bluuebunny/crossref_metadata_2025 huggingface dataset:
Ocular Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors in Lung Cancer
Authors: Zhou Lin , Wei Xin
Published: August 2021

Immune checkpoint inhibitors (ICIs) are novel immunotherapy-based drugs that have become increasingly popular in the treatment of lung cancer. Researchers have recognized ocular immune-related adverse events (irAEs) secondary to ICIs because of their vision-threatening characteristics. However, they are incompletely characterized and no studies have reported the ICI-related ocular irAEs in lung cancer. Therefore, we aimed to comprehensively illustrate the clinical characteristics, contributory factors, diagnosis, and management of ICI-related ocular irAEs in lung cancer, based on previously reported 79 patients. Ophthalmoplegia (40.51%), uveitis (20.25%), and dry eye (17.72%) were the most common ICI-related ocular irAEs in lung cancer. Ptosis was the most common (36.71%) and the highest mortality (23.33%) of ophthalmoplegia. Patients in Asia and patients who underwent combination therapy with programmed cell death-1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors demonstrated significantly higher frequency of ophthalmoplegia than other ocular irAEs. Most ICI-related ophthalmoplegia and uveitis in lung cancer were observed in the first 10 weeks following the initiation of ICIs. Furthermore, the onset time of dry eye and other ocular irAEs was much longer. In addition, 92.31% of the patients with ocular irAEs other than ophthalmoplegia could be remised. In conclusion, ocular irAEs secondary to ICIs in lung cancer are non-negligible, particularly ophthalmoplegia. Ethnicity and the type of ICIs play important roles in the distribution of ocular irAEs. ICI-related ophthalmoplegia in lung cancer presented with early onset and worse prognosis features, thus necessitating further attention.
CD38 Deficiency Ameliorates Chronic Graft-Versus-Host Disease Murine Lupus via a B-Cell-Dependent Mechanism
Authors: Martínez-Blanco África , Domínguez-Pantoja Marilú , Botía-Sánchez María , Pérez-Cabrera Sonia , Bello-Iglesias Nerea , Carrillo-Rodríguez Paula , Martin-Morales Natividad , Lario-Simón Antonio , Pérez-Sánchez-Cañete María M. , Montosa-Hidalgo Laura , Guerrero-Fernández Salvador , Longobardo-Polanco Victoria M. , Redondo-Sánchez Sandra , Cornet-Gomez Alberto , Torres-Sáez María , Fernández-Ibáñez Ana , Terrón-Camero Laura , Andrés-León Eduardo , O’Valle Francisco , Merino Ramón , Zubiaur Mercedes , Sancho Jaime
Published: August 2021

The absence of the mouse cell surface receptor CD38 inCd38−/−mice suggests that this receptor acts as a positive regulator of inflammatory and autoimmune responses. Here, we report that, in the context of the chronic graft-versus-host disease (cGVHD) lupus inducible model, the transfer of B6.C-H2bm12/KhEg(bm12) spleen cells into co-isogenicCd38−/−B6 mice causes milder lupus-like autoimmunity with lower levels of anti-ssDNA autoantibodies than the transfer of bm12 spleen cells into WT B6 mice. In addition, significantly lower percentages of Tfh cells, as well as GC B cells, plasma cells, and T-bet+CD11chiB cells, were observed inCd38−/−mice than in WT mice, while the expansion of Treg cells and Tfr cells was normal, suggesting that the ability ofCd38−/−B cells to respond to allogeneic help from bm12 CD4+T cells is greatly diminished. The frequencies of T-bet+CD11chiB cells, which are considered the precursors of the autoantibody-secreting cells, correlate with anti-ssDNA autoantibody serum levels, IL-27, and sCD40L. Proteomics profiling of the spleens from WT cGVHD mice reflects a STAT1-driven type I IFN signature, which is absent inCd38−/−cGVHD mice. Kidney, spleen, and liver inflammation was mild and resolved faster inCd38−/−cGVHD mice than in WT cGVHD mice. We conclude that CD38 in B cells functions as a modulator receptor that controls autoimmune responses.
A Novel Bifunctional Fusion Protein, Vunakizumab-IL22, for Protection Against Pulmonary Immune Injury Caused by Influenza Virus
Authors: Han Lei , Shi Chenchen , Zeng Xian , Cen Lifeng , Mei Xiaobin , Fan Jiajun , Ju Dianwen , Zhu Haiyan
Published: August 2021

Influenza A virus infection is usually associated with acute lung injury, which is typically characterized by tracheal mucosal barrier damage and an interleukin 17A (IL-17A)-mediated inflammatory response in lung tissues. Although targeting IL-17A has been proven to be beneficial for attenuating inflammation around lung cells, it still has a limited effect on pulmonary tissue recovery after influenza A virus infection. In this research, interleukin 22 (IL-22), a cytokine involved in the repair of the pulmonary mucosal barrier, was fused to the C-terminus of the anti-IL-17A antibody vunakizumab to endow the antibody with a tissue recovery function. The vunakizumab-IL22 (vmab-IL-22) fusion protein exhibits favorable stability and retains the biological activities of both the anti-IL-17A antibody and IL-22 in vitro. Mice infected with lethal H1N1 influenza A virus and treated with vmab-mIL22 showed attenuation of lung index scores and edema when compared to those of mice treated with saline or vmab or mIL22 alone. Our results also illustrate that vmab-mIL22 triggers the upregulation of MUC2 and ZO1, as well as the modulation of cytokines such as IL-1β, HMGB1 and IL-10, indicating the recovery of pulmonary goblet cells and the suppression of excessive inflammation in mice after influenza A virus infection. Moreover, transcriptome profiling analysis suggest the downregulation of fibrosis-related genes and signaling pathways, including genes related to focal adhesion, the inflammatory response pathway, the TGF-β signaling pathway and lung fibrosis upon vmab-mIL22 treatment, which indicates that the probable mechanism of vmab-mIL22 in ameliorating H1N1 influenza A-induced lung injury. Our results reveal that the bifunctional fusion protein vmab-mIL22 can trigger potent therapeutic effects in H1N1-infected mice by enhancing lung tissue recovery and inhibiting pulmonary inflammation, which highlights a potential approach for treating influenza A virus infection by targeting IL-17A and IL-22 simultaneously.
Potential for Mesopelagic Fishery Compared to Economy and Fisheries Dynamics in Current Large Scale Danish Pelagic Fishery
Authors: Paoletti Silvia , Nielsen J. Rasmus , Sparrevohn Claus R. , Bastardie Francois , Vastenhoud Berthe M. J.
Published: August 2021

Mesopelagic fish species represent a large potentially unexploited resource for the fishing industry and the fish meal, oil, nutraceutical, and pharmaceutical production. However, thorough investigation on ecological sustainability and socio-economic viability are fundamental prerequisites for potential exploitation. The current study explores the economic viability of a potential mesopelagic fishery investigating minimum catch rates, under the assumption of previous assessments of biological sustainability of such exploitation. We analyzed fishery data from the North-East Atlantic fisheries of the Danish large pelagic fleet from 2015 to 2019, by comparing the combined data on fishing dynamics and cost-structures with data from interviews of key pelagic producer organization representatives to develop scenarios of profitability. The results show full year-round fleet occupation with the ongoing fisheries, exposing the need of switching from existing activities, or investing into new vessels for conducting potential mesopelagic fishery. Economic analyses revealed that the minimum revenue to break even (zero profit) by trip varies among métiers between 60,000 and 200,000 euro showing strong positive correlation with vessel sizes. High profitability was discovered for herring, Atlantic mackerel and blue whiting fisheries while low profitability was observed for the Norway pout fishery. Due to the lack of mesopelagic fishery data, different scenarios of profitability were investigated as informed by the pelagic catch sector stakeholder perceptions of prices and costs and compared to current economic dynamics. A high break-even revenue per trip was forecasted given the increased perceived costs for fuel, modifications of gears and on-board processing methods and potential new vessel investments. High profitability may be reached if the catches exceed 220–1,060 tons per trip depending on costs and vessel storage capacity. If the conservation methods are improved from current refrigerated sea water, fishing trips could last longer than 5 days, being the major limiting economic factor for potential mesopelagic fishery. Future investigations on realistic mesopelagic catches, trip durations and spatio-temporal distribution of fisheries in relation to location, resource abundance, fishing rights, storage and conservation methods will be essential to test the robustness of the scenarios proposed in this study, and will in turn benefit of the economic requirements evaluated herein.
COVID-19 and Tuberculosis Coinfection: An Overview of Case Reports/Case Series and Meta-Analysis
Authors: Song Wan-mei , Zhao Jing-yu , Zhang Qian-yun , Liu Si-qi , Zhu Xue-han , An Qi-qi , Xu Ting-ting , Li Shi-jin , Liu Jin-yue , Tao Ning-ning , Liu Yao , Li Yi-fan , Li Huai-chen
Published: August 2021

Background: Coronavirus disease 2019 (COVID-19) and tuberculosis (TB) are two major infectious diseases posing significant public health threats, and their coinfection (aptly abbreviated COVID-TB) makes the situation worse. This study aimed to investigate the clinical features and prognosis of COVID-TB cases.

Methods: The PubMed, Embase, Cochrane, CNKI, and Wanfang databases were searched for relevant studies published through December 18, 2020. An overview of COVID-TB case reports/case series was prepared that described their clinical characteristics and differences between survivors and deceased patients. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for death or severe COVID-19 were calculated. The quality of outcomes was assessed using GRADEpro.

Results: Thirty-six studies were included. Of 89 COVID-TB patients, 19 (23.46%) died, and 72 (80.90%) were male. The median age of non-survivors (53.95 ± 19.78 years) was greater than that of survivors (37.76 ± 15.54 years) (p < 0.001). Non-survivors were more likely to have hypertension (47.06 vs. 17.95%) or symptoms of dyspnea (72.73% vs. 30%) or bilateral lesions (73.68 vs. 47.14%), infiltrates (57.89 vs. 24.29%), tree in bud (10.53% vs. 0%), or a higher leucocyte count (12.9 [10.5–16.73] vs. 8.015 [4.8–8.97] × 109/L) than survivors (p < 0.05). In terms of treatment, 88.52% received anti-TB therapy, 50.82% received antibiotics, 22.95% received antiviral therapy, 26.23% received hydroxychloroquine, and 11.48% received corticosteroids. The pooled ORs of death or severe disease in the COVID-TB group and the non-TB group were 2.21 (95% CI: 1.80, 2.70) and 2.77 (95% CI: 1.33, 5.74) (P < 0.01), respectively.

Conclusion: In summary, there appear to be some predictors of worse prognosis among COVID-TB cases. A moderate level of evidence suggests that COVID-TB patients are more likely to suffer severe disease or death than COVID-19 patients. Finally, routine screening for TB may be recommended among suspected or confirmed cases of COVID-19 in countries with high TB burden.
Stent Retriever Thrombectomy for Anterior vs. Posterior Circulation Ischemic Stroke: Analysis of the STRATIS Registry
Authors: Jahan Reza , Liebeskind David S. , Zaidat Osama O. , Mueller-Kronast Nils H. , Froehler Michael T. , Saver Jeffrey L.
Published: August 2021

Background and Purpose: The benefits of mechanical thrombectomy (MT) in vertebrobasilar artery occlusions have not been well-studied. We compared clinical, procedural, and safety outcomes of MT for posterior circulation (PC) vs. anterior circulation (AC) occlusions among patients in the STRATIS registry.

Methods: Data from STRATIS including patient demographics, procedural characteristics, and outcomes including symptomatic intracranial hemorrhage (sICH) at 24 h, serious adverse events (SAE), substantial reperfusion [modified thrombolysis in cerebral infarction (mTICI) 2b/3], 90-day functional independence [modified Rankin Scale (mRS) 0–2], and 90-day mortality were analyzed. Univariate logistic regression was used to calculate predictors of good clinical outcome.

Results: Of 984 STRATIS patients, 43 (4.4%) patients with PC occlusions [mean age 63.0 ± 13.6, 25.6% (11/43) female] and 932 (94.7%) with AC occlusions [mean age 68.5 ± 14.8, 46.9% (437/932) female] were included for analysis. Median National Institutes of Health Stroke Scale (NIHSS) scores at baseline were 17.0 (13.0, 12.0) for the AC group and 12.0 (11.0, 24.0) for the PC group. Time from onset to procedure end was longer for the PC group [median (IQR): 322.0 min (255.0–421.0) vs. 271.0 min (207.0–360.0); p = 0.007]. PC and AC groups had similar rates of substantial reperfusion [89.2% (33/37) vs. 87.7% (684/780)], procedure-related SAE [0.0% (0/43) vs. 1.7% (16/932)], sICH [0.0% (0/38) vs. 1.5% (12/795)], 90-day functional independence [66.7% (26/39) vs. 55.9% (480/858)] and mortality [12.8% (5/39) vs. 15.8% (136/861)]. National Institutes of Health Stroke Scale score and patient sex were significant univariate predictors of good clinical outcome (p < 0.05).

Conclusions: Despite longer reperfusion times, MT in PC stroke has similar rates of 90-day functional independence with no significant difference in procedure-related SAE, sICH, or mortality, supporting the use of MT in PC acute ischemic stroke (AIS).

Clinical Trial Registration:https://www.clinicaltrials.gov, Identifier: NCT02239640.
Neural Encoding of the Reliability of Directional Information During the Preparation of Targeted Movements
Authors: Tzagarakis Charidimos , West Sarah , Pellizzer Giuseppe
Published: August 2021

Visual information about the location of an upcoming target can be used to prepare an appropriate motor response and reduce its reaction time. Here, we investigated the brain mechanisms associated with the reliability of directional information used for motor preparation. We recorded brain activity using magnetoencephalography (MEG) during a delayed reaching task in which a visual cue provided valid information about the location of the upcoming target with 50, 75, or 100% reliability. We found that reaction time increased as cue reliability decreased and that trials with invalid cues had longer reaction times than trials with valid cues. MEG channel analysis showed that during the late cue period the power of the beta-band from left mid-anterior channels, contralateral to the responding hand, correlated with the reliability of the cue. This effect was source localized over a large motor-related cortical and subcortical network. In addition, during invalid-cue trials there was a phasic increase of theta-band power following target onset from left posterior channels, localized to the left occipito-parietal cortex. Furthermore, the theta-beta cross-frequency coupling between left mid-occipital and motor cortex transiently increased before responses to invalid-cue trials. In conclusion, beta-band power in motor-related areas reflected the reliability of directional information used during motor preparation, whereas phasic theta-band activity may have signaled whether the target was at the expected location or not. These results elucidate mechanisms of interaction between attentional and motor processes.
A Microbiome-Driven Approach to Combating Depression During the COVID-19 Pandemic
Authors: Ghannoum Mahmoud A. , Ford MaryKate , Bonomo Robert A. , Gamal Ahmed , McCormick Thomas S.
Published: August 2021

The significant stressors brought about and exacerbated by COVID-19 are associated with startling surges in mental health illnesses, specifically those related to depressive disorders. Given the huge impact of depression on society, and an incomplete understanding of impactful therapeutics, we have examined the current literature surrounding the microbiome and gut-brain axis to advance a potential complementary approach to address depression and depressive disorders that have increased during the COVID-19 pandemic. While we understand that the impact of the human gut microbiome on emotional health is a newly emerging field and more research needs to be conducted, the current evidence is extremely promising and suggests at least part of the answer to understanding depression in more depth may lie within the microbiome. As a result of these findings, we propose that a microbiome-based holistic approach, which involves carefully annotating the microbiome and potential modification through diet, probiotics, and lifestyle changes, may address depression. This paper's primary purpose is to shed light on the link between the gut microbiome and depression, including the gut-brain axis and propose a holistic approach to microbiome modification, with the ultimate goal of assisting individuals to manage their battle with depression through diet, probiotics, and lifestyle changes, in addition to offering a semblance of hope during these challenging times.
Dietary Risk-Related Colorectal Cancer Burden: Estimates From 1990 to 2019
Authors: Deng Yujiao , Wei Bajin , Zhai Zhen , Zheng Yi , Yao Jia , Wang Shuqian , Xiang Dong , Hu Jingjing , Ye Xianghua , Yang Si , Wu Ying , Li Na , Xu Peng , Lyu Jun , Dai Zhijun
Published: August 2021

Background: Colorectal cancer remains a public health problem worldwide. Dietary risk factors play a key role in the carcinogenesis and progression of colorectal cancer. This study aimed to explore the geographical and temporal trends in various dietary factor-related colorectal cancers.

Methods: Data were extracted from the Global Burden of Disease (GBD) 2019 study, including the deaths, disability-adjusted life-years (DALYs), age-standardized rate (ASR), and summary exposure value (SEV) among 4 world regions, 11 age groups, 21 regions, and 204 countries and territories between 1990 and 2019. The estimated annual percentage changes (EAPCs) were calculated to evaluate the variation trend of ASR.

Results: Dietary factors were the leading cause of colorectal cancer death and DALY rate, regardless of age. Dietary factor-related deaths and DALYs accounted for 32 and 34% of global colorectal cancer, respectively. Further analysis showed that low whole grain intake remained the leading cause of cancer death and DALY rate, followed by milk and calcium. Diets that were low in whole grains, milk, and calcium accounted for 81.61% of deaths and 81.64% of DALYs. Deaths and DALYs of dietary factors related to colorectal cancer grew by half from 1990 to 2019. All ASRs remained higher for men than women. Asia carried the highest colorectal cancer burden attributed to dietary risks, especially for East Asia [age-standardized death rate (ASDR): EAPC = 1.15, 95% CI:0.88–1.42; DALY: EAPC = 1.08, 95% CI:0.82–1.34]. The heavy burden also existed in high-middle and middle socio-demographic index (SDI) quintiles. China has always had the highest deaths and DALYs of colorectal cancer attributable to dietary risks, followed by the USA, India, and Japan.

Conclusions: Large variations existed in the dietary risk-related colorectal cancer burdens among sexes, regions, and countries. More targeted interventions to address modifiable dietary risk factors would save 32% of deaths and 34% of DALYs for colorectal cancer.
Marine-Derived Collagen as Biomaterials for Human Health
Authors: Xu Ning , Peng Xue-Liang , Li Hao-Ru , Liu Jia-Xuan , Cheng Ji-Si-Yu , Qi Xin-Ya , Ye Shao-Jie , Gong Hai-Lun , Zhao Xiao-Hong , Yu Jiangming , Xu Guohua , Wei Dai-Xu
Published: August 2021

Collagen is a kind of biocompatible protein material, which is widely used in medical tissue engineering, drug delivery, cosmetics, food and other fields. Because of its wide source, low extraction cost and good physical and chemical properties, it has attracted the attention of many researchers in recent years. However, the application of collagen derived from terrestrial organisms is limited due to the existence of diseases, religious beliefs and other problems. Therefore, exploring a wider range of sources of collagen has become one of the main topics for researchers. Marine-derived collagen (MDC) stands out because it comes from a variety of sources and avoids issues such as religion. On the one hand, this paper summarized the sources, extraction methods and characteristics of MDC, and on the other hand, it summarized the application of MDC in the above fields. And on the basis of the review, we found that MDC can not only be extracted from marine organisms, but also from the wastes of some marine organisms, such as fish scales. This makes further use of seafood resources and increases the application prospect of MDC.
Diagnostic Value of Serum Pepsinogen Levels for Screening Gastric Cancer and Atrophic Gastritis in Asymptomatic Individuals: A Cross-Sectional Study
Authors: Tong Yuling , Wang Hongguang , Zhao Yi , He Xueqiang , Xu Hongwei , Li Hong , Shuai Ping , Gong Lirong , Wu Hongbo , Xu Hongzhi , Luo Yinhu , Wang Dong , Liu Shizhu , Song Zhenya
Published: August 2021

Background

Pepsinogens (PGs) can be used for gastric cancer (GC) screening, but the cutoff levels vary among studies, and PG levels are influenced by numerous factors. The aim of this article is to examine the diagnostic value of PG levels and Helicobacter pylori (Hp) status for GC and atrophic gastritis screening in asymptomatic individuals undergoing health checkup in China.

Patients and Methods

This was a multicenter cross-sectional study of subjects who underwent health checkup from 10/2016 to 10/2018 at nine International Healthcare Centers in China. All participants underwent gastroscopy and pathological examination, serum PG, 13C-urea breath test, and/or Hp serological current infection marker rapid test, all on the same day. PG-related parameters were analyzed in different Hp subgroups and regions.

Results

The patients were grouped as non-atrophic (NAG, n = 1,590), mild to moderate atrophic (MAG, n = 273), severe atrophic (SAG, n = 49), and GC (n = 10). The serum PG levels in these groups decreased with increasing pathological severity. In the same pathological groups, PGI and PGII levels were higher in the Hp-positive subgroup, while PGR (PGI/PGII ratio) was lower (P < 0.05). The best cutoff values for atrophy diagnosis were PGI ≤73.1 ng/ml and PGR ≤9.8, for severe atrophy were PGI ≤63.9 ng/ml and PGR ≤9.09, and for GC was PGR ≤4.7 (all P < 0.05 and area under the curve >0.7). The cutoff points varied with Hp status and China regions.

Conclusion

Serum PG levels might be used for the screening of gastric atrophic gastritis lesions. The results suggest that different cutoff values should possibly be used in different Hp status groups and geographical regions, but it will have to be validated in future studies. Future studies should also examine the value of PG levels for GC detection.
The Impact of Artificial Intelligence CNN Based Denoising on FDG PET Radiomics
Authors: Jaudet Cyril , Weyts Kathleen , Lechervy Alexis , Batalla Alain , Bardet Stéphane , Corroyer-Dulmont Aurélien
Published: August 2021

Background

With a constantly increasing number of diagnostic images performed each year, Artificial Intelligence (AI) denoising methods offer an opportunity to respond to the growing demand. However, it may affect information in the image in an unknown manner. This study quantifies the effect of AI-based denoising on FDG PET textural information in comparison to a convolution with a standard gaussian postfilter (EARL1).

Methods

The study was carried out on 113 patients who underwent a digital FDG PET/CT (VEREOS, Philips Healthcare). 101 FDG avid lesions were segmented semi-automatically by a nuclear medicine physician. VOIs in the liver and lung as reference organs were contoured. PET textural features were extracted with pyradiomics. Texture features from AI denoised and EARL1 versus original PET images were compared with a Concordance Correlation Coefficient (CCC). Features with CCC values ≥ 0.85 threshold were considered concordant. Scatter plots of variable pairs with R2 coefficients of the more relevant features were computed. A Wilcoxon signed rank test to compare the absolute values between AI denoised and original images was performed.

Results

The ratio of concordant features was 90/104 (86.5%) in AI denoised versus 46/104 (44.2%) with EARL1 denoising. In the reference organs, the concordant ratio for AI and EARL1 denoised images was low, respectively 12/104 (11.5%) and 7/104 (6.7%) in the liver, 26/104 (25%) and 24/104 (23.1%) in the lung. SUVpeak was stable after the application of both algorithms in comparison to SUVmax. Scatter plots of variable pairs showed that AI filtering affected more lower versus high intensity regions unlike EARL1 gaussian post filters, affecting both in a similar way. In lesions, the majority of texture features 79/100 (79%) were significantly (p<0.05) different between AI denoised and original PET images.

Conclusions

Applying an AI-based denoising on FDG PET images maintains most of the lesion’s texture information in contrast to EARL1-compatible Gaussian filter. Predictive features of a trained model could be thus the same, however with an adapted threshold. Artificial intelligence based denoising in PET is a very promising approach as it adapts the denoising in function of the tissue type, preserving information where it should.
A Retrospective Observation of Treatment Outcomes Using Decitabine-Combined Standard Conditioning Regimens Before Transplantation in Patients With Relapsed or Refractory Acute Myeloid Leukemia
Authors: Li Yuhang , Cheng Longcan , Xu Chen , Chen Jianlin , Hu Jiangwei , Liu Na , Lan Sanchun , Xie Jing , Sun Ting , Wang Lei , Zhang Yu , Sun Yao , Chen Shuiping , Hu Liangding
Published: August 2021

Hypomethylating agents, decitabine (DAC) and azacitidine, can act as prophylactic and pre-emptive approaches after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a non-intensive bridging approach before allo-HSCT. However, they are rarely used as a part of conditioning regimens in patients with relapsed or refractory acute myeloid leukemia (AML). This retrospectively study included a total of 65 patients (median, 37; range, 13–63) with relapsed or refractory AML who were treated by allo-HSCT after myeloablative conditioning regimens without or with DAC (high-dose DAC schedule, 75 mg/m2 on day −9 and 50 mg/m2 on day −8; low-dose DAC schedule, 25 mg/m2/day on day −10 to −8). DAC exerted no impact on hematopoietic reconstitution. However, patients who were treated with the high-dose DAC schedule had significantly higher incidence of overall survival (OS, 50.0%) and leukemia-free survival (LFS, 35.0%), and lower incidence of relapse (41.1%) and grade II–IV acute graft versus host disease (aGVHD, 10.0%) at 3 years, when compared with those treated with standard conditioning regimens or with the low-dose DAC schedule. In conclusion, high-dose DAC combined with standard conditioning regimens before allo-HSCT is feasible and efficient and might improve outcomes of patients with relapsed or refractory AML, which provides a potential approach to treat these patients.
A Novel Oral Arginase 1/2 Inhibitor Enhances the Antitumor Effect of PD-1 Inhibition in Murine Experimental Gliomas by Altering the Immunosuppressive Environment
Authors: Pilanc Paulina , Wojnicki Kamil , Roura Adria-Jaume , Cyranowski Salwador , Ellert-Miklaszewska Aleksandra , Ochocka Natalia , Gielniewski Bartłomiej , Grzybowski Marcin M. , Błaszczyk Roman , Stańczak Paulina S. , Dobrzański Paweł , Kaminska Bozena
Published: August 2021

Glioblastomas (GBM) are the common and aggressive primary brain tumors that are incurable by conventional therapies. Immunotherapy with immune checkpoint inhibitors is not effective in GBM patients due to the highly immunosuppressive tumor microenvironment (TME) restraining the infiltration and activation of cytotoxic T cells. Clinical and experimental studies showed the upregulation of expression of the arginase 1 and 2 (ARG1 and ARG2, respectively) in murine and human GBMs. The elevated arginase activity leads to the depletion of L-arginine, an amino-acid required for the proliferation of T lymphocytes and natural killer cells. Inhibition of ARG1/2 in the TME may unblock T cell proliferation and activate effective antitumor responses. To explore the antitumor potential of ARG1/2 inhibition, we analyzed bulk and single-cell RNA sequencing (scRNA-seq) data from human and murine gliomas. We found the upregulation of ARG1/2 expression in GBMs, both in tumor cells and in tumor infiltrating microglia and monocytes/macrophages. We employed selective arginase inhibitors to evaluate if ARG1/2 inhibition in vitro and in vivo exerts the antitumor effects. A novel, selective ARG1/2 inhibitor - OAT-1746 blocked microglia-dependent invasion of U87-MG and LN18 glioma cells in a Matrigel invasion assay better than reference compounds, without affecting the cell viability. OAT-1746 effectively crossed the blood brain barrier in mice and increased arginine levels in the brains of GL261 glioma bearing mice. We evaluated its antitumor efficacy against GL261 intracranial gliomas as a monotherapy and in combination with the PD-1 inhibition. The oral treatment with OAT-1746 did not affect the immune composition of TME, it induced profound transcriptomic changes in CD11b+ cells immunosorted from tumor-bearing brains as demonstrated by RNA sequencing analyses. Treatment with OAT-1746 modified the TME resulting in reduced glioma growth and increased antitumor effects of the anti-PD-1 antibody. Our findings provide the evidence that inhibition of ARG1/2 activity in tumor cells and myeloid cells in the TME unblocks antitumor responses in myeloid cells and NK cells, and improves the efficacy of the PD-1 inhibition.
Endoscopy in Pediatric Eosinophilic Esophagitis
Authors: Nguyen Nathalie , Kramer Robert E. , Menard-Katcher Calies
Published: August 2021

Endoscopy and mucosal biopsies are essential to the diagnosis of EoE. Together they either confirm or exclude mucosal eosinophilia and provide a visual inspection of the esophagus that may be consistent with EoE or suggest other underlying etiologies. Endoscopy also plays an important therapeutic role in the management of EoE including the assessment of treatment response and treatment of associated complications including esophageal stricture and food impaction. Assessment of treatment response largely depends on endoscopy and mucosal biopsies although less invasive strategies may eventually provide alternative means to assess mucosal inflammation. Herein we will review current use of endoscopy in EoE, including recently developed technologies and their role in the management of EoE.
New Developments in Prokinetic Therapy for Gastric Motility Disorders
Authors: Camilleri Michael , Atieh Jessica
Published: August 2021

Prokinetic agents amplify and coordinate the gastrointestinal muscular contractions to facilitate the transit of intra-luminal content. Following the institution of dietary recommendations, prokinetics are the first medications whose goal is to improve gastric emptying and relieve symptoms of gastroparesis. The recommended use of metoclopramide, the only currently approved medication for gastroparesis in the United States, is for a duration of less than 3 months, due to the risk of reversible or irreversible extrapyramidal tremors. Domperidone, a dopamine D2 receptor antagonist, is available for prescription through the FDA’s program for Expanded Access to Investigational Drugs. Macrolides are used off label and are associated with tachyphylaxis and variable duration of efficacy. Aprepitant relieves some symptoms of gastroparesis. There are newer agents in the pipeline targeting diverse gastric (fundic, antral and pyloric) motor functions, including novel serotonergic 5-HT4 agonists, dopaminergic D2/3 antagonists, neurokinin NK1 antagonists, and ghrelin agonist. Novel targets with potential to improve gastric motor functions include the pylorus, macrophage/inflammatory function, oxidative stress, and neurogenesis. In the current review, we discuss the use of pharmacological approaches with potential to enhance motor functions in the management of gastroparesis.
Cell-Penetrating Peptides Predicted From CASC3, AKIP1, and AHRR Proteins
Authors: Porosk Ly , Põhako Kaisa , Arukuusk Piret , Langel Ülo
Published: August 2021

Peptides can be used as research tools and for diagnostic or therapeutic applications. Peptides, alongside small molecules and antibodies, are used and are gaining further interest as protein-protein interaction (PPI) modulators. Peptides have high target specificity and high affinity, but, unlike small molecule modulators, they are not able to cross the cell membranes to reach their intracellular targets. To overcome this limitation, the special property of the cell-penetrating peptides (CPPs) could benefit their cause. CPPs are a class of peptides that can enter the cells and with them also deliver the attached cargoes. Today, with the advancement of in silico prediction tools and the availability of protein databases, designing new and multifunctional peptides that are able to reach intracellular targets and inhibit certain cellular processes in a very specific manner is reachable. Although there are several efficient CPP sequences already known, the discovery of new CPPs is crucial for the development of efficient delivery methods for both biotechnological and therapeutic applications. In this work, we chose 10 human nuclear proteins from which we predicted new potential CPP sequences by using three different CPP predictors: cell-penetrating peptide prediction tool, CellPPD, and SkipCPP-Pred. From each protein, one predicted CPP sequence was synthesized and its internalization into cells was assessed. Out of the tested sequences, three peptides displayed features characteristic to CPPs. These peptides and also the predicted peptide sequences could be used to design and modify new CPPs. In this work, we show that we can use protein sequences as input for generating new peptides with cell internalization properties. Three new CPPs, AHRR8-24, CASC3251-264, and AKIP127-37, can be further used for the delivery of other cargoes or designed into multifunctional peptides with capability of internalizing cells.
Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway
Authors: Li Linyi , Yang Yunyun , Zhang Huina , Du Yunhui , Jiao Xiaolu , Yu Huahui , Wang Yu , Lv Qianwen , Li Fan , Sun Qiuju , Qin Yanwen
Published: August 2021

Background: Endothelial barrier dysfunction plays a key role in atherosclerosis progression. The primary pathology of obstructive sleep apnea-hypopnea syndrome is chronic intermittent hypoxia (IH), which induces reactive oxygen species (ROS) overproduction, endothelial barrier injury, and atherosclerosis. Salidroside, a typical pharmacological constituent of Rhodiola genus, has documented antioxidative, and cardiovascular protective effects. However, whether salidroside can improve IH-aggravated endothelial barrier dysfunction and atherosclerosis has not been elucidated.

Methods and results: In normal chow diet-fed ApoE−/− mice, salidroside (100 mg/kg/d, p. o.) significantly ameliorated the formation of atherosclerotic lesions and barrier injury aggravated by 7-weeks IH (21%–5%–21%, 120 s/cycle). In human umbilical vein endothelial cells (HUVECs), exposure to IH (21%–5%–21%, 40 min/cycle, 72 cycles) decreased transendothelial electrical resistance and protein expression of vascular endothelial cadherin (VE-cadherin) and zonula occludens 1. In addition, IH promoted ROS production and activated ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway. All of these effects of IH were reversed by salidroside. Similar to salidroside, ROCK-selective inhibitors Y26732, and Fasudil protected HUVECs from IH-induced ROS overproduction and endothelial barrier disruption. Furthermore, salidroside increased intracellular cAMP levels, while the PKA-selective inhibitor H-89 attenuated the effects of salidroside on IH-induced RhoA/ROCK suppression, ROS scavenging, and barrier protection.

Conclusion: Our findings demonstrate that salidroside effectively ameliorated IH-aggravated endothelial barrier injury and atherosclerosis, largely through the cAMP/PKA/RhoA signaling pathway.
Systematic Safety Evaluation of Cold Plasma-Activated Liquid in Rabbits
Authors: Xu Yujing , Peng Sansan , Li Bing , Wang Shuai , Zhang Hao , Li Qiaosong , Liu Zhijie , Guo Bo , Liu Dingxin , Xu Dehui
Published: August 2021

Plasma-activated liquid (PAL) can effectively and selectively kill various types of cancer cells both in superficial and deeper tumors. As a promising novel approach to oncotherapy, the safety of PAL is essential in the clinic but has not been thoroughly assessed. In myeloma and blood tumors, the pathogenesis is in the bone marrow cavity. We have therefore evaluated the safety of PAL in New Zealand rabbits by intra-bone marrow injection, and provide a basis of further clinical research and application of PALs. In this study, both a plasma jet and plasma surface were used to treat saline solution, phosphate-buffered solution, and cell culture medium, to produce PAL. Then, oscillograms and optical emission spectra were evaluated to characterize the plasma discharge. Acute toxicity tests and safety evaluation studies were conducted by intra-bone marrow injection of PAL into New Zealand rabbits, while control rabbits received saline only. Body weight, vital organ coefficient, organ appearance, organ histopathology, blood cell and hemoglobin parameters, and blood biochemical indicators were tested on the 30th day after injection. We found that there was no mortality or loss of mobility throughout the experimental period. Acute toxicity tests showed that there were no PAL-related side effects in rabbits receiving the maximum dose of 700 μL PAL. PAL treatments did not affect body weight, organ coefficient, organ appearance, organ histopathology, or blood biochemical indicators. However, the percentage of lymphocytes decreased while the percentage of neutrophil granulocytes increased compared with the control group. In summary, our results indicate that PAL can be safely injected into bone marrow of New Zealand rabbits without significant toxicity.
Fusion Coding of 3D Real and Virtual Scenes Information for Augmented Reality-Based Holographic Stereogram
Authors: Liu Yunpeng , Yan Xingpeng , Liu Xinlei , Wang Xi , Jing Tao , Lin Min , Chen Song , Li Pei , Jiang Xiaoyu
Published: August 2021

In this paper, an optical field coding method for the fusion of real and virtual scenes is proposed to implement an augmented reality (AR)-based holographic stereogram. The occlusion relationship between the real and virtual scenes is analyzed, and a fusion strategy based on instance segmentation and depth determination is proposed. A real three-dimensional (3D) scene sampling system is built, and the foreground contour of the sampled perspective image is extracted by the Mask R-CNN instance segmentation algorithm. The virtual 3D scene is rendered by a computer to obtain the virtual sampled images as well as their depth maps. According to the occlusion relation of the fusion scenes, the pseudo-depth map of the real scene is derived, and the fusion coding of 3D real and virtual scenes information is implemented by the depth information comparison. The optical experiment indicates that AR-based holographic stereogram fabricated by our coding method can reconstruct real and virtual fused 3D scenes with correct occlusion and depth cues on full parallax.
A Kinetic Response Model for Standardized Regression Analyses of Inflammation-Triggered Hypothermic Body Temperature-Time Courses in Mice
Authors: Diebner Hans H. , Reinke Sören , Rösen-Wolff Angela , Winkler Stefan
Published: August 2021

LPS is frequently used to induce experimental endotoxic shock, representing a standard model of acute inflammation in mice. The resulting inflammatory response leads to hypothermia of the experimental animals, which in turn can be used as surrogate for the severity of systemic inflammation. Although increasingly applied as a humane endpoint in murine studies, differences between obtained temperature-time curves are typically evaluated at a single time point with t-tests or ANOVA analyses. We hypothesized that analyses of the entire temperature-time curves using a kinetic response model could fit the data, which show a temperature decrease followed by a tendency to return to normal temperature, and could increase the statistical power. Using temperature-time curves obtained from LPS stimulated mice, we derived a biologically motivated kinetic response model based on a differential equation. The kinetic model includes four parameters: (i) normal body temperature (Tn), (ii) a coefficient related to the force of temperature autoregulation (r), (iii) damage strength (p0), and (iv) clearance rate (k). Kinetic modeling of temperature-time curves obtained from LPS stimulated mice is feasible and leads to a high goodness-of-fit. Here, modifying key enzymes of inflammatory cascades induced a dominant impact of genotypes on the damage strength and a weak impact on the clearance rate. Using a likelihood-ratio test to compare modeled curves of different experimental groups yields strongly enhanced statistical power compared to pairwise t-tests of single temperature time points. Taken together, the kinetic model presented in this study has several advantages compared to simple analysis of individual time points and therefore may be used as a standard method for assessing inflammation-triggered hypothermic response curves in mice.
Engineering Musculoskeletal Grafts for Multi-Tissue Unit Repair: Lessons From Developmental Biology and Wound Healing
Authors: Zhang Xu , Wang Dan , Mak King-Lun Kingston , Tuan Rocky S. , Ker Dai Fei Elmer
Published: August 2021

In the musculoskeletal system, bone, tendon, and skeletal muscle integrate and act coordinately as a single multi-tissue unit to facilitate body movement. The development, integration, and maturation of these essential components and their response to injury are vital for conferring efficient locomotion. The highly integrated nature of these components is evident under disease conditions, where rotator cuff tears at the bone-tendon interface have been reported to be associated with distal pathological alterations such as skeletal muscle degeneration and bone loss. To successfully treat musculoskeletal injuries and diseases, it is important to gain deep understanding of the development, integration and maturation of these musculoskeletal tissues along with their interfaces as well as the impact of inflammation on musculoskeletal healing and graft integration. This review highlights the current knowledge of developmental biology and wound healing in the bone-tendon-muscle multi-tissue unit and perspectives of what can be learnt from these biological and pathological processes within the context of musculoskeletal tissue engineering and regenerative medicine. Integrating these knowledge and perspectives can serve as guiding principles to inform the development and engineering of musculoskeletal grafts and other tissue engineering strategies to address challenging musculoskeletal injuries and diseases.
Can Inoculation With the Bacterial Biostimulant Enterobacter sp. Strain 15S Be an Approach for the Smarter P Fertilization of Maize and Cucumber Plants?
Authors: Alzate Zuluaga Mónica Yorlady , Martinez de Oliveira André Luiz , Valentinuzzi Fabio , Tiziani Raphael , Pii Youry , Mimmo Tanja , Cesco Stefano
Published: August 2021

Phosphorus (P) is an essential nutrient for plants. The use of plant growth-promoting bacteria (PGPB) may also improve plant development and enhance nutrient availability, thus providing a promising alternative or supplement to chemical fertilizers. This study aimed to evaluate the effectiveness of Enterobacter sp. strain 15S in improving the growth and P acquisition of maize (monocot) and cucumber (dicot) plants under P-deficient hydroponic conditions, either by itself or by solubilizing an external source of inorganic phosphate (Pi) [Ca3(PO4)2]. The inoculation with Enterobacter 15S elicited different effects on the root architecture and biomass of cucumber and maize depending on the P supply. Under sufficient P, the bacterium induced a positive effect on the whole root system architecture of both plants. However, under P deficiency, the bacterium in combination with Ca3(PO4)2 induced a more remarkable effect on cucumber, while the bacterium alone was better in improving the root system of maize compared to non-inoculated plants. In P-deficient plants, bacterial inoculation also led to a chlorophyll content [soil-plant analysis development (SPAD) index] like that in P-sufficient plants (p < 0.05). Regarding P nutrition, the ionomic analysis indicated that inoculation with Enterobacter 15S increased the allocation of P in roots (+31%) and shoots (+53%) of cucumber plants grown in a P-free nutrient solution (NS) supplemented with the external insoluble phosphate, whereas maize plants inoculated with the bacterium alone showed a higher content of P only in roots (36%) but not in shoots. Furthermore, in P-deficient cucumber plants, all Pi transporter genes (CsPT1.3, CsPT1.4, CsPT1.9, and Cucsa383630.1) were upregulated by the bacterium inoculation, whereas, in P-deficient maize plants, the expression of ZmPT1 and ZmPT5 was downregulated by the bacterial inoculation. Taken together, these results suggest that, in its interaction with P-deficient cucumber plants, Enterobacter strain 15S might have solubilized the Ca3(PO4)2 to help the plants overcome P deficiency, while the association of maize plants with the bacterium might have triggered a different mechanism affecting plant metabolism. Thus, the mechanisms by which Enterobacter 15S improves plant growth and P nutrition are dependent on crop and nutrient status.
Genomic Prediction and the Practical Breeding of 12 Quantitative-Inherited Traits in Cucumber (Cucumis sativus L.)
Authors: Liu Ce , Liu Xiaoxiao , Han Yike , Wang Xi'ao , Ding Yuanyuan , Meng Huanwen , Cheng Zhihui
Published: August 2021

Genomic prediction is an effective way for predicting complex traits, and it is becoming more essential in horticultural crop breeding. In this study, we applied genomic prediction in the breeding of cucumber plants. Eighty-one cucumber inbred lines were genotyped and 16,662 markers were identified to represent the genetic background of cucumber. Two populations, namely, diallel cross population and North Carolina II population, having 268 combinations in total were constructed from 81 inbred lines. Twelve cucumber commercial traits of these two populations in autumn 2018, spring 2019, and spring 2020 were collected for model training. General combining ability (GCA) models under five-fold cross-validation and cross-population validation were applied to model validation. Finally, the GCA performance of 81 inbred lines was estimated. Our results showed that the predictive ability for 12 traits ranged from 0.38 to 0.95 under the cross-validation strategy and ranged from −0.38 to 0.88 under the cross-population strategy. Besides, GCA models containing non-additive effects had significantly better performance than the pure additive GCA model for most of the investigated traits. Furthermore, there were a relatively higher proportion of additive-by-additive genetic variance components estimated by the full GCA model, especially for lower heritability traits, but the proportion of dominant genetic variance components was relatively small and stable. Our findings concluded that a genomic prediction protocol based on the GCA model theoretical framework can be applied to cucumber breeding, and it can also provide a reference for the single-cross breeding system of other crops.