathy Identifies Molecular Signatures of Disease and Informs in silico Prediction of a Network-Based Rationale for Therapy
Authors: Singh Kamayani , Fang Hai , Davies Graham , Wright Benjamin , Lockstone Helen , Williams Richard O. , Ciháková Daniela , Knight Julian C. , Bhattacharya Shoumo
Published: March 2021

Inflammatory cardiomyopathy covers a group of diseases characterized by inflammation and dysfunction of the heart muscle. The immunosuppressive agents such as prednisolone, azathioprine and cyclosporine are modestly effective treatments, but a molecular rationale underpinning such therapy or the development of new therapeutic strategies is lacking. We aimed to develop a network-based approach to identify therapeutic targets for inflammatory cardiomyopathy from the evolving myocardial transcriptome in a mouse model of the disease. We performed bulk RNA sequencing of hearts at early, mid and late time points from mice with experimental autoimmune myocarditis. We identified a cascade of pathway-level events involving early activation of cytokine and chemokine-signaling pathways that precede leucocyte infiltration and are followed by innate immune, antigen-presentation, complement and cell-adhesion pathway activation. We integrated these pathway events into a network-like representation from which we further identified a 50-gene subnetwork that is predominantly induced during the course of autoimmune myocardial inflammation. We developed a combinatorial attack strategy where we quantify network tolerance to combinatorial node removal to determine target-specific therapeutic potential. We find that combinatorial attack of Traf2, Nfkb1, Rac1, and Vav1 disconnects 80% of nodes from the largest network component. Two of these nodes, Nfkb1 and Rac1, are directly targeted by prednisolone and azathioprine respectively, supporting the idea that the methodology developed here can identify valid therapeutic targets. Whereas Nfkb1 and Rac1 removal disconnects 56% of nodes, we show that additional removal of Btk and Pik3cd causes 72% node disconnection. In conclusion, transcriptome profiling, pathway integration, and network identification of autoimmune myocardial inflammation provide a molecular signature applicable to the diagnosis of inflammatory cardiomyopathy. Combinatorial attack provides a rationale for immunosuppressive therapy of inflammatory cardiomyopathy and provides an in silico prediction that the approved therapeutics, ibrutinib and idelalisib targeting Btk and Pik3cd respectively, could potentially be re-purposed as adjuncts to immunosuppression.
Adverse Life Events: Do Home Care Clients Have Resources for Mastering Them?
Authors: Garms-Homolová Vjenka , Declercq Anja , Finne-Soveri Harriet , Notthoff Nanna , van der Roest Henriëtte G. , van Hout Hein P. J.
Published: March 2021

Objectives: Research on life stressors and adverse life events has a long tradition. Few studies have addressed this topic in connection to very old people. Life stressors, especially major life stressors (MLSs) experienced by clients of home care services in the community have rarely been the subject of studies. Considering this gap, we investigated the prevalence of MLSs in home care clients. We examined the effects that MLSs have on their mood and health status as well as the impact of clients' social resources on MLSs and their outcomes.

Method: We used assessment data from 2,884 home care clients in six European countries. The methodological basis was the comprehensive and standardized interRAI Home Care Assessment (interRAI HC).

Results: Fifteen point four percent of the sample—that consisted of women and men with an average age of 82.89 years–experienced an MLS in the last 6 months before the assessment. They were more depressed than persons without these experiences, and their health status indicated a higher level of instability and deterioration. At reassessment after 6 months, the situation changed. Despite the fact that both outcomes of the MLSs, depression and health status became worse in the reassessment-sample, home care clients without MLS were more affected by the worsening, especially that of depression. The expected buffering impact of social resources was low.

Discussion: Although this study worked with limited information on MLSs, it could contribute to closing various knowledge gaps. The study shows that the MLSs represent a prevalent problem in a population of home care clients and that this problem has negative consequences for their mood and the stability of their health status. Furthermore, this research took up the situation of very old and vulnerable adults, who have previously rarely been considered in studies on major critical life events and stressors.

Conclusion and Research Perspective: Future research on MLSs has to take up the issue of the time passage between the MLS and the impact on health and well-being of individuals dependent on care. It has to determine immediate as well as later consequences and identify those factors that are appropriate to reduce the MLS-effects on very old people dependent on care.
C3AR1 mRNA as a Potential Therapeutic Target Associates With Clinical Outcomes and Tumor Microenvironment in Osteosarcoma
Authors: Zou Tiannan , Liu Weibing , Wang Zeyu , Chen Jiayu , Lu Sheng , Huang Kun , Li Weichao
Published: March 2021

Objective: Targeting cancer-specific messenger RNAs (mRNAs) may offer novel insights into therapeutic strategies in osteosarcoma. This study aimed to discover possible osteosarcoma-specific mRNA and probe its biological functions.

Methods: Based on mRNA-seq data from the TARGET database, stromal and immune scores were estimated for each osteosarcoma sample via the ESTIMATE algorithm. Stromal and immune mRNAs were obtained via integration of differentially expressed mRNAs between high and low stromal / immune score groups. Among hub and prognostic mRNAs, C3AR1 mRNA was focused and its prognostic value was assessed. The associations between C3AR1 mRNA and immune cells were analyzed via the CIBERSORT algorithm. Its expression was verified in osteosarcoma tissues and cells by RT-qPCR and western blot. The functions of C3AR1 were investigated by a series of experiments.

Results: Low stromal and immune scores were both indicative of unfavorable outcomes for osteosarcoma patients. Eighty-eight up-regulated and seven down-regulated stromal and immune mRNAs were identified. Among 30 hub mRNAs, low expression of C3AR1 mRNA indicated worse outcomes than its high expression. There was a lower mRNA expression of C3AR1 in metastatic than non-metastatic osteosarcoma. C3AR1 mRNA was closely correlated to various immune cells such as macrophages. C3AR1 was verified to be down-regulated in osteosarcoma tissues and cells. Its overexpression suppressed proliferation, migration and invasion and induced apoptosis in osteosarcoma cells.

Conclusion: C3AR1 mRNA could be a promising therapeutic target for osteosarcoma, linked with prognosis and tumor microenvironment.
Comprehensive Analysis Identifies Potential Ferroptosis-Associated mRNA Therapeutic Targets in Ovarian Cancer
Authors: Zhang Jiyan , Xi Jie , Huang Ping , Zeng Saitian
Published: March 2021

Objective: This study aimed to explore ferroptosis-related mRNAs as potential therapeutic targets for ovarian cancer treatment.

Methods: Molecular subtypes were classified based on ferroptosis-related mRNAs via ConsensusClusterPlus package. The differences in prognosis, stromal score, immune score, immune function, and immune checkpoints were assessed between subtypes. Small molecular drugs were predicted via the CMap database. The sensitivity to chemotherapy drugs was estimated through the GDSC. A LASSO Cox regression model was conducted via the glmnet package, followed by a nomogram model.

Results: Based on ferroptosis mRNA expression profile, two molecular subtypes (C1 and C2) were classified, with distinct clinical outcomes. C1 subtype exhibited higher stromal score, immune cell score (T helper, Treg, neutrophil) and immune function (APC co-inhibition, parainflammation and Type II IFN response). Higher mRNA expression levels of immune checkpoints (like PDCD1) were found in C1 than C2. Potential small molecular drugs (PI3K and mTOR inhibitors) were found for treatment of ovarian cancer. C1 was more sensitive to eight chemotherapy drugs (A.443654, AZD.0530, AZD6482, AZD7762, AZD8055, BAY.61.3606, Bicalutamide, and CGP.60474). A 15-ferroptosis-related mRNA signature was developed, which could robustly and independently predict the outcomes. Moreover, a nomogram was established combining the signature and age, which could intuitively and accurately predict the 5-year overall survival probability.

Conclusion: Our study characterized two ferroptosis-related subtypes with distinct prognosis and tumor immune features, which could assist clinicians make decisions and individual therapy. Moreover, 15 ferroptosis-related mRNAs were identified, which could become potential therapeutic targets for ovarian cancer.
Dysbiosis From a Microbial and Host Perspective Relative to Oral Health and Disease
Authors: Cugini Carla , Ramasubbu Narayanan , Tsiagbe Vincent K. , Fine Daniel H.
Published: March 2021

The significance of microbiology and immunology with regard to caries and periodontal disease gained substantial clinical or research consideration in the mid 1960's. This enhanced emphasis related to several simple but elegant experiments illustrating the relevance of bacteria to oral infections. Since that point, the understanding of oral diseases has become increasingly sophisticated and many of the original hypotheses related to disease causality have either been abandoned or amplified. The COVID pandemic has reminded us of the importance of history relative to infectious diseases and in the words of Churchill “those who fail to learn from history are condemned to repeat it.” This review is designed to present an overview of broad general directions of research over the last 60 years in oral microbiology and immunology, reviewing significant contributions, indicating emerging foci of interest, and proposing future directions based on technical advances and new understandings. Our goal is to review this rich history (standard microbiology and immunology) and point to potential directions in the future (omics) that can lead to a better understanding of disease. Over the years, research scientists have moved from a position of downplaying the role of bacteria in oral disease to one implicating bacteria as true pathogens that cause disease. More recently it has been proposed that bacteria form the ecological first line of defense against “foreign” invaders and also serve to train the immune system as an acquired host defensive stimulus. While early immunological research was focused on immunological exposure as a modulator of disease, the “hygiene hypothesis,” and now the “old friends hypothesis” suggest that the immune response could be trained by bacteria for long-term health. Advanced “omics” technologies are currently being used to address changes that occur in the host and the microbiome in oral disease. The “omics” methodologies have shaped the detection of quantifiable biomarkers to define human physiology and pathologies. In summary, this review will emphasize the role that commensals and pathobionts play in their interaction with the immune status of the host, with a prediction that current “omic” technologies will allow researchers to better understand disease in the future.
Comparative Analysis of Outer Membrane Vesicle Isolation Methods With an Escherichia coli tolA Mutant Reveals a Hypervesiculating Phenotype With Outer-Inner Membrane Vesicle Content
Authors: Reimer Shelby L. , Beniac Daniel R. , Hiebert Shannon L. , Booth Timothy F. , Chong Patrick M. , Westmacott Garrett R. , Zhanel George G. , Bay Denice C.
Published: March 2021

Outer membrane vesicles (OMVs) produced by Gram-negative bacteria are mediators of cell survival and pathogenesis by facilitating virulence factor dissemination and resistance to antimicrobials. Studies of OMV properties often focus on hypervesiculatingEscherichia colimutants that have increased OMV production when compared to their corresponding wild-type (WT) strains. Currently, two conventional techniques, ultracentrifugation (UC) and ultradiafiltration (UF), are used interchangeably to isolate OMVs, however, there is concern that each technique may inadvertently alter the properties of isolated OMVs during study. To address this concern, we compared two OMV isolation methods, UC and UF, with respect to final OMV quantities, size distributions, and morphologies using a hypervesiculatingEscherichia coliK-12 ΔtolAmutant. Nanoparticle tracking analysis (NTA) indicated that UC techniques result in lower vesicle yields compared to UF. However, UF permitted isolation of OMVs with smaller average sizes than UC, highlighting a potential OMV isolation size bias by each technique. Cryo-transmission electron microscopy (cryo-TEM) visualization of isolated OMVs revealed distinct morphological differences between WT and ΔtolAOMVs, where ΔtolAOMVs isolated by either UC or UF method possessed a greater proportion of OMVs with two or more membranes. Proteomic OMV analysis of WT and ΔtolAOMVs confirmed that ΔtolAenhances inner plasma membrane carryover in multi-lamellar OMVs. This study demonstrates that UC and UF are useful techniques for OMV isolation, where UF may be preferable due to faster isolation, higher OMV yields and enrichment of smaller sized vesicles.
Case Report: Deep Cerebellar Stimulation for Tremor and Dystonia
Authors: Horisawa Shiro , Kohara Kotaro , Nonaka Taku , Mochizuki Tatsuki , Kawamata Takakazu , Taira Takaomi
Published: March 2021

Background: The cerebellum plays an important role in the pathogenesis and pathophysiology of movement disorders, including tremor and dystonia. To date, there have been few reports on deep cerebellar stimulation.

Case Report: The patient was a 35-year-old previously healthy man with no history of movement disorders. He developed a tremor and stiffness in his left hand at the age of 27 years, which was diagnosed as a dystonic tremor. We performed right thalamotomy, which resulted in a complete resolution of the tremor; however, the dystonia persisted. Subsequently, the patient developed left foot dystonia with inversion and a newly developed tremor in the right hand and foot. The patient underwent left ventralis intermedius (VIM) deep brain stimulation (VIM-DBS) and left pallidothalamic tract DBS (PTT-DBS). Left VIM-DBS completely resolved the right hand and foot tremor, and PTT-DBS significantly improved the left hand and foot dystonia. Three months postoperatively, the patient developed an infection and wound disruption at the surgical site. We performed palliative surgery for deep cerebellar stimulation via the posterior cranial region, which was not infected. The surgery was performed under general anesthesia with the patient lying in the prone position. Eight contact DBS electrodes were used. The placement of electrodes extended from the superior cerebellar peduncle to the dentate nucleus. Both the right hand and foot tremor improved with right cerebellar stimulation. Further, both the left hand and foot dystonia improved with left cerebellar stimulation. Right and left cerebellar stimulation led to no improvement in the left hand and foot dystonia and right hand and foot tremor, respectively. Stimulation-induced complications observed in the patient included dizziness, dysphagia, and dysarthria. After the surgery, the patient developed hypersalivation and hyperhidrosis in the left side of the body, both of which did not improve with adjustments of stimulation parameters. At the 6-month follow-up, the tremor and dystonia had almost completely resolved.

Conclusion: Deep cerebellar stimulation deserves consideration as a potential treatment for tremor and dystonia.
Spontaneous Alpha and Theta Oscillations Are Related to Complementary Aspects of Cognitive Control in Younger and Older Adults
Authors: Clements Grace M. , Bowie Daniel C. , Gyurkovics Mate , Low Kathy A. , Fabiani Monica , Gratton Gabriele
Published: March 2021

The resting-state human electroencephalogram (EEG) power spectrum is dominated by alpha (8–12 Hz) and theta (4–8 Hz) oscillations, and also includes non-oscillatory broadband activity inversely related to frequency (1/f activity). Gratton proposed that alpha and theta oscillations are both related to cognitive control function, though in a complementary manner. Alpha activity is hypothesized to facilitate the maintenance of representations, such as task sets in preparation for expected task conditions. In contrast, theta activity would facilitate changes in representations, such as the updating of task sets in response to unpredicted task demands. Therefore, theta should be related to reactive control (which may prompt changes in task representations), while alpha may be more relevant to proactive control (which implies the maintenance of current task representations). Less is known about the possible relationship between 1/f activity and cognitive control, which was analyzed here in an exploratory fashion. To investigate these hypothesized relationships, we recorded eyes-open and eyes-closed resting-state EEG from younger and older adults and subsequently tested their performance on a cued flanker task, expected to elicit both proactive and reactive control processes. Results showed that alpha power and 1/f offset were smaller in older than younger adults, whereas theta power did not show age-related reductions. Resting alpha power and 1/f offset were associated with proactive control processes, whereas theta power was related to reactive control as measured by the cued flanker task. All associations were present over and above the effect of age, suggesting that these resting-state EEG correlates could be indicative of trait-like individual differences in cognitive control performance, which may be already evident in younger adults, and are still similarly present in healthy older adults.
Case Report: Management of a Patient With Chylomicronemia Syndrome During Pregnancy With Medical Nutrition Therapy
Authors: Zahedi Maryam , Asghari Golaleh , Mirmiran Parvin , Hosseinpanah Farhad
Published: March 2021

Background: Hypertriglyceridemia (HTG) during pregnancy may be accompanied by acute pancreatitis, hyperviscosity syndrome, and preeclampsia. HTG during pregnancy should be managed by a multidisciplinary team; however, no clinical guidelines exist for severe gestational HTG.

Case Presentation: We herein present a case of a 36-year-old in the first pregnancy (G1P0Ab0), with a history of severe HTG-induced necrotizing pancreatitis 9 years earlier. There was no family history of HTG. During these years, she did not follow any appropriate diet or medical therapy for HTG. She became pregnant in May 2019, without preconception counseling. Eruptive and tuberoeruptive xanthomas appeared in the 27th week of pregnancy. Serum triglycerides (TGs) and fasting blood sugar (FBS) were 6,620 and 124 mg/dL, respectively, indicating HTG and gestational diabetes (GDM). After admission for the management of severe HTG, she was put on parenteral nutrition with dextrose water 5% and infusion insulin therapy without receiving any enteral carbohydrate for 2 days. Following that, a very low-fat diet and omega-3 fatty acids (1,200 mg/day) were started. After 4 weeks, TG levels reached 1,000 mg/dL, and her self-monitoring blood glucose levels showed appropriate blood glucose for pregnancy. She underwent a successful elective cesarean section in the 39th of pregnancy.

Conclusion: This case report demonstrates that HTG during pregnancy could be managed by medical nutrition therapy (MNT).
Characterization of Tumor Microenvironment in Lung Adenocarcinoma Identifies Immune Signatures to Predict Clinical Outcomes and Therapeutic Responses
Authors: Chen Donglai , Wang Yifei , Zhang Xi , Ding Qifeng , Wang Xiaofan , Xue Yuhang , Wang Wei , Mao Yiming , Chen Chang , Chen Yongbing
Published: March 2021

Background and Objective

Increasing evidence has elucidated the clinicopathological significance of individual TME component in predicting outcomes and immunotherapeutic efficacy in lung adenocarcinoma (LUAD). Therefore, we aimed to investigate whether comprehensive TME-based signatures could predict patient survival and therapeutic responses in LUAD, and to assess the associations among TME signatures, single nucleotide variations and clinicopathological characteristics.

Methods

In this study, we comprehensively estimated the TME infiltration patterns of 493 LUAD patients and systematically correlated the TME phenotypes with genomic characteristics and clinicopathological features of LUADs using two proposed computational algorithms. A TMEscore was then developed based on the TME signature genes, and its prognostic value was validated in different datasets. Bioinformatics analysis was used to evaluate the efficacy of the TMEscore in predicting responses to immunotherapy and chemotherapy.

Results

Three TME subtypes were identified with no prognostic significance exhibited. Among them, naïve B cells accounted for the majority in TMEcluster1, while M2 TAMs and M0 TAMs took the largest proportion in TMEcluster2 and TMEcluster3, respectively. A total of 3395 DEGs among the three TME clusters were determined, among which 217 TME signature genes were identified. Interestingly, these signature genes were mainly involved in T cell activation, lymphocyte proliferation and mononuclear cell proliferation. With somatic variations and tumor mutation burden (TMB) of the LUAD samples characterized, a genomic landscape of the LUADs was thereby established to visualize the relationships among the TMEscore, mutation spectra and clinicopathological profiles. In addition, the TMEscore was identified as not only a prognosticator for long-term survival in different datasets, but also a predictive biomarker for the responses to immune checkpoint blockade (ICB) and chemotherapeutic agents. Furthermore, the TMEscore exhibited greater accuracy than other conventional biomarkers including TMB and microsatellite instability in predicting immunotherapeutic response (p < 0.001).

Conclusion

In conclusion, our present study depicted a comprehensive landscape of the TME signatures in LUADs. Meanwhile, the TMEscore was proved to be a promising predictor of patient survival and therapeutic responses in LUADs, which might be helpful to the future administration of personalized adjuvant therapy.
Image Guidance in Ablation for Hepatocellular Carcinoma: Contrast-Enhanced Ultrasound and Fusion Imaging
Authors: Minami Yasunori , Kudo Masatoshi
Published: March 2021

The ultrasound (US) imaging technology, including contrast-enhanced US (CEUS) and fusion imaging, has experienced radical improvement, and advancement in technology thus overcoming the problem of poor conspicuous hepatocellular carcinoma (HCC). On CEUS, the presence or absence of enhancement distinguishes the viable portion from the ablative necrotic portion. Using volume data of computed tomography (CT) or magnetic resonance imaging (MRI), fusion imaging enhances the three-dimensional relationship between the liver vasculature and HCC. Therefore, CT/MR-US fusion imaging provides synchronous images of CT/MRI with real-time US, and US-US fusion imaging provides synchronous US images before and after ablation. Moreover, US-US overlay fusion can visualize the ablative margin because it focuses the tumor image onto the ablation zone. Consequently, CEUS and fusion imaging are helpful to identify HCC with little conspicuity, and with more confidence, we can perform ablation therapy. CEUS/fusion imaging guidance has improved the clinical effectiveness of ablation therapy in patients with poor conspicuous HCCs. Therefore; this manuscript reviews the status of CEUS/fusion imaging guidance in ablation therapy of poor conspicuous HCC.
Genomic Mutation Profile of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma
Authors: Li Peifeng , Chai Jia , Chen Zi , Liu Yang , Wei Jie , Liu Yixiong , Zhao Danhui , Ma Jing , Wang Kaijing , Li Xia , Shao Yang , Gong Li , Zhang Wei , Guo Shuangping , Yan Qingguo , Li Mingyang , Fan Linni , Wang Zhe
Published: March 2021

Primary gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common gastrointestinal lymphoma, but its genetic features are poorly understood. We performed whole-exome sequencing of 25 primary tumor samples from patients with GI-DLBCL and 23 matched normal tissue samples. Oncogenic mutations were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Twenty-five patients with GI-DLBCL were enrolled in the genetic mutation analysis with a median of 184 (range 79–382) protein-altering variants per patient. We identified recurrent oncogenic mutations in GI-DLBCL, including those in TP53, MUC16, B2M, CCND3, HIST1H1C, NEB, and ID3. Compared with nodal DLBCL, GI-DLBCL exhibited an increased mutation frequency of TP53 and reduced mutation frequencies of PIM1, CREBBP, BCL2, KMT2D, and EZH2. Moreover, GI-DLBCL exhibited fewer MYD88 and CD79B mutations than DLBCL in the testis and central nervous system. GI-DLBCLs with HLA-B, MEF2A, RHOA, and NAV3 mutations exhibited a tendency toward a high proliferation index. MUC16 and ETV6 mutations often occurred in tumors with early clinical staging. Our data provide a comprehensive understanding of the landscape of mutations in a small subset of GI-DLBCLs. The genetic mutation profiles of GI-DLBCL differ from those of nodal DLBCL and DLBCL in immune-privileged sites. The different mutated genes are related to the NF-κB and JAK-STAT pathways, and the different pathogenetic mechanisms leading to the development of DLBCL may be influenced by the tissue microenvironment. Differences in genetic alterations might influence the clinicopathological characteristics of GI-DLBCL.
Daratumumab as Single Agent in Relapsed/Refractory Myeloma Patients: A Retrospective Real-Life Survey
Authors: Markovic Uros , Romano Alessandra , Del Fabro Vittorio , Bellofiore Claudia , Bulla Anna , Parisi Marina Silvia , Leotta Salvatore , Gentile Massimo , Cangialosi Clotilde , Vincelli Iolanda , Mineo Giuseppe , Rossi Marco , Poidomani Massimo , Uccello Giuseppina , Maugeri Cinzia , Mannina Donato , Innao Vanessa , Di Raimondo Francesco , Conticello Concetta
Published: March 2021

Background

The anti-CD38 monoclonal antibody daratumumab is approved as a single agent for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who received at least three prior lines of therapy, including proteasome inhibitor and immunomodulatory agent. A retrospective multicentric study was designed to evaluate feasibility, tolerability, and efficacy of daratumumab in monotherapy in RRMM.

Methods

This study included 44 consecutive RRMM patients that underwent daratumumab monotherapy after a median number of four prior therapies (range 2–9). Patients were treated in seven Sicilian centers, as part of Sicilian Myeloma Network and three Calabrian centers outside of controlled clinical trials from August 2016 through July 2020.

Results

The regimen was well tolerated with few grade 3–4 haematological and rare non-haematological adverse events, such as pneumonia. Definitive discontinuation was due to disease progression in 25 (57%) patients. Since three patients did not complete at least one full cycle, a total of 41 patients was evaluated for response. Overall response rate was 37%, and the disease control rate (stable disease or better) was high (73%). The best achieved responses within 6 months were very good partial remission or better (27%), partial remission (10%), minimal response (14%) and stable disease (22%). After a median follow up of 7.8 months, median progression free survival (PFS) was 7.2 months and overall survival (OS) 7.8 months. Univariate analysis showed that patients with PR or better after 6 months of therapy had longer median PFS and OS (respectively 29.5 vs 3.6 months, p=0.0001 and 30.6 vs 3.9 months p=0.0001), confirmed by multivariate analysis. Furthermore, standard cytogenetic risk and biochemical relapse type had prolonged median PFS, but not OS (respectively unreached vs 2.6, p=0.03 and 23.9 vs 6.2, p=0.05) in both univariate and multivariate analysis. Additionally, univariate analysis showed that patients treated with carfilzomib-lenalidomide-dexamethasone prior to daratumumab had significantly shorter PFS compared to pomalidomide-dexamethasone (3.4 months vs 9.3 months, p=0.03), that multivariate analysis failed to confirm.

Conclusions

Our findings indicate that daratumumab as single agent is safe and well-tolerated regimen in real-life, associated to prolonged PFS and OS in responding patients. No new safety signals were identified.
West Syndrome Is an Exceptional Presentation of Pyridoxine- and Pyridoxal Phosphate-Dependent Epilepsy: Data From a French Cohort and Review of the Literature
Authors: Gibaud Marc , Barth Magalie , Lefranc Jérémie , Mention Karine , Villeneuve Nathalie , Schiff Manuel , Maurey Hélène , Barthez Marie-Anne , Caubel Isabelle , Chouchane Mondher , Doummar Diane , Kossorotoff Manoëlle , Lamblin Marie-Dominique , Roubertie Agathe , Nabbout Rima , Van Bogaert Patrick
Published: March 2021

Objective: To characterize the electro-clinical presentation of patients with pyridoxine-dependent epilepsy (PDE) and pyridoxal phosphate (PLP)-dependent epilepsy in order to determine whether some of them could be diagnosed as de novo West syndrome, i. e., West syndrome that starts after the age of 2 months without other types of seizures (focal seizures for instance) before the onset of epileptic spasms.

Methods: We analyzed data from an unpublished cohort of 28 genetically confirmed cases of PDE with antiquitine (ATQ) deficiency and performed a review of the literature looking for description of West syndrome in patients with either PDE with ATQ deficiency or PLP-dependent epilepsy with Pyridox(am)ine phosphate oxidase (PNPO) deficiency.

Results: Of the 28 cases from the ATQ deficiency French cohort, 5 had spasms. In four cases, spasms were associated with other types of seizures (myoclonus, focal seizures). In the last case, seizures started on the day of birth. None of these cases corresponded to de novo West syndrome. The review of the literature found only one case of PNPO deficiency presenting as de novo West syndrome and no case of ATQ deficiency.

Significance: The presentation of PDE- and PLP-dependent epilepsy as de novo West syndrome is so exceptional that it probably does not justify a systematic trial of pyridoxine or PLP. We propose considering a therapeutic trial with these vitamins in West syndrome if spasms are associated with other seizure types or start before the age of 2 months.
The Effectiveness and Safety of Commonly Used Injectates for Ultrasound-Guided Hydrodissection Treatment of Peripheral Nerve Entrapment Syndromes: A Systematic Review
Authors: Buntragulpoontawee Montana , Chang Ke-Vin , Vitoonpong Timporn , Pornjaksawan Sineenard , Kitisak Kittipong , Saokaew Surasak , Kanchanasurakit Sukrit
Published: March 2021

Background: Peripheral nerve entrapment syndromes commonly result in pain, discomfort, and ensuing sensory and motor impairment. Many conservative measures have been proposed as treatment, local injection being one of those measures. Now with high-resolution ultrasound, anatomical details can be visualized allowing diagnosis and more accurate injection treatment. Ultrasound-guided injection technique using a range of injectates to mechanically release and decompress the entrapped nerves has therefore developed called hydrodissection or perineural injection therapy. Several different injectates from normal saline, local anesthetics, corticosteroids, 5% dextrose in water (D5W), and platelet-rich plasma (PRP) are available and present clinical challenges when selecting agents regarding effectiveness and safety.

Aims: To systematically search and summarize the clinical evidence and mechanism of different commonly used injectates for ultrasound-guided hydrodissection entrapment neuropathy treatment.

Methods: Four databases, including PubMed, EMBASE, Scopus, and Cochrane were systematically searched from the inception of the database up to August 22, 2020. Studies evaluating the effectiveness and safety of different commonly used injectates for ultrasound-guided hydrodissection entrapment neuropathy treatment were included. Injectate efficacy presents clinical effects on pain intensity, clinical symptoms/function, and physical performance, electrodiagnostic findings, and nerve cross-sectional areas. Safety outcomes and mechanism of action of each injectate were also described.

Results: From ten ultrasound-guided hydrodissection studies, nine studies were conducted in carpal tunnel syndrome and one study was performed in ulnar neuropathy at the elbow. All studies compared different interventions with different comparisons. Injectates included normal saline, D5W, corticosteroids, local anesthetics, hyaluronidase, and PRP. Five studies investigated PRP or PRP plus splinting comparisons. Both D5W and PRP showed a consistently favorable outcome than those in the control group or corticosteroids. The improved outcomes were also observed in comparison groups using injections with normal saline, local anesthetics, or corticosteroids, or splinting. No serious adverse events were reported. Local steroid injection side effects were reported in only one study.

Conclusion: Ultrasound-guided hydrodissection is a safe and effective treatment for peripheral nerve entrapment. Injectate selection should be considered based on the injectate mechanism, effectiveness, and safety profile.
Intra-Arterial, but Not Intrathecal, Baclofen and Codeine Attenuates Cough in the Cat
Authors: Olsen Wendy L. , Rose Melanie , Golder Frank J. , Wang Cheng , Hammond Julie C. , Bolser Donald C.
Published: March 2021

Centrally-acting antitussive drugs are thought to act solely in the brainstem. However, the role of the spinal cord in the mechanism of action of these drugs is unknown. The purpose of this study was to determine if antitussive drugs act in the spinal cord to reduce the magnitude of tracheobronchial (TB) cough-related expiratory activity. Experiments were conducted in anesthetized, spontaneously breathing cats (n = 22). Electromyograms (EMG) were recorded from the parasternal (PS) and transversus abdominis (TA) or rectus abdominis muscles. Mechanical stimulation of the trachea or larynx was used to elicit TB cough. Baclofen (10 and 100 μg/kg, GABA-B receptor agonist) or codeine (30 μg/kg, opioid receptor agonist) was administered into the intrathecal (i.t.) space and also into brainstem circulation via the vertebral artery. Cumulative doses of i.t. baclofen or codeine had no effect on PS, abdominal muscle EMGs or cough number during the TB cough. Subsequent intra-arterial (i.a.) administration of baclofen or codeine significantly reduced magnitude of abdominal and PS muscles during TB cough. Furthermore, TB cough number was significantly suppressed by i.a. baclofen. The influence of these drugs on other behaviors that activate abdominal motor pathways was also assessed. The abdominal EMG response to noxious pinch of the tail was suppressed by i.t. baclofen, suggesting that the doses of baclofen that were employed were sufficient to affect spinal pathways. However, the abdominal EMG response to expiratory threshold loading was unaffected by i.t. administration of either baclofen or codeine. These results indicate that neither baclofen nor codeine suppress cough via a spinal action and support the concept that the antitussive effect of these drugs is restricted to the brainstem.
A Modified Version of the Transactional Stress Concept According to Lazarus and Folkman Was Confirmed in a Psychosomatic Inpatient Sample
Authors: Obbarius Nina , Fischer Felix , Liegl Gregor , Obbarius Alexander , Rose Matthias
Published: March 2021

Background

Stress is a major risk factor for the impairment of psychological well-being. The present study aimed to evaluate the empirical evidence of the Transactional Stress Model proposed by Lazarus and Folkman in patients with psychosomatic health conditions.

Methods

A structural equation model was applied in two separate subsamples of inpatients from the Department of Psychosomatic Medicine (totaln= 2,216) for consecutive model building (sample 1,n= 1,129) and confirmatory analyses (sample 2,n= 1,087) using self-reported health status information about perceived stress, personal resources, coping mechanisms, stress response, and psychological well-being.

Results

The initial model was created to reflect the theoretical assumptions by Lazarus and Folkman about their transactional stress concept. This model was modified until a sufficient model fit was reached (sample 1: CFI = 0.904, TLI = 0.898, RMSEA = 0.072 [0.071–0.074], SRMR = 0.061). The modified model was confirmed in a second sample (sample 2: CFI = 0.932, TLI = 0.928, RMSEA = 0.066 [0.065–0.068], SRMR = 0.052). Perceived external stressors and personal resources explained 91% of the variance of the stress response, which was closely related to symptoms of depression (63% variance explained). The attenuating effect of resources on stress response was higher (standardized β = -0.73,p< 0.001) than the impact of perceived stressors on stress response (standardized β = 0.34,p< 0.001).

Conclusion

The empirical data largely confirmed the theoretical assumption of the Transactional Stress Model, which was first presented by Lazarus and Folkman, in patients with a wide range of psychosomatic conditions. However, data analyses were solely based on self-reported health status. Thus, proposed inner psychological mechanisms such as the appraisal process could not be included in this empirical validation. The operationalization and understanding of coping processes should be further improved.
Ecological Thresholds of Toxicological Concern: A Review
Authors: Barron Mace G. , Otter Ryan R. , Connors Kristin A. , Kienzler Aude , Embry Michelle R.
Published: March 2021

The ecological threshold of toxicological concern (ecoTTC) is analogous to traditional human health-based TTCs but with derivation and application to ecological species. An ecoTTC is computed from the probability distribution of predicted no effect concentrations (PNECs) derived from either chronic or extrapolated acute toxicity data for toxicologically or chemically similar groups of chemicals. There has been increasing interest in using ecoTTCs in screening level environmental risk assessments and a computational platform has been developed for derivation with aquatic species toxicity data (https://envirotoxdatabase.org/). Current research and development areas include assessing mode of action-based chemical groupings, conservatism in estimated PNECs and ecoTTCs compared to existing regulatory values, and the influence of taxa (e.g., algae, invertebrates, and fish) composition in the distribution of PNEC values. The ecoTTC continues to develop as a valuable alternative strategy within the toolbox of traditional and new approach methods for ecological chemical assessment. This brief review article describes the ecoTTC concept and potential applications in ecological risk assessment, provides an overview of the ecoTTC workflow and how the values can be derived, and highlights recent developments and ongoing research. Future applications of ecoTTC concept in different disciplines are discussed along with opportunities for its use.