bluuebunny/crossref_metadata_2025 huggingface dataset:
Metal and Metalloid Contamination in Green Sea Turtles (Chelonia mydas) Found Stranded in Southeastern Brazil
Authors: Bruno Daphne de Albuquerque , Willmer Isabel Q. , Pereira Lucia Helena S. de S. , Rocha Rafael C. C. , Saint’Pierre Tatiana D. , Baldassin Paula , Scarelli Ana Carolina S. , Tadeu Amanda Dias , Correia Fábio V. , Saggioro Enrico M. , Lemos Leila S. , Siciliano Salvatore , Hauser-Davis Rachel Ann
Published: March 2021

Sea turtles tend to accumulate high metal levels in their tissues and are considered excellent pollution bioindicators. Studies concerning metal contamination in hatchlings, however, are non-existent for one of the most abundant species in Brazil, green sea turtles, while several other metal assessments in juvenile muscles are still scarce. In this context, this study aimed to analyze the concentrations of 12 elements in kidney and muscle samples from green sea turtles (Chelonia mydas; n = 24) found stranded in Rio de Janeiro, southeastern Brazil. Elemental concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS). The presence of fibropapillomatosis, an increasingly common disease in sea turtles which has been associated to metal contamination, was also evaluated. Most elements (Mn, Fe, Co, Ni, Cu, Zn, Cd, Hg, and Pb) were significantly higher in liver, while Al and As were significantly higher in muscle tissue, indicating bioaccumulation of the latter two elements. No differences between juvenile male and female green turtles were observed for either liver or kidney concerning the investigated elements. Literature comparisons of studies conducted in other areas throughout the Brazilian coast indicate higher concentrations of Cd, Mn, As, Hg, and Zn in kidneys, of probable anthropogenic origin. Several statistically significant inter-elemental correlations were observed between toxic elements, indicating similar sources for these environmental contaminants. Significant correlations between Hg in muscle and kidney and As in the same organs suggest bioaccumulation of both elements in muscle. Three individuals assessed herein exhibited fibropapillomatosis, and further assessments in this regard and potential correlations to the detected metal concentrations are currently being carried out. In addition, evaluations concerning other toxic compounds, as well as deleterious cellular effects, are also underway, since total metal concentrations do not reflect total elemental bioavailability.
A System to Enable Mixing Controlled Combustion With High Octane Fuels Using a Prechamber and High-Pressure Direct Injector
Authors: Dempsey Adam B. , Zeman Jared , Wall Martin
Published: March 2021

The demand for transportation energy is growing and thus improving the efficiency and reducing the pollutant emissions from this energy sector is critical. Transportation has historically been powered by the internal combustion engine (ICE). Many alternative technologies are being evaluated to replace the ICE, such as hydrogen fuel cells and battery electrics. These technologies appear attractive at the vehicle-level but have many challenges regarding life cycle emissions and lack of infrastructure. A more pragmatic approach would be to use the current liquid fuels infrastructure with cleaner burning, renewable fuels that have the potential to be carbon neutral, such as low carbon alcohols (e.g., methanol, ethanol, propanol, and butanol). These alternative fuels tend to have a high-octane number, making them great candidates for conventional spark ignition (SI) engines. However, SI engines are plagued by several challenges when it comes to high load operation, such as pre-ignition, knock-limited peak torque, poor snap torque response, high levels of cyclic variability, and sensitivity to varying fuel properties. The objective of this research is to develop a technology that will allow high octane fuels to be utilized in engines and utilize robust mixing controlled combustion. The proposed technology is a system which utilizes an active prechamber in the shape of an annulus and a high-pressure direct fuel injector. The active prechamber and the high-pressure direct injector use the same liquid fuel, which could be any fuel that has relatively high volatility and high resistance to autoignition (i.e., high-octane number). The active prechamber is fired late in the compression stroke and hot jet flames are ejected from the prechamber. These jets ignite the direct injected fuel sprays near top dead center, establishing a mixing controlled combustion event. This will allow for robust operation across the full engine operating space with clean burning renewable fuels, without the shortcomings of SI engines regarding knock-limited operation and part load efficiency.
Red Cell Distribution Width Upon Hospital Admission Predicts Short-Term Mortality in Hospitalized Patients With COVID-19: A Single-Center Experience
Authors: Kaufmann Christoph C. , Ahmed Amro , Brunner Ulrich , Jäger Bernhard , Aicher Gabriele , Equiluz-Bruck Susanne , Spiel Alexander O. , Funk Georg-Christian , Gschwantler Michael , Fasching Peter , Huber Kurt
Published: March 2021

Background: Coronavirus disease (COVID-19) was first described at the end of 2019 in China and has since spread across the globe. Red cell distribution width (RDW) is a potent prognostic marker in several medical conditions and has recently been suggested to be of prognostic value in COVID-19.

Methods: This retrospective, observational study of consecutive patients with COVID-19 was conducted from March 12, 2020 to December 4, 2020 in the Wilhelminenhospital, Vienna, Austria. RDWlevels on admission were collected and tested for their predictive value of 28-day mortality.

Results: A total of 423 eligible patients with COVID-19 were included in the final analyses and 15.4% died within 28 days (n = 65). Median levels of RDWwere significantly higher in non-survivors compared to survivors [14.6% (IQR, 13.7–16.3) vs. 13.4% (IQR, 12.7– 14.4), P < 0.001]. Increased RDW was a significant predictor of 28-day mortality [crude odds ratio (OR) 1.717, 95% confidence interval (CI) 1.462–2.017; P = < 0.001], independent of clinical confounders, comorbidities and established prognostic markers of COVID-19 (adjusted OR of the final model 1.368, 95% CI 1.126–1.662; P = 0.002). This association remained consistent upon sub-group analysis. Our study data also demonstrate that RDW levels upon admission for COVID-19 were similar to previously recorded, non-COVID-19 associated RDW levels [14.2% (IQR, 13.3–15.7) vs. 14.0% [IQR, 13.2–15.1]; P = 0.187].

Conclusions: In this population, RDWwas a significant, independent prognostic marker of short-term mortality in patients with COVID-19.
Economic Evaluation of Rituximab + Recombinant Human Thrombopoietin vs. Rituximab for the Treatment of Second-Line Idiopathic Thrombocytopenic Purpura in China
Authors: Rui Mingjun , Wang Yingcheng , Fei Zhengyang , Shang Ye , Ma Aixia , Li Hongchao
Published: March 2021

Objective: This study aimed to compare the economic evaluation of recombinant human thrombopoietin+rituximab (rhTPO + RTX) vs. RTX as second-line treatment for adult patients with immunologic thrombocytopenic purpura in China.

Methods: The Markov model was used in our research. The response rate and relapse rate data were derived from two clinical trials and one retrospective study. Cost and utility values were derived from published literature, a third-party database, and healthcare documents. In addition, one-way sensitivity analysis and probabilistic sensitivity analysis were performed to observe the stability of the model and data source.

Results: In the Markov model, compared with RTX, rhTPO+RTX yielded an additional 0.04 QALYs, with an incremental cost of 2,802 USD. The ICER was 69,097 USD/QALY. According to the results from the one-way sensitivity analysis, complete response of rhTPO+RTX, utility of complete response and response of RTX were the main drivers in the model. The results from the probabilistic sensitivity analysis demonstrated that there was a 100% probability that rhTPO+RTX was not cost-effective vs. RTX alone at a threshold of $10,805/QALY and an 84% probability at a threshold of $32,415/QALY.

Conclusion: RTX+rhTPO was not more cost-effective than RTX alone as second-line treatment for adult patients with immunologic thrombocytopenic purpura in China.
Transcriptional Variability Associated With CRISPR-Mediated Gene Replacements at the Phytophthora sojae Avr1b-1 Locus
Authors: Gu Biao , Shao Guangda , Gao Wenxin , Miao Jianqiang , Wang Qinhu , Liu Xili , Tyler Brett M.
Published: March 2021

Transcriptional plasticity enables oomycetes to rapidly adapt to environmental challenges including emerging host resistance. For example, the soybean pathogen Phytophthora sojae can overcome resistance conferred by the host resistance gene Rps1b through natural silencing of its corresponding effector gene, Avr1b-1. With the Phytophthora CRISPR/Cas9 genome editing system, it is possible to generate site-specific knock-out (KO) and knock-in (KI) mutants and to investigate the biological functions of target genes. In this study, the Avr1b-1 gene was deleted from the P. sojae genome using a homology-directed recombination strategy that replaced Avr1b-1 with a gene encoding the fluorescent protein mCherry. As expected, all selected KO transformants gained virulence on Rps1b plants, while infection of plants lacking Rps1b was not compromised. When a sgRNA-resistant version of Avr1b-1 was reintroduced into the Avr1b-1 locus of an Avr1b KO transformant, KI transformants with a well-transcribed Avr1b-1 gene were unable to infect Rps1b-containing soybeans. However, loss of expression of the incoming Avr1b-1 gene was frequently observed in KI transformants, which resulted in these transformants readily infecting Rps1b soybeans. A similar variability in the expression levels of the incoming gene was observed with AVI- or mCherry-tagged Avr1b-1 constructs. Our results suggest that Avr1b-1 may be unusually susceptible to transcriptional variation.
Genetic Variability in Molecular Pathways Implicated in Alzheimer's Disease: A Comprehensive Review
Authors: Vogrinc David , Goričar Katja , Dolžan Vita
Published: March 2021

Alzheimer's disease (AD) is a complex neurodegenerative disease, affecting a significant part of the population. The majority of AD cases occur in the elderly with a typical age of onset of the disease above 65 years. AD presents a major burden for the healthcare system and since population is rapidly aging, the burden of the disease will increase in the future. However, no effective drug treatment for a full-blown disease has been developed to date. The genetic background of AD is extensively studied; numerous genome-wide association studies (GWAS) identified significant genes associated with increased risk of AD development. This review summarizes more than 100 risk loci. Many of them may serve as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, we used GWAS data to identify key pathways of AD pathogenesis: cellular processes, metabolic processes, biological regulation, localization, transport, regulation of cellular processes, and neurological system processes. Gene clustering into molecular pathways can provide background for identification of novel molecular targets and may support the development of tailored and personalized treatment of AD.
Telitacicept Following Plasma Exchange in the Treatment of Subjects With Recurrent NMOSD: Study Protocol for a Single-Center, Single-Arm, Open-Label Study
Authors: Ding Jie , Cai Yu , Deng Ye , Jiang Xianguo , Gao Meichun , Lin Yan , Zhao Nan , Wang Ze , Yu Haojun , Lv Wenwen , Zhang Ying , Hao Yong , Guan Yangtai
Published: March 2021

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease that recurrently relapses and leads to severe disability. The available choices for disease prevention are few or intolerable. Previous studies suggested that telitacicept may provide a promising therapeutic strategy for autoimmune diseases involving B cells. Therefore, this study aims to assess the effectiveness and safety of telitacicept for recurrent NMOSD.

Methods: We will perform a single-arm, single-center, open-label, specialist study with a total enrollment of eight participants. The treatment regimen includes plasma exchange three times and subcutaneous injection of telitacicept for 46 cycles, with a total period of 48 weeks. The primary endpoint is the time to first recurrence after enrollment. Secondary endpoints are Expanded Disability Status Scale (EDSS) score, Opticospinal Impairment Scale (OSIS) score, Hauser Ambulation Index, number of lesions on MRI, and changes in visual evoked potential (VEP), optical coherence tomography (OCT) and immunologic status. All adverse events after medication will be documented and investigated.

Discussion: This study will explore the safety and effectiveness of telitacicept following plasma exchange regarding the time to recurrence in neuromyelitis optica spectrum disorder (NMOSD) for the first time.

Clinical Trial Registration:Chictr.org.cn, identifier ChiCTR1800019427
Co-occurrence of Hyperacusis Accelerates With Tinnitus Burden Over Time and Requires Medical Care
Authors: Refat Fatma , Wertz Jakob , Hinrichs Pauline , Klose Uwe , Samy Hesham , Abdelkader Rafeek Mohamed , Saemisch Jörg , Hofmeier Benedikt , Singer Wibke , Rüttiger Lukas , Knipper Marlies , Wolpert Stephan
Published: March 2021

Although tinnitus represents a major global burden, no causal therapy has yet been established. Ongoing controversies about the neuronal pathophysiology of tinnitus hamper efforts in developing advanced therapies. Hypothesizing that the unnoticed co-occurrence of hyperacusis and differences in the duration of tinnitus may possibly differentially influence the neural correlate of tinnitus, we analyzed 33 tinnitus patients without (T-group) and 20 tinnitus patients with hyperacusis (TH-group). We found crucial differences between the T-group and the TH-group in the increase of annoyance, complaints, tinnitus loudness, and central neural gain as a function of tinnitus duration. Hearing thresholds did not differ between T-group and TH-group. In the TH-group, the tinnitus complaints (total tinnitus score) were significantly greater from early on and the tinnitus intensity distinctly increased over time from ca. 12 to 17 dB when tinnitus persisted more than 5 years, while annoyance responses to normal sound remained nearly constant. In contrast, in the T-group tinnitus complaints remained constant, although the tinnitus intensity declined over time from ca. 27 down to 15 dB beyond 5 years of tinnitus persistence. This was explained through a gradually increased annoyance to normal sound over time, shown by a hyperacusis questionnaire. Parallel a shift from a mainly unilateral (only 17% bilateral) to a completely bilateral (100%) tinnitus percept occurred in the T-group, while bilateral tinnitus dominated in the TH-group from the start (75%). Over time in the T-group, ABR wave V amplitudes (and V/I ratios) remained reduced and delayed. By contrast, in the TH-group especially the ABR wave III and V (and III/I ratio) continued to be enhanced and shortened in response to high-level sound stimuli. Interestingly, in line with signs of an increased co-occurrence of hyperacusis in the T-group over time, ABR wave III also slightly increased in the T-group. The findings disclose an undiagnosed co-occurrence of hyperacusis in tinnitus patients as a main cause of distress and the cause of complaints about tinnitus over time. To achieve urgently needed and personalized therapies, possibly using the objective tools offered here, a systematic sub-classification of tinnitus and the co-occurrence of hyperacusis is recommended.
Differences in Clinical Features and Diagnostic Strategies Between IgG4-Related Autoimmune Cholangitis and Cholangiocarcinoma
Authors: Zhu Ke , Yang Jin , Chen Ying-zhen , Zhang Xue-rong , Yu Xian-huan , Wang Jie , Zhang Rui , Liu Chao
Published: March 2021

IgG4-related autoimmune cholangitis (IgG4-AIC) is often difficult to distinguish from cholangiocarcinoma (CCA). This study aimed to determine a practical clinical strategy for distinguishing between IgG4-AIC and CCA to avoid unnecessary surgical resection. We retrospectively collected and compared the clinicopathological data between IgG4-AIC and CCA patients, including the clinical, serological, and radiological characteristics, to follow up on these patients to investigate the prognosis. Among the 377 patients who received surgical resection for suspecting CCA at the Sun Yat-Sen Memorial Hospital between June 2004 and June 2014, 14 patients were diagnosed as IgG4-AIC through histochemistry after surgery. Immunohistochemistry revealed that IgG4 was up-regulated in the plasma cells of IgG4-AIC tissues in 13 out of 14 patients. The serum CA19-9 level was significantly lower than in the CCA group. Patients with IgG4-AIC can only see slight or no enhancement under the contrast enhancement CT scan, while there are no signs of ring-like or delayed enhancement that is unique to CCA. Thirteen patients were followed up, and the time was 12 to 92 months. Three of them were regularly treated with prednisone after surgery, and original symptoms disappeared. Our study demonstrated that the combination of imaging with serum CA19-9 could improve the preoperative diagnostic value and reduce the rate of unnecessary resection.
HILPDA Is a Prognostic Biomarker and Correlates With Macrophage Infiltration in Pan-Cancer
Authors: Liu Chengdong , Zhou Xiaohan , Zeng Hanyi , Wu Dehua , Liu Li
Published: March 2021

Background: The protein hypoxia-inducible lipid droplet-associated (HILPDA) is differentially expressed in various tumors. However, its role and correlation with immune cell infiltration in most tumors remain unclear.

Methods: HILPDA expression was analyzed in pan-cancer data from The Cancer Genome Atlas (TCGA) database. The influence of HILPDA in clinical prognosis was evaluated using clinical survival data from TCGA. Enrichment analysis of HILPDA was conducted using the R package “clusterProfiler.” We downloaded the immune cell infiltration score of TCGA samples from published articles and analyzed the correlation between the magnitude of immune cell infiltration and HILPDA expression.

Results: HILPDA was highly expressed and associated with worse overall survival, disease-specific survival, and progression-free interval in most tumor types. In addition, HILPDA expression was significantly associated with the glycolysis pathway and infiltration of immune cells. Tumor-associated macrophage (TAM) infiltration increased in tissues with high HILPDA expression in most tumor types. Immunosuppressive genes, such as PD-L1, PD-1, TGFB1, and TGFBR1 were positively correlated with HILPDA.

Conclusions: Our study suggests that HILPDA is a marker of poor prognosis. High HILPDA may contribute to TAM infiltration and be associated with tumor immunosuppression status.
Risk for Invasive Cancers in Women With Breast Cancer In Situ: Results From a Population Not Covered by Organized Mammographic Screening
Authors: Karavasiloglou Nena , Matthes Katarina L. , Pestoni Giulia , Limam Manuela , Korol Dimitri , Wanner Miriam , Rohrmann Sabine
Published: March 2021

Background

Even though breast cancer in situ (BCIS) incidence has been increasing, the prognosis of BCIS patients has not been extensively investigated. According to the literature, women with BCIS have a higher risk of developing subsequent invasive breast cancer; conflicting information has been reported regarding their potential risk for a subsequent invasive non-breast cancer.

Methods

Data from 1,082 women, whose first-ever cancer diagnosis was primary BCIS between 2003 and 2015 and were living in the canton of Zurich, were used. Standardized incidence ratios (SIRs) were calculated to compare the risk of an invasive breast or non-breast cancer among women with a primary BCIS with the corresponding risk of the adult female population. SIRs were calculated overall and by patient and tumor characteristics. To investigate potential risk factors (e.g., age at diagnosis, treatment) for a subsequent invasive breast or non-breast cancer we used Cox proportional hazards regression models.

Results

BCIS patients had 6.85 times [95% confidence interval (CI): 5.52–8.41] higher risk of being diagnosed with invasive breast cancer compared to the general population. They additionally faced 1.57 times (95% CI: 1.12–2.12) higher risk of an invasive non-breast cancer. The SIRs were higher for women < 50-years old for both invasive breast and non-breast cancer at BCIS diagnosis. Age ≥ 70-years old at BCIS diagnosis was statistically significantly associated with a subsequent invasive non-breast cancer diagnosis.

Conclusions

BCIS patients had a higher risk of being diagnosed with invasive breast and non-breast cancer compared to the general population. Age 70 years or older at BCIS diagnosis was the only risk factor statistically significantly associated with a subsequent invasive non-breast cancer. Our results support the increased risk for subsequent cancers in BCIS patients reported in the literature. Future studies should establish the risk factors for subsequent cancers, highlight the need for intensive monitoring in this population, and help distinguish BCIS patients who could benefit from systemic therapy to prevent distant cancers.
AWP1 Restrains the Aggressive Behavior of Breast Cancer Cells Induced by TNF-α
Authors: Kim Eun-Young , Kim Ji-Eun , Choi Bongkun , Kweon Jiyeon , Park Si-On , Lee Hee-Seop , Lee Eun-Jin , Oh Soyoon , Shin Ha Rim , Choi Hyuksu , Kim Yongsub , Chang Eun-Ju
Published: March 2021

TNF-α plays a crucial role in cancer initiation and progression by enhancing cancer cell proliferation, survival, and migration. Even though the known functional role of AWP1 (zinc finger AN1 type-6, ZFAND6) is as a key mediator of TNF-α signaling, its potential role in the TNF-α-dependent responses of cancer cells remains unclear. In our current study, we found that an AWP1 knockdown using short hairpin RNAs increases the migratory potential of non-aggressive MCF-7 breast cancer cells with no significant alteration of their proliferation in response to TNF-α. A CRISPR/Cas9-mediated AWP1 knockout in MCF-7 cells led to mesenchymal cell type morphological changes and an accelerated motility. TNF-α administration further increased this migratory capacity of these AWP1-depleted cells through the activation of NF-κB accompanied by increased epithelial-mesenchymal transition-related gene expression. In particular, an AWP1 depletion augmented the expression of Nox1, reactive oxygen species (ROS) generating enzymes, and ROS levels and subsequently promoted the migratory potential of MCF-7 cells mediated by TNF-α. These TNF-α-mediated increases in the chemotactic migration of AWP1 knockout cells were completely abrogated by an NF-κB inhibitor and a ROS scavenger. Our results suggest that a loss-of-function of AWP1 alters the TNF-α response of non-aggressive breast cancer cells by potentiating ROS-dependent NF-κB activation.
NRBP2 Functions as a Tumor Suppressor and Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer
Authors: Li Zhiyu , Liu Bingxiong , Li Chenyuan , Sun Si , Zhang Hanpu , Sun Shengrong , Wang Zhong , Zhang Xiongjie
Published: March 2021

Nuclear Receptor Binding Protein 2 (NRBP2), one of the pseudokinases discovered during a screen of neural differentiation genes, inhibits tumor progression in medulloblastoma and hepatocellular carcinoma. However, the role and the mechanism of NRBP2 in the regulation of the progression of breast cancer (BC) have not been reported. In our study, NRBP2 was downregulated in human BC tissues compared with the corresponding normal tissues. Moreover, bioinformatics and cellular experiments illustrated that a lower level of NRBP2 contributed to a poor prognosis for patients with BC. In addition, we characterized the NRBP2-overexpressing BC cells and found that NRBP2 overexpression dramatically suppressed cell proliferation and invasion and inhibited the epithelial-mesenchymal transition (EMT) in cells in vitro, whereas knockdown of NRBP2 reversed these effects. Furthermore, overexpression of NRBP2 in the orthotopic breast tumor model significantly reduced lung metastatic nodules in nude mice. Mechanistically, NRBP2 regulated the activation of the 5′-adenosine monophosphate (AMP)-activated protein kinase/ mammalian target of rapamycin (AMPK/mTOR) signaling pathway. Moreover, the inhibition of cell proliferation, invasion and the EMT by NRBP2 overexpression was partially rescued after treatment with an AMPK inhibitor. Conversely, mTOR-specific inhibitors eliminated the effects of NRBP2 knockdown on increasing cell proliferation, invasion and the EMT, which suggested the anti-tumor effect of NRBP2, which may be partially related to the regulation of the AMPK/mTOR pathway. Taken together, NRBP2, a novel and effective prognostic indicator, inhibited the progression of BC and may become a potential therapeutic target for BC.
A Clinical-Radiomics Nomogram Based on Computed Tomography for Predicting Risk of Local Recurrence After Radiotherapy in Nasopharyngeal Carcinoma
Authors: Zhu Chaohua , Huang Huixian , Liu Xu , Chen Hao , Jiang Hailan , Liao Chaolong , Pang Qiang , Dang Junming , Liu Pei , Lu Heming
Published: March 2021

Purpose: We aimed to establish a nomogram model based on computed tomography (CT) imaging radiomic signature and clinical factors to predict the risk of local recurrence in nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT).

Methods: This was a retrospective study consisting of 156 NPC patients treated with IMRT. Radiomics features were extracted from the gross tumor volume for nasopharynx (GTVnx) in pretreatment CT images for patients with or without local recurrence. Discriminative radiomics features were selected after t-test and the least absolute shrinkage and selection operator (LASSO) analysis. The most stable model was obtained to generate radiomics signature (Rad_Score) by using machine learning models including Logistic Regression, K-Nearest neighbor, Naive Bayes, Decision Tree, Stochastic Gradient Descent, Gradient Booting Tree and Linear Support Vector Classification. A nomogram for local recurrence was established based on Rad_Score and clinical factors. The predictive performance of nomogram was evaluated by discrimination ability and calibration ability. Decision Curve Analysis (DCA) was used to evaluate the clinical benefits of the multi-factor nomogram in predicting local recurrence after IMRT.

Results: Local recurrence occurred in 42 patients. A total of 1,452 radiomics features were initially extracted and seven stable features finally selected after LASSO analysis were used for machine learning algorithm modeling to generate Rad_Score. The nomogram showed that the greater Rad_Score was associated with the higher risk of local recurrence. The concordance index, specificity and sensitivity in the training cohort were 0.931 (95%CI:0.8765–0.9856), 91.2 and 82.8%, respectively; whereas, in the validation cohort, they were 0.799 (95%CI: 0.6458–0.9515), 79.4, and 69.2%, respectively.

Conclusion: The nomogram based on radiomics signature and clinical factors can predict the risk of local recurrence after IMRT in patients with NPC and provide evidence for early clinical intervention.
The Promise of Liquid Biopsy to Predict Response to Immunotherapy in Metastatic Melanoma
Authors: Fattore Luigi , Ruggiero Ciro Francesco , Liguoro Domenico , Castaldo Vittorio , Catizone Angiolina , Ciliberto Gennaro , Mancini Rita
Published: March 2021

Metastatic melanoma is the deadliest form of skin cancer whose incidence has been rising dramatically over the last few decades. Nowadays, the most successful approach in treating advanced melanoma is immunotherapy which encompasses the use of immune checkpoint blockers able to unleash the immune system’s activity against tumor cells. Immunotherapy has dramatically changed clinical practice by contributing to increasing long term overall survival. Despite these striking therapeutic effects, the clinical benefits are strongly mitigated by innate or acquired resistance. In this context, it is of utmost importance to develop methods capable of predicting patient response to immunotherapy. To this purpose, one major step forward may be provided by measuring non-invasive biomarkers in human fluids, namely Liquid Biopsies (LBs). Several LB approaches have been developed over the last few years thanks to technological breakthroughs that have allowed to evaluate circulating components also when they are present in low abundance. The elements of this so-called “circulome” mostly encompass: tumor DNA, tumor and immune cells, soluble factors and non-coding RNAs. Here, we review the current knowledge of these molecules as predictors of response to immunotherapy in metastatic melanoma and predict that LB will soon enter into routine practice in order to guide clinical decisions for cancer immunotherapy.
Survival Benefits of Anti-PD-1 Therapy in Combination With Radiotherapy in Chinese Melanoma Patients With Brain Metastasis
Authors: Wu Shuang , Yuan Chuanping , Chen Lei , Guo Lanlan , Chen Yong , Peng Zhenwei , Lu Lixia
Published: March 2021

Limited data reported the synergistic anti-tumor effect of anti-PD-1 (programmed death 1) therapy and radiotherapy on melanoma BM (brain metastasis). And the efficacy in the Chinese population is unclear. This study aimed to evaluate the efficacy of anti-PD-1 therapy and radiotherapy in Chinese melanoma patients with BM. We retrospectively reviewed 96 consecutive melanoma patients with BM treated at Sun Yat-Sen University Cancer Center. Patient demographics, BM characteristics and treatment details were carefully collected. The intracranial PFS (progression free survival) and OS (overall survival) were estimated using the Kaplan-Meier method. Twenty-five patients were treated with anti-PD-1 therapy and radiotherapy. Eighteen (72.0%) patients had SBRT (stereotactic body radiation therapy) or SRS (stereotactic radiosurgery) for BM, 1 (4.0%) patient had WBRT (whole brain radiation therapy), 6 (24.0%) patients had SBRT/SRS and WBRT. The median treatment period of anti-PD-1 therapy was 10.77 months. Objective intracranial response was observed in 15 (60%) patients, and 5 (20%) patients achieved CR (complete response). After a median follow-up of 16 months, 11 (44%) patients experienced intracranial PD (progressive disease), and 15 (60%) patients died. The median intracranial PFS and OS were 10.73 months (range, 1.67–38.83 months) and 15.87 months (range, 2.47–41.50 months), respectively. The 1-year intracranial PFS and OS were 61.9% (95% CI, 44.1–86.9%) and 62.5% (95%CI, 45.8–85.2%), respectively. Patients with BM can benefit from a combination of anti-PD-1 therapy and radiotherapy. It merits further investigation in melanoma patients with BM.
Differences in Tumor Immune Microenvironment in Metastatic Sites of Breast Cancer
Authors: Lee Hyunjong , Na Kwon Joong , Choi Hongyoon
Published: March 2021

Introduction: Tumor immune microenvironment (TIME) promotes immune escape, allowing for tumor progression and metastasis. In spite of the current evidence of the complicated role of immune cells in promoting or suppressing cancer progression, the heterogeneity of TIME according to the tumor site has been scarcely investigated. Here, we analyzed transcriptomic profiles of metastatic breast cancer to understand how TIME varies according to tumor sites.

Methods: Two gene expression datasets from metastatic breast cancer of various sites and a single-cell RNA sequencing dataset of primary breast cancer and metastatic lymph nodes were analyzed. The immune cell-type enrichment of each tumor was estimated. Immune cell types were identified by clustering analysis, and the proportions of cell types in TIME were assessed according to the tumor site.

Results: Metastatic bone lesions showed more neutrophils than breast lesions. Tumors clustered according to immune cell type were significantly associated with tumor site. In single-cell analyses, the TIMEs of metastatic lymph nodes showed fewer macrophages than those of primary tumors. Differentially expressed gene signatures in the primary tumor and metastatic lymph nodes were associated with macrophage activation.

Conclusion: We conclude that metastatic sites show variable enrichment patterns of immune cells, and that the TIME of metastatic lesions should be considered in precise immuno-oncology treatments.
Case Report: EBV-Positive Extra-Nodal Marginal Zone Lymphoma Associated With XMEN Disease Caused by a Novel Hemizygous Mutation in MAGT1
Authors: Huang Xin , Liu Dan , Gao Zifen , Liu Cuiling
Published: March 2021

Background

X-linked immunodeficiency with magnesium defect and Epstein-Barr virus infection and neoplasia (XMEN) disease is an X-linked genetic disorder of immune system caused by loss-of-function mutation in gene encoding Magnesium transporter 1 (MAGT1). Individuals with XMEN disease are prone to developing Epstein Barr Virus (EBV)-associated lymphomas. Herein, we report the first known case of an EBV+ EMZL associated with XMEN disease.

Case presentation

The patient was an 8-year-old Chinese boy who suffered from recurrent infections from birth. Six months before, the patient presented with a painless mass on his upper lip and excisional biopsy revealed an EBV-positive extra-nodal marginal zone lymphoma (EBV+ EMZL). Furthermore, molecular investigations with next-generation sequencing identified a novel germline mutation in MAGT1 (c.828_829insAT) in the patient. The c.828_829insAT variant was predicted to cause premature truncation of MAGT1 (p.A277M.fs*11) and consequently was defined as likely pathogenic. The mutation was inherited from his asymptomatic heterozygous carrier mother. Hence the patient was diagnosed with an XMEN disease both clinically and genetically.

Conclusion

Our results expand the genetic spectrum of XMEN disease and also the clinical spectrum of EBV+ EMZL. We highlight the importance of the genetic etiology underlying EBV+ lymphoma in the pediatric population.
Characteristics of Children With Kawasaki Disease-Like Signs in COVID-19 Pandemic: A Systematic Review
Authors: Mardi Parham , Esmaeili Marzieh , Iravani Parisa , Abdar Mohammad Esmail , Pourrostami Kumars , Qorbani Mostafa
Published: March 2021

Recent studies have shown that several children diagnosed with COVID-19 have developed Kawasaki Disease (KD)-like symptoms. This systematic review aims to assess the demographic, laboratory, and clinical characteristics of children with KD-like syndrome during the COVID-19 pandemic and evaluate efficacy of treatments and patients' outcome. A comprehensive search was carried out systematically through PubMed, Scopus, and Web of Science (WoS), medRxiv, and bioRxiv by two reviewers independently for all studies or preprints data on the demographic, laboratory, and clinical characteristics of children with K.D-like signs during the COVID-19 outbreak. Overall, 378 studies were identified by the systematic search, of which 25 studies were included in the study. The included studies involved 599 patients in total. Thirteen studies (52%) were case reports or case series, and the rest (48%) were cohort studies. In 19 studies, patients were diagnosed with Multisystem inflammatory syndrome in children (MIS-C). In 16 studies COVID-19 was diagnosed in all patients based on their polymerase chain reaction result, serological findings, and computed tomography results. Higher C-reactive protein and erythrocyte sedimentation rate level were the most prevalent laboratory findings. In most studies, patients had leucopenia with marked lymphopenia, hypoalbuminemia, and increased ferritin, as well as hyponatremia. Abnormal echocardiography and respiratory outcomes were the most common clinical outcomes. In 11 studies, all patients required intensive care unit admission. Findings of the present systematic review show that the incidence of KD-like syndrome in the COVID-19 pandemic increased significantly. Moreover, this study offers new insights in the KD-like syndrome pathogenesis and clinical spectrum during COVID-19 pandemic.
The Influence of Treatment of Inflammatory Arthritis During Pregnancy on the Long-Term Children’s Outcome
Authors: Nalli Cecilia , Galli Jessica , Lini Daniele , Merlini Angela , Piantoni Silvia , Lazzaroni Maria Grazia , Bitsadze Victoria , Khizroeva Jamilya , Zatti Sonia , Andreoli Laura , Fazzi Elisa , Franceschini Franco , Makatsariya Alexander , Shoenfeld Yehuda , Tincani Angela
Published: March 2021

The management of reproductive issues in women with inflammatory arthritis has greatly changed over decades. In the 1980–1990s, women with refractory forms of arthritis were either not able to get pregnant or did choose not to get pregnant because of their disabling disease. Hence, the traditional belief that pregnancy can induce a remission of arthritis. The availability of biologic agents has allowed a good control of aggressive forms of arthritis. The main topic of discussion during preconception counselling is the use of drugs during pregnancy and breastfeeding. Physicians are now supported by international recommendations released by the European League Against Rheumatism and the American College of Rheumatology, but still they must face with cultural reluctance in accepting that a pregnant woman can take medications. Patient-physician communication should be centered on the message that active maternal disease during pregnancy is detrimental to fetal health. Keeping maternal disease under control with drugs which are not harmful to the fetus is the best way to ensure the best possible outcome for both the mother and the baby. However, there might be concerns about the influence of the in utero exposure to medications on the newborn’s health conditions. Particularly, studies suggesting an increased risk of autism-spectrum-disorders in children born to women with rheumatoid arthritis has raised questions about neuropsychological impairment in the offspring of women with chronic arthritis. As a multidisciplinary group of rheumatologists and child neuropsychiatrists, we conducted a study on 16 women with chronic forms of arthritis whose diagnosis was determined before pregnancy and their 18 school-age children. The children underwent a complete neurological examination and validated tests/questionnaires. Behavioral aspects of somatization and anxiety/depression (internalizing problem) or an “adult profile” were found in nearly one third of children. Children at a high risk of neurodevelopmental problems were born to mothers with a longer history of arthritis and were breastfeed for less than 6 months of age or were not breastfeed at all. No association was found with other maternal characteristics such as autoantibody existence and disease activity during and after the pregnancy.
Photomorphogenesis in the Picocyanobacterium Cyanobium gracile Includes Increased Phycobilisome Abundance Under Blue Light, Phycobilisome Decoupling Under Near Far-Red Light, and Wavelength-Specific Photoprotective Strategies
Authors: Bernát Gábor , Zavřel Tomáš , Kotabová Eva , Kovács László , Steinbach Gábor , Vörös Lajos , Prášil Ondřej , Somogyi Boglárka , Tóth Viktor R.
Published: March 2021

Photomorphogenesis is a process by which photosynthetic organisms perceive external light parameters, including light quality (color), and adjust cellular metabolism, growth rates and other parameters, in order to survive in a changing light environment. In this study we comprehensively explored the light color acclimation of Cyanobium gracile, a common cyanobacterium in turbid freshwater shallow lakes, using nine different monochromatic growth lights covering the whole visible spectrum from 435 to 687 nm. According to incident light wavelength, C. gracile cells performed great plasticity in terms of pigment composition, antenna size, and photosystem stoichiometry, to optimize their photosynthetic performance and to redox poise their intersystem electron transport chain. In spite of such compensatory strategies, C. gracile, like other cyanobacteria, uses blue and near far-red light less efficiently than orange or red light, which involves moderate growth rates, reduced cell volumes and lower electron transport rates. Unfavorable light conditions, where neither chlorophyll nor phycobilisomes absorb light sufficiently, are compensated by an enhanced antenna size. Increasing the wavelength of the growth light is accompanied by increasing photosystem II to photosystem I ratios, which involve better light utilization in the red spectral region. This is surprisingly accompanied by a partial excitonic antenna decoupling, which was the highest in the cells grown under 687 nm light. So far, a similar phenomenon is known to be induced only by strong light; here we demonstrate that under certain physiological conditions such decoupling is also possible to be induced by weak light. This suggests that suboptimal photosynthetic performance of the near far-red light grown C. gracile cells is due to a solid redox- and/or signal-imbalance, which leads to the activation of this short-term light acclimation process. Using a variety of photo-biophysical methods, we also demonstrate that under blue wavelengths, excessive light is quenched through orange carotenoid protein mediated non-photochemical quenching, whereas under orange/red wavelengths state transitions are involved in photoprotection.
Genome-Wide Analysis of the Catharanthus roseus RLK1-Like in Soybean and GmCrRLK1L20 Responds to Drought and Salt Stresses
Authors: Wang Zhi-Qi , Yu Tai-Fei , Sun Guo-Zhong , Zheng Jia-Cheng , Chen Jun , Zhou Yong-Bin , Chen Ming , Ma You-Zhi , Wei Wen-Liang , Xu Zhao-Shi
Published: March 2021

Abiotic stresses, such as drought and salinity, severely affects the growth, development and productivity of the plants. The Catharanthus roseus RLK1-like (CrRLK1L) protein kinase family is involved in several processes in the plant life cycle. However, there have been few studies addressing the functions of CrRLK1L proteins in soybean. In this study, 38 CrRLK1L genes were identified in the soybean genome (Glycine max Wm82.a2.v1). Phylogenetic analysis demonstrated that soybean CrRLK1L genes were grouped into clusters, cluster I, II, III. The chromosomal mapping demonstrated that 38 CrRLK1L genes were located in 14 of 20 soybean chromosomes. None were discovered on chromosomes 1, 4, 6, 7, 11, and 14. Gene structure analysis indicated that 73.6% soybean CrRLK1L genes were characterized by a lack of introns.15.7% soybean CrRLK1L genes only had one intron and 10.5% soybean CrRLK1L genes had more than one intron. Five genes were obtained from soybean drought- and salt-induced transcriptome databases and were found to be highly up-regulated. GmCrRLK1L20 was notably up-regulated under drought and salinity stresses, and was therefore studied further. Subcellular localization analysis revealed that the GmCrRLK1L20 protein was located in the cell membrane. The overexpression of the GmCrRLK1L20 gene in soybean hairy roots improved both drought tolerance and salt stresses and enhanced the expression of the stress-responsive genes GmMYB84, GmWRKY40, GmDREB-like, GmGST15, GmNAC29, and GmbZIP78. These results indicated that GmCrRLK1L20 could play a vital role in defending against drought and salinity stresses in soybean.
Association Mapping and Transcriptome Analysis Reveal the Genetic Architecture of Maize Kernel Size
Authors: Ma Juan , Wang Lifeng , Cao Yanyong , Wang Hao , Li Huiyong
Published: March 2021

Kernel length, kernel width, and kernel thickness are important traits affecting grain yield and product quality. Here, the genetic architecture of the three kernel size traits was dissected in an association panel of 309 maize inbred lines using four statistical methods. Forty-two significant single nucleotide polymorphisms (SNPs;p< 1.72E-05) and 70 genes for the three traits were identified under five environments. One and eight SNPs were co-detected in two environments and by at least two methods, respectively, and they explained 5.87–9.59% of the phenotypic variation. Comparing the transcriptomes of two inbred lines with contrasting seed size, three and eight genes identified in the association panel showed significantly differential expression between the two genotypes at 15 and 39 days after pollination, respectively. Ten and 17 genes identified by a genome-wide association study were significantly differentially expressed between the two development stages in the two genotypes. Combining environment−/method-stable SNPs and differential expression analysis, ribosomal protein L7, jasmonate-regulated gene 21, serine/threonine-protein kinase RUNKEL, AP2-EREBP-transcription factor 16, and Zm00001d035222 (cell wall protein IFF6-like) were important candidate genes for maize kernel size and development.
Teams in Small Organizations: Conceptual, Methodological, and Practical Considerations
Authors: Reiter-Palmon Roni , Kennel Victoria , Allen Joseph A.
Published: March 2021

Research on teams and teamwork has flourished in the last few decades. Much of what we know about teams and teamwork comes from research using short-term student teams in the lab, teams in larger organizations, and, more recently, teams in rather unique and extreme environments. The context in which teams operate influences team composition, processes, and effectiveness. Small organizations are an understudied and often overlooked context that presents a rich opportunity to augment our understanding of teams and team dynamics. In this paper, we discuss how teams and multi-team systems in small organizations may differ from those found in larger organizations. Many of these differences present both methodological and practical challenges to studying team composition and processes in small complex organizational settings. We advocate for applying and accepting new and less widely used methodological approaches to advance our understanding of the science of teams and teamwork in such contexts.