bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of methylation-driven genes prognosis signature and immune microenvironment in uterus corpus endometrial cancer
Authors: Liu JinHui , Ji ChengJian , Wang Yichun , Zhang Cheng , Zhu HongJun
Published: July 2021

Background

Uterus corpus endometrial cancer (UCEC) is the main malignant tumor in gynecology, with a high degree of heterogeneity, especially in terms of prognosis and immunotherapy efficacy. DNA methylation is one of the most important epigenetic modifications. Studying DNA methylation can help predict the prognosis of cancer patients and provide help for clinical treatment. Our research aims to discover whether abnormal DNA methylation can predict the prognosis of UCEC and reflect the patient's tumor immune microenvironment.

Patients and methods

The clinical data, DNA methylation data, gene expression data and somatic mutation data of UCEC patients were all downloaded from the TCGA database. The MethylMix algorithm was used to integrate DNA methylation data and mRNA expression data. Univariate Cox regression analysis, Multivariate Cox regression analysis, and Lasso Cox regression analysis were used to determine prognostic DNA methylation-driven genes and to construct an independent prognostic index (MDS). ROC curve analysis and Kaplan–Meier survival curve analysis were used to evaluate the predictive ability of MDS. GSEA analysis was used to explore possible mechanisms that contribute to the heterogeneity of the prognosis of UCEC patients.

Results

3 differential methylation-driven genes (DMDGs) (PARVG, SYNE4 and CDO1) were considered as predictors of poor prognosis in UCEC. An independent prognostic index was finally established based on 3 DMDGs. From the results of ROC curve analysis and survival curve analysis, MDS showed excellent prognostic ability in TCGA-UCEC. A new nomogram based on MDS and other prognostic clinical indicators has also been successfully established. The C-index of the nomogram for OS prediction was 0.764 (95% CI = 0.702–0.826). GSEA analysis suggests that there were differences in immune-related pathways among patients with different prognosis. The abundance of M2 macrophages and M0 macrophages were significantly enhanced in the high-risk group while T cells CD8, Eosinophils and Neutrophils were markedly elevated in the low-risk group. Meanwhile, patients in the low-risk group had higher levels of immunosuppressant expression, higher tumor mutational burden and immunophenoscore (IPS) scores. Joint survival analysis revealed that 7 methylation-driven genes could be independent prognostic factors for overall survival for UCEC.

Conclusion

We have successfully established a risk model based on 3 DMDGs, which could accurately predict the prognosis of patients with UCEC and reflect the tumor immune microenvironment.
Markov chain Monte Carlo Gibbs sampler approach for estimating haplotype frequencies among multiple malaria infected human blood samples
Authors: Ken-Dror Gie , Sharma Pankaj
Published: July 2021

Background

Malaria patients can have two or more haplotypes in their blood sample making it challenging to identify which haplotypes they carry. In addition, there are challenges in measuring the type and frequency of resistant haplotypes in populations. This study presents a novel statistical method Gibbs sampler algorithm to investigate this issue.

Results

The performance of the algorithm is evaluated on simulated datasets consisting of patient blood samples characterized by their multiplicity of infection (MOI) and malaria genotype. The simulation used different resistance allele frequencies (RAF) at each Single Nucleotide Polymorphisms (SNPs) and different limit of detection (LoD) of the SNPs and the MOI. The Gibbs sampler algorithm presents higher accuracy among high LoD of the SNPs or the MOI, validated, and deals with missing MOI compared to previous related statistical approaches.

Conclusions

The Gibbs sampler algorithm provided robust results when faced with genotyping errors caused by LoDs and functioned well even in the absence of MOI data on individual patients.
Residual malaria in Jazan region, southwestern Saudi Arabia: the situation, challenges and climatic drivers of autochthonous malaria
Authors: Al-Mekhlafi Hesham M. , Madkhali Aymen M. , Ghailan Khalid Y. , Abdulhaq Ahmed A. , Ghzwani Ahmad Hassn , Zain Khalid Ammash , Atroosh Wahib M. , Alshabi Alkhansa , Khadashi Hussein A. , Darraj Majid A. , Eisa Zaki M.
Published: July 2021

Background

Saudi Arabia and Yemen are the only two countries in the Arabian Peninsula that are yet to achieve malaria elimination. Over the past two decades, the malaria control programme in Saudi Arabia has successfully reduced the annual number of malaria cases, with the lowest incidence rate across the country reported in 2014. This study aims to investigate the distribution of residual malaria in Jazan region and to identify potential climatic drivers of autochthonous malaria cases in the region.

Methods

A cross-sectional study was carried out from 1 April 2018 to 31 January 2019 in Jazan region, southwestern Saudi Arabia, which targeted febrile individuals attending hospitals and primary healthcare centres. Participants’ demographic data were collected, including age, gender, nationality, and residence. Moreover, association of climatic variables with the monthly autochthonous malaria cases reported during the period of 2010–2017 was retrospectively analysed.

Results

A total of 1124 febrile subjects were found to be positive for malaria during the study period. Among them, 94.3 and 5.7% were infected with Plasmodium falciparum and Plasmodium vivax, respectively. In general, subjects aged 18–30 years and those aged over 50 years had the highest (42.7%) and lowest (5.9%) percentages of malaria cases. Similarly, the percentage of malaria-positive cases was higher among males than females (86.2 vs 13.8%), among non-Saudi compared to Saudi subjects (70.6 vs 29.4%), and among patients residing in rural rather than in urban areas (89.8 vs 10.2%). A total of 407 autochthonous malaria cases were reported in Jazan region between 2010 and 2017. Results of zero-inflated negative binomial regression analysis showed that monthly average temperature and relative humidity were the significant climatic determinants of autochthonous malaria in the region.

Conclusion

Malaria remains a public health problem in most governorates of Jazan region. The identification and monitoring of malaria transmission hotspots and predictors would enable control efforts to be intensified and focused on specific areas and therefore expedite the elimination of residual malaria from the whole region.
Association between egg consumption and arterial stiffness: a longitudinal study
Authors: Ji Naiwen , Huang Zhe , Zhang Xinyuan , Sun Yuanyuan , Ye Shumao , Chen Shuohua , Tucker Katherine L. , Wu Shouling , Gao Xiang
Published: July 2021

Background

Inconsistent associations between egg consumption and cardiovascular disease (CVD) risk have been observed in previous studies. This study aims to longitudinally investigate the association between egg consumption and altered risk of arterial stiffness, a major pre-clinical pathogenic change of CVD, which was assessed by brachial-ankle pulse wave velocity (baPWV).

Methods

A total of 7315 Chinese participants from the Kailuan Study, free of CVD and cancer were included in this study. Egg consumption was assessed by a semi-quantitative validated food frequency questionnaire in 2014. baPWV was repeatedly measured at baseline and during follow-up (mean follow-up: 3.41 years). General linear regression was used to calculate means of baPWV change rate across different egg consumption groups, adjusting for age, sex, baseline baPWV, healthy eating index, total energy, social-economic status, blood pressure, obesity, smoking, lipid profiles, and fasting glucose concentrations.

Results

Compared to the annual baPWV change rate in participants with 0–1.9 eggs/wk. (adjusted mean: 35.9 ± 11.2 cm/s/y), those consuming 3–3.9 eggs/wk. (adjusted mean: 0.2 ± 11.4 cm/s/y) had the lowest increase in baPWV during follow-up (P-difference = 0.002). Individuals with low (0–1.9 eggs/wk) vs. high (5+ eggs /wk) egg intake showed similar changes in baPWV.

Conclusions

In this large-scale longitudinal analysis, we did not find a significant difference in arterial stiffness, as assessed by baPWV level, between low and high egg consumption groups. However, moderate egg consumption (3–3.9 eggs/wk) appeared to have beneficial effects on arterial stiffness.
LDL mediated delivery of Paclitaxel and MRI imaging probes for personalized medicine applications
Authors: Rakhshan Sahar , Alberti Diego , Stefania Rachele , Bitonto Valeria , Geninatti Crich Simonetta
Published: July 2021

Background

The combination of imaging and therapeutic agents in the same smart nanoparticle is a promising option to perform a minimally invasive imaging guided therapy. In this study, Low density lipoproteins (LDL), one of the most attractive biodegradable and biocompatible nanoparticles, were used for the simultaneous delivery of Paclitaxel (PTX), a hydrophobic antitumour drug and an amphiphilic contrast agent, Gd-AAZTA-C17, in B16-F10 melanoma cell line. These cells overexpress LDL receptors, as assessed by flow cytometry analysis.

Results

PTX and Gd-AAZTA-C17 loaded LDLs (LDL-PTX-Gd) have been prepared, characterized and their stability was assessed under 72 h incubation at 37 °C and compared to LDL loaded with Gd-AAZTA-C17 (LDL-Gd) and LDL-PTX. The cytotoxic effect of LDL-PTX-Gd was evaluated by MTT assay. The anti-tumour drug loaded into LDLs showed a significantly higher toxicity on B16-F10 cells with respect to the commercially available formulation Paclitaxel kabi (PTX Kabi) used in clinical applications. Tumour cells uptake was initially assessed by ICP-MS and MRI on B16-F10 cell line. By the analysis of the image signal intensity, it was possible to extrapolate the amount of internalized PTX indirectly by the decrease of relaxation times caused by Gd, proportional to its concentration. Finally, the treatment with PTX loaded LDL on B16-F10 tumour bearing mice resulted in a marked reduction of tumour growth compared to the administration of PTX Kabi alone.

Conclusions

LDLs are selectively taken-up by tumour cells and can be successfully exploited for the selective delivery of Paclitaxel and imaging agents. For the first time the anon invasive “in vivo” determination of the amount of PTX accumulated in the tumour was possible, thanks to the use of theranostic agents of natural origin.

Graphic abstract
Bone mesenchymal stem cells stimulation by magnetic nanoparticles and a static magnetic field: release of exosomal miR-1260a improves osteogenesis and angiogenesis
Authors: Wu Di , Chang Xiao , Tian Jingjing , Kang Lin , Wu Yuanhao , Liu Jieying , Wu Xiangdong , Huang Yue , Gao Bo , Wang Hai , Qiu Guixing , Wu Zhihong
Published: July 2021

Background

The therapeutic potential of exosomes derived from stem cells has attracted increasing interest recently, because they can exert similar paracrine functions of stem cells and overcome the limitations of stem cells transplantation. Exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been confirmed to promote osteogenesis and angiogenesis. The magnetic nanoparticles (eg. Fe3O4, γ-Fe2O3) combined with a static magnetic field (SMF) has been commonly used to increase wound healing and bone regeneration. Hence, this study aims to evaluate whether exosomes derived from BMSCs preconditioned with a low dose of Fe3O4 nanoparticles with or without the SMF, exert superior pro-osteogenic and pro-angiogenic activities in bone regeneration and the underlying mechanisms involved.

Methods

Two novel types of exosomes derived from preconditioned BMSCs that fabricated by regulating the contents with the stimulation of magnetic nanoparticles and/or a SMF. Then, the new exosomes were isolated by ultracentrifugation and characterized. Afterwards, we conducted in vitro experiments in which we measured osteogenic differentiation, cell proliferation, cell migration, and tube formation, then established an in vivo critical-sized calvarial defect rat model. The miRNA expression profiles were compared among the exosomes to detect the potential mechanism of improving osteogenesis and angiogenesis. At last, the function of exosomal miRNA during bone regeneration was confirmed by utilizing a series of gain- and loss-of-function experiments in vitro.

Results

50 µg/mL Fe3O4 nanoparticles and a 100 mT SMF were chosen as the optimum magnetic conditions to fabricate two new exosomes, named BMSC-Fe3O4-Exos and BMSC-Fe3O4-SMF-Exos. They were both confirmed to enhance osteogenesis and angiogenesis in vitro and in vivo compared with BMSC-Exos, and BMSC-Fe3O4-SMF-Exos had the most marked effect. The promotion effect was found to be related to the highly riched miR-1260a in BMSC-Fe3O4-SMF-Exos. Furthermore, miR-1260a was verified to enhance osteogenesis and angiogenesis through inhibition of HDAC7 and COL4A2, respectively.

Conclusion

These results suggest that low doses of Fe3O4 nanoparticles combined with a SMF trigger exosomes to exert enhanced osteogenesis and angiogenesis and that targeting of HDAC7 and COL4A2 by exosomal miR-1260a plays a crucial role in this process. This work could provide a new protocol to promote bone regeneration for tissue engineering in the future.

Graphical abstract
The MCM3AP-AS1/miR-126/VEGF axis regulates cancer cell invasion and migration in endometrioid carcinoma
Authors: Yu Jie , Fan Qiqi , Li Lingling
Published: July 2021

Background

Long non-coding RNA (lncRNA) MCM3AP-AS1 plays an oncogenic role in several malignancies, but its role in endometrioid carcinoma (EC) is unclear. This study was carried out to explore the role of MCM3AP-AS1 in EC.

Methods

A total of 60 EC patients were enrolled in this study. Expression levels of MCM3AP Antisense RNA 1 (MCM3AP-AS1), microRNA-126 (miR-126), and vascular endothelial growth factor (VEGF) in tissues and transfetced cells were measured by RT-qPCR. Cell transfections were performed to explore the interaction among MCM3AP-AS1, miR-126 and VEGF. Transwell assays were perfromed to evaluate the invasion and migration abilities of HEC-1 cells after transfection.

Results

MCM3AP-AS1 was upregulated in EC and predicted poor survival. MCM3AP-AS1 directly interacted with miR-126. In EC cells, overexpression of MCM3AP-AS1 and miR-126 did not significantly affect the expression of each other. In addition, overexpression of MCM3AP-AS1 increased the expression levels of VEGF, a target of miR-126. Moreover, overexpression of MCM3AP-AS1 and VEGF increased the migration and invasion rates of EC cells, while overexpression of miR-126 suppressed these cell behaviors. Overexpression of MCM3AP-AS1 attenuated the role of miR-126 in cell invasion and migration.

Conclusions

Therefore, MCM3AP-AS1 may serve as a competing endogenous RNA (ceRNA) of miR-126 to upregulate VEGF, thereby regulating cancer cell behaviors in EC.
MiR-191-5p is upregulated in culture media of implanted human embryo on day fifth of development
Authors: Acuña-González Ricardo Josué , Olvera-Valencia Mercedes , López-Canales Jorge Skiold , Lozano-Cuenca Jair , Osorio-Caballero Mauricio , Flores-Herrera Héctor
Published: July 2021

Background

Morphological features are the most common criteria used to select human embryos for transfer to a receptive uterine cavity. However, such characteristics are not valid for embryos in cellular arrest. Even aneuploid embryos can have normal morphology, and some euploid embryos have aberrant morphology. The aim of this study was to quantify the expression profile of hsa-miR-21-3p, -24-1-5p, -191-5p, and -372-5pin culture media on day 5 ofin vitroembryo development, and compare the profiles of two groups of media classified by outcome: successful (n = 25) or unsuccessful (n = 25) implantation pregnancy.

Methods

Fifty patients were accepted in the Department of Reproductive Biology of a Hospital in México City, based on the Institutional inclusion criteria forin vitrofertilization. Embryos were transferred to the women on day 5 of cultivation, and the culture media were collected. RNA was isolated from each culture medium with TRIzol reagent, and microRNA (miRNA) expression was detected through RT-PCR with specific primers. Expression bands were quantified by reading optical density.

Results

There was a 5.2-fold greater expression of hsa-miR-191-5pin the pregnancy-related culture media (p ≤ 0.001) and a 1.6-fold greater level of hsa-miR-24-1-5p(p = 0.043) in the media corresponding to non-pregnant women. No significant difference existed between the two groups hsa-miR-21-3p(p = 0.38) or hsa-miR-372-5p(p = 0.41).

Conclusions

Regarding adequatein vitroembryo development, hsa-miR-191-5pcould possibly represent a positive biomarker, while has-miR-24-1-5pmay indicate poor prognosis. This former miRNA modulates IGF2BP-1 and IGF2R, associated with the implantation window. On the other hand, hsa-miR-24-1-5pmay be related to a poor prognosis of human embryo development.
Determinant factors for adherence to antiretroviral therapy among adult HIV patients at Dessie Referral Hospital, South Wollo, Northeast Ethiopia: a case–control study
Authors: Abdu Mehd , Walelgn Betelhem
Published: July 2021

Introduction

World health organization defined adherence as the extent to which a person’s behavior – taking medications, following a diet, or executing lifestyle changes correspond with agreed recommendations from the health care provider. There is a contradiction among studies and previous studies conducted in the study area used a cross-sectional study design. This study aimed to identify determinant factors for adherence to antiretroviral treatment among people living with HIV at Dessie Referral Hospital by using an unmatched case–control study design.

Methods and materials

an institution-based unmatched case–control study design was used on a total sample of 582 (146 controls and 436 cases). Each respondent was selected by consecutive random sampling. The collected data were entered and analyzed by using Statistical Package for Social Science version 25.0. Multivariable binary logistic regression analysis was used to identify variables that were statistically significant determinants.

Result

The mean age of the respondents was 41.64 years. About 61.5% of the participants were females. Patients with baseline HIV stage I was more likely to be adherent to the prescribed HIV medicine (AOR: 2.194 95% CI: 1.116, 4.314) as compared with those with baseline WHO stage IV. Patients who did not take anti-tuberculosis medication collaterally with the prescribed HIV medicine were more likely to be adherent (AOR: 2.271 95% CI: 1.257, 4.102). Patients who took antiretroviral therapy for more than 24 months were more likely to be adherent (AOR: 3.665 95% CI: 1.321, 10.170).

Conclusion

Initiation of antiretroviral therapy at the later stage of the disease and taking anti-tuberculosis concomitantly were negatively associated with adherence. Being on antiretroviral therapy for a longer duration has a positive association. Health facilities and professionals should strictly apply strategies for the prevention of tuberculosis among HIV patients to avoid concomitant use of anti-tuberculosis medications.
Fluorescence of ocular surface in a Covid -19 patient after Favipiravir treatment: a case report
Authors: Doran Mehmet Ali , Aytogan Hasan , Ayıntap Emre
Published: July 2021

Background

Favipiravir is used in treatment of Covid-19 patients. We aimed to share of ocular surface fluorescence in a patient after Favipiravir treatment in this case report.

Case presentation

A 20-year-old male patient declared no known systemic disease prior to Covid-19. He applied to us with blurry vision and blue light reflection after Covid-19 treatment with Favipiravir. We observed bilateral fluorescence on his eyes and fluorescence of his nails. Biomicroscopic examination was insignificant.

Conclusion

We investigated the fluorescence of favipiravir tablets under ultraviolet light. Drug demonstrated fluorescence. We recorded the favipiravir fluorescence in-vitro. This appears to be a strong evidence in terms of the linkage between the fluorescence of the ocular surface and favipiravir.
Novel TNC-PDGFD fusion in fibrosarcomatous dermatofibrosarcoma protuberans: a case report
Authors: Chen Yuan , Shi Ying-zhou , Feng Xiao-he , Wang Xiao-tong , He Xiang-lei , Zhao Ming
Published: July 2021

Background

Dermatofibrosarcoma protuberans (DFSP) is a superficial fibroblastic tumor characterized by high rate of local recurrence and low metastatic potential. Fibrosarcomatous transformation can rarely arise in DFSP either de novo or as recurrent, which represents a form of tumor progression and carries an increased risk of metastasis over classic DFSP. Cytogenetically, DFSP is characterized by a recurrent unbalanced chromosome translocation t (17;22)(q22;q13), leading to the formation of COL1A1-PDGFB fusion transcript that is present in more than 90% of cases. Alternative fusions involving the PDGFD with partners of COL6A3 or EMILIN2 have recently been documented in less than 2% of cases. Herein, we report a DFSP with fibrosarcomtous morphology harboring a novel TNC-PDGFD fusion.

Case presentation

A 54-year-old female presented with a slowly growing mass in the right thigh. Excision demonstrated a 2-cm ovoid, well-circumscribed, gray-white, mass. Microscopic examination revealed a partially encapsulated subcutaneous nodule without dermal connection. The neoplasm was composed of cellular and fairly uniform spindle cells with brisk mitoses, arranged in elongated fascicles and herringbone patterns, with focal collagenized stroma. The neoplastic cells were positive for CD34 and smooth muscle actin. Fluorescence in-situ hybridization analyses showed negative for COL1A1-PDGFB fusion as well as NTRK1/2/3 rearrangements. A subsequent RNA sequencing detected an in-frame fusion between exon 15 of TNC and exon 6 of PDGFD. This fusion was further confirmed by nested reverse transcription polymerase chain reaction amplification followed by Sanger sequencing. A diagnosis of fibrosarcomatous DFSP was rendered and the patient was in good status at a follow-up of 12 months after the operation.

Conclusions

We report a fibrosarcomatous DFSP with novel TNC-PDGFD fusion, which adds to the pathologic and genetic spectrum of PDGFD-rearranged DFSP.
Ethnozoology among the Berbers: pre-Islamic practices survive in the Rif (northwestern Africa)
Authors: Budjaj Aymane , Benítez Guillermo , Pleguezuelos Juan Manuel
Published: July 2021

Background

Ethnozoological knowledge is less documented than ethnobotanical. With this field study, we aim to record and analyze the Riffian Berber knowledge about the use of animals in traditional human and veterinary medicine. Our research question is what is their knowledge of ethnozoological practices?

Methods

We performed semi-structured interviews with local inhabitants in Riffian vernacular language. The reliability of the sampling effort was assessed by a rarefaction curve. Data were compared with previous studies in order to determine the geographical and historical extensions of described uses and possible conservation implications for the species used.

Results

We obtained information regarding 107 ethnozoological uses based on 197 use reports. Among the 31 species used, mammals were most frequently cited. Diseases related to the traditional medicinal system were most frequently treated with these resources, as well as those of the respiratory, digestive, and musculoskeletal systems. Thirty percent of uses are associated with magico-religious practices. Only three of the species used are threatened at the global level, two of them extinct in the study area, indicating low potential damage to regional biodiversity from current practices utilizing native animals. Within modern Morocco, Riffians have continued practicing ethnozoological uses anathema to Islam, like the consumption of animals considered impure (dogs, jackals, wild boars, and hyenas).

Conclusions

The use of primarily mammalian species and of many animal body parts is likely related to the Berber belief in homology between the area of the human body in which the ailment occurs and the corresponding animal body part. These findings unveil the nature of ethnozoological practices, highly linked to folklore and culture-bound conditions, and lacking in the Western empirical rationale for nearly one third of reported uses. The consumption of animals considered impure according to Islam was probably initiated before the conquering of the Maghreb by Arabs in the seventh century and was maintained through the secular isolation of Riffians in mountain areas. This can reflect traditional healing habits being maintained over thousands of years.
Highly efficient Agrobacterium rhizogenes-mediated hairy root transformation for gene functional and gene editing analysis in soybean
Authors: Cheng Yuanyuan , Wang Xiaoli , Cao Li , Ji Jing , Liu Tengfei , Duan Kaixuan
Published: July 2021

Background

Agrobacterium-mediated genetic transformation is a widely used and efficient technique for gene functional research in crop breeding and plant biology. While in some plant species, including soybean, genetic transformation is still recalcitrant and time-consuming, hampering the high-throughput functional analysis of soybean genes. Thus we pursue to develop a rapid, simple, and highly efficient hairy root system induced by Agrobacterium rhizogenes (A. rhizogenes) to analyze soybean gene function.

Results

In this report, a rapid, simple, and highly efficient hairy root transformation system for soybean was described. Only sixteen days were required for the whole workflow and the system was suitable for various soybean genotypes, with an average transformation frequency of 58–64%. Higher transformation frequency was observed when wounded cotyledons from 1-day-germination seeds were inoculated and co-cultivated with A. rhizogenes in 1/2 B5 (Gamborg’ B-5) medium. The addition of herbicide selection to root production medium increased the transformation frequency to 69%. To test the applicability of the hairy root system for gene functional analysis, we evaluated the protein expression and subcellular localization in transformed hairy roots. Transgenic hairy roots exhibited significantly increased GFP fluorescence and appropriate protein subcellular localization. Protein–protein interactions by BiFC (Bimolecular Fluorescent Complimentary) were also explored using the hairy root system. Fluorescence observations showed that protein interactions could be observed in the root cells. Additionally, hairy root transformation allowed soybean target sgRNA screening for CRISPR/Cas9 gene editing. Therefore, the protocol here enables high-throughput functional characterization of candidate genes in soybean.

Conclusion

A rapid, simple, and highly efficient A. rhizogenes-mediated hairy root transformation system was established for soybean gene functional analysis, including protein expression, subcellular localization, protein–protein interactions and gene editing system evaluation.
Complete response to neoadjuvant chemoradiotherapy in rectal cancer is associated with RAS/AKT mutations and high tumour mutational burden
Authors: Stockton Joanne D. , Tee Louise , Whalley Celina , James Jonathan , Dilworth Mark , Wheat Rachel , Nieto Thomas ,   S-CORT Consortium, Geh Ian , Barros-Silva João D. , Beggs Andrew D.
Published: July 2021

Background

Pathological complete response (pathCR) in rectal cancer is beneficial, as up to 75% of patients do not experience regrowth of the primary tumour, but it is poorly understood. We hypothesised that the changes seen in the pre-treatment biopsies of pathCR but not seen in residual tumour after chemoradiotherapy were the determinants of responsiveness.

Methods

Two groups of patients with either complete response (pathCR group, N = 24) or no response (poor response group, N = 24) were retrieved. Pre-treatment biopsies of cancers from these patients underwent high read depth amplicon sequencing for a targeted panel, exome sequencing, methylation profiling and immunohistochemistry for DNA repair pathway proteins.

Results

Twenty four patients who underwent pathCR and twenty-four who underwent poor response underwent molecular characterisation. Patients in the pathCR group had significantly higher tumour mutational burden and neoantigen load, frequent copy number alterations but fewer structural variants and enrichment for driver mutations in the PI3K/AKT/mTOR signalling pathway. There were no significant differences in tumour heterogeneity as measured by MATH score. Methylation analysis demonstrated enrichment for hypomethyation in the PI3K/AKT/mTOR signalling pathway.

Discussion

The phenomenon of pathCR in rectal cancer may be related to immunovisibility caused by a high tumour mutational burden phenotype. Potential therapy resistance mechanisms involve the PI3K/AKT/mTOR signalling pathway, but tumour heterogeneity does not seem to play a role in resistance.
Clinical, molecular and glycophenotype insights in SLC39A8-CDG
Authors: Bonaventura Eleonora , Barone Rita , Sturiale Luisa , Pasquariello Rosa , Alessandrì Maria Grazia , Pinto Anna Maria , Renieri Alessandra , Panteghini Celeste , Garavaglia Barbara , Cioni Giovanni , Battini Roberta
Published: July 2021

Background

SLC39A8, a gene located on chromosome 4q24, encodes for the manganese (Mn) transporter ZIP8 and its detrimental variants cause a type 2 congenital disorder of glycosylation (CDG). The common SLC39A8 missense variant A391T is associated with increased risk for multiple neurological and systemic disorders and with decreased serum Mn. Patients with SLC39A8-CDG present with different clinical and neuroradiological features linked to variable transferrin glycosylation profile. Galactose and Mn supplementation therapy results in the biochemical and clinical amelioration of treated patients.

Results

Here, we report clinical manifestations, neuroradiological features and glycophenotypes associated with novel SLC39A8 variants (c.1048G > A; p.Gly350Arg and c.131C > G; p.Ser44Trp) in two siblings of the same Italian family. Furthermore, we describe a third patient with overlapping clinical features harbouring the homozygous missense variant A391T. The clinical phenotype of the three patients was characterized by severe developmental disability, dystonic postural pattern and dyskinesia with a more severe progression of the disease in the two affected siblings. Neuroimaging showed a Leigh syndrome-like pattern involving the basal ganglia, thalami and white matter. In the two siblings, atrophic cerebral and cerebellum changes consistent with SLC39A8-CDG were detected as well. Serum transferrin isoelectric focusing (IEF) yielded variable results with slight increase of trisialotransferrin isoforms or even normal pattern. MALDI-MS showed the presence of hypogalactosylated transferrin N-glycans, spontaneously decreasing during the disease course, only in one affected sibling. Total serum N-glycome depicted a distinct pattern for the three patients, with increased levels of undergalactosylated and undersialylated precursors of fully sialylated biantennary glycans, including the monosialo-monogalacto-biantennary species A2G1S1.

Conclusions

Clinical, MRI and glycosylation features of patients are consistent with SLC39A8-CDG. We document two novel variants associated with Leigh syndrome-like disease presentation of SLC39A8-CDG. We show, for the first time, a severe neurological phenotype overlapping with that described for SLC39A8-CDG in association with the homozygous A391T missense variant. We observed a spontaneous amelioration of transferrin N-glycome, highlighting the efficacy of MS-based serum glycomics as auxiliary tool for the diagnosis and clinical management of therapy response in patients with SLC39A8-CDG. Further studies are needed to analyse more in depth the influence of SLC39A8 variants, including the common missense variant, on the expression and function of ZIP8 protein, and their impact on clinical, biochemical and neuroradiological features.
Corticosteroid treatment for acute/acute-on-chronic experimental and naturally occurring pancreatitis in several species: a scoping review to inform possible use in dogs
Authors: Bjørnkjær-Nielsen Kari-Anne , Bjørnvad Charlotte Reinhard
Published: July 2021

Acute pancreatitis in dogs is a prevalent disease characterised by mild to severe inflammation. Treatment with anti-inflammatory corticosteroids has been widely debated but is not generally recommended in veterinary medicine. The objective of the present study was to present current evidence on the effect of corticosteroid treatment for acute/acute-on-chronic pancreatitis across species. These findings were then used to evaluate if and how corticosteroid treatment could influence disease outcome in canine acute/acute-on-chronic pancreatitis. A scoping review was performed by searching the Agricola, CAB Abstracts, MEDLINE and Embase databases to identify relevant articles published before June 24, 2021. The inclusion criteria were English language, original research published in a peer-reviewed journal, and investigation of corticosteroid treatment effects on acute/acute-on-chronic pancreatitis by the outcome parameters clinical score, circulating CRP level, hospitalisation duration, mortality and pancreas histopathology. Research on any species was considered. Studies were rated based on the level of evidence, and methodological quality was evaluated based on similarity between groups at baseline, risk of bias and study group size. The reporting method was based on the PRISMA extension for scoping reviews. One thousand nine hundred fifty-four studies were identified, and 31 met the inclusion criteria. Five were canine studies, with 4 investigating experimentally induced pancreatitis; 5 were human clinical studies; and 21 were rodent studies of experimentally induced pancreatitis. The level of evidence ranged between randomised controlled trials and case series, the estimated risk of bias ranged from low to high, and the sample sizes ranged from very small to moderate. Evidence indicates that adding corticosteroid to symptomatic treatment of acute/acute-on-chronic canine pancreatitis could have a positive influence on disease outcome. However, the analysed evidence was based on several species, including both naturally occurring and experimentally induced pancreatitis; thus, the authors suggest that large randomised controlled studies should be performed in dogs with spontaneously occurring acute/acute-on-chronic pancreatitis to further elucidate a potential benefit of corticosteroid treatment.
Successful surgical and medical treatment of a severe, acute epidural bleed in a young dog due to steroid responsive meningitis-arteritis
Authors: Zilli Jessica , Olszewska Agnieszka , Farke Daniela , Schmidt Martin Jürgen
Published: July 2021

Background

Steroid responsive meningitis-arteritis (SRMA) is an immune-mediated disease of the leptomeninges and its associated blood vessels, typically responsive to corticosteroids. Clinically relevant haemorrhage is a rare finding in such patients and for this reason surgical decompression of the spinal cord is normally not considered. The diagnosis of SRMA is supported by serum C-reactive protein (CRP) increase, cerebrospinal fluid (CSF) examination, including cytology (polymorphonuclear pleocytosis in the acute form), nucleated cell-, red blood cell- and protein count, as well as by evaluating CSF and serum IgA concentrations. D-dimer concentrations in serum and CSF should be elevated as well and therefore can be also evaluated as a further diagnostic tool.

Case presentation

A 1.5-year-old mixed breed dog was presented with pyrexia, cervical pain and acute tetraparesis. Magnetic resonance imaging revealed an extradural mass lesion at the level of the sixth cervical vertebra, consistent with a subacute epidural haemorrhage, causing severe compression of the spinal cord. Based on the dog’s signalment, clinical history and results of the blood and CSF analyses (incl. D-dimer determination), SRMA with secondary epidural haemorrhage was suspected. Decompressive surgery was performed through a right sided partial dorsal laminectomy. Post-surgical immunosuppressive treatment was started with cytarabine and then continued with prednisolone after completion of wound healing.

Conclusions

This is the first report in which medical and surgical treatment were combined in a patient with SRMA and it highlights the possibility of performing a successful surgical intervention despite the need for immunosuppressive therapy. Moreover, while SRMA diagnosis is normally based on CSF analysis and CSF and serum IgA concentrations, D-dimer concentrations in serum and CSF were also useful in this patient.
Immuno-genomic classification of colorectal cancer organoids reveals cancer cells with intrinsic immunogenic properties associated with patient survival
Authors: Cho Eun Jeong , Kim Minsuh , Jo Daum , Kim Jihye , Oh Ji-Hye , Chung Hee Chul , Lee Sun-hye , Kim Deokhoon , Chun Sung-Min , Kim Jihun , Lee Hyeonjin , Kim Tae Won , Yu Chang Sik , Sung Chang Ohk , Jang Se Jin
Published: July 2021

Background

The intrinsic immuno-ge7nomic characteristics of colorectal cancer cells that affect tumor biology and shape the tumor immune microenvironment (TIM) are unclear.

Methods

We developed a patient-derived colorectal cancer organoid (CCO) model and performed pairwise analysis of 87 CCOs and their matched primary tumors. The TIM type of the primary tumor was classified as immuno-active, immuno-exhausted, or immuno-desert.

Results

The gene expression profiles, signaling pathways, major oncogenic mutations, and histology of the CCOs recapitulated those of the primary tumors, but not the TIM of primary tumors. Two distinct intrinsic molecular subgroups of highly proliferative and mesenchymal phenotypes with clinical significance were identified in CCOs with various cancer signaling pathways. CCOs showed variable expression of cancer-specific immune-related genes such as those encoding HLA-I and HLA-II, and molecules involved in immune checkpoint activation/inhibition. Among these genes, the expression of HLA-II in CCOs was associated with favorable patient survival. K-means clustering analysis based on HLA-II expression in CCOs revealed a subgroup of patients, in whom cancer cells exhibited Intrinsically Immunogenic Properties (Ca-IIP), and were characterized by high expression of signatures associated with HLA-I, HLA-II, antigen presentation, and immune stimulation. Patients with the Ca-IIP phenotype had an excellent prognosis, irrespective of age, disease stage, intrinsic molecular type, or TIM status. Ca-IIP was negatively correlated with intrinsic E2F/MYC signaling. Analysis of the correlation between CCO immuno-genotype and TIM phenotype revealed that the TIM phenotype was associated with microsatellite instability, Wnt/β-catenin signaling, APC/KRAS mutations, and the unfolded protein response pathway linked to the FBXW7 mutation in cancer cells. However, Ca-IIP was not associated with the TIM phenotype.

Conclusions

We identified a Ca-IIP phenotype from a large set of CCOs. Our findings may provide an unprecedented opportunity to develop new strategies for optimal patient stratification in this era of immunotherapy.
Revealing the full biosphere structure and versatile metabolic functions in the deepest ocean sediment of the Challenger Deep
Authors: Chen Ping , Zhou Hui , Huang Yanyan , Xie Zhe , Zhang Mengjie , Wei Yuli , Li Jia , Ma Yuewei , Luo Min , Ding Wenmian , Cao Junwei , Jiang Tao , Nan Peng , Fang Jiasong , Li Xuan
Published: July 2021

Background

The full biosphere structure and functional exploration of the microbial communities of the Challenger Deep of the Mariana Trench, the deepest known hadal zone on Earth, lag far behind that of other marine realms.

Results

We adopt a deep metagenomics approach to investigate the microbiome in the sediment of Challenger Deep, Mariana Trench. We construct 178 metagenome-assembled genomes (MAGs) representing 26 phyla, 16 of which are reported from hadal sediment for the first time. Based on the MAGs, we find the microbial community functions are marked by enrichment and prevalence of mixotrophy and facultative anaerobic metabolism. The microeukaryotic community is found to be dominated by six fungal groups that are characterized for the first time in hadal sediment to possess the assimilatory and dissimilatory nitrate/sulfate reduction, and hydrogen sulfide oxidation pathways. By metaviromic analysis, we reveal novel hadal Caudovirales clades, distinctive virus-host interactions, and specialized auxiliary metabolic genes for modulating hosts’ nitrogen/sulfur metabolism. The hadal microbiome is further investigated by large-scale cultivation that cataloged 1070 bacterial and 19 fungal isolates from the Challenger Deep sediment, many of which are found to be new species specialized in the hadal habitat.

Conclusion

Our hadal MAGs and isolates increase the diversity of the Challenger Deep sediment microbial genomes and isolates present in the public. The deep metagenomics approach fills the knowledge gaps in structure and diversity of the hadal microbiome, and provides novel insight into the ecology and metabolism of eukaryotic and viral components in the deepest biosphere on earth.
2dFDR: a new approach to confounder adjustment substantially increases detection power in omics association studies
Authors: Yi Sangyoon , Zhang Xianyang , Yang Lu , Huang Jinyan , Liu Yuanhang , Wang Chen , Schaid Daniel J. , Chen Jun
Published: July 2021

One challenge facing omics association studies is the loss of statistical power when adjusting for confounders and multiple testing. The traditional statistical procedure involves fitting a confounder-adjusted regression model for each omics feature, followed by multiple testing correction. Here we show that the traditional procedure is not optimal and present a new approach, 2dFDR, a two-dimensional false discovery rate control procedure, for powerful confounder adjustment in multiple testing. Through extensive evaluation, we demonstrate that 2dFDR is more powerful than the traditional procedure, and in the presence of strong confounding and weak signals, the power improvement could be more than 100%.
Listening to Mom in the NICU: effects of increased maternal speech exposure on language outcomes and white matter development in infants born very preterm
Authors: Brignoni-Pérez Edith , Morales Maya Chan , Marchman Virginia A. , Scala Melissa , Feldman Heidi M. , Yeom Kristen , Travis Katherine E.
Published: July 2021

Background

Infants born very preterm (< 32 weeks gestational age (GA)) are at risk for developmental language delays. Poor language outcomes in children born preterm have been linked to neurobiological factors, including impaired development of the brain’s structural connectivity (white matter), and environmental factors, including decreased exposure to maternal speech in the neonatal intensive care unit (NICU). Interventions that enhance preterm infants’ exposure to maternal speech show promise as potential strategies for improving short-term health outcomes. Intervention studies have yet to establish whether increased exposure to maternal speech in the NICU offers benefits beyond the newborn period for brain and language outcomes.

Methods

This randomized controlled trial assesses the long-term effects of increased maternal speech exposure on structural connectivity at 12 months of age (age adjusted for prematurity (AA)) and language outcomes between 12 and 18 months of age AA. Study participants (N = 42) will include infants born very preterm (24–31 weeks 6/7 days GA). Newborns are randomly assigned to the treatment (n = 21) or standard medical care (n = 21) group. Treatment consists of increased maternal speech exposure, accomplished by playing audio recordings of each baby’s own mother reading a children’s book via an iPod placed in their crib/incubator. Infants in the control group have the identical iPod setup but are not played recordings. The primary outcome will be measures of expressive and receptive language skills, obtained from a parent questionnaire collected at 12–18 months AA. The secondary outcome will be measures of white matter development, including the mean diffusivity and fractional anisotropy derived from diffusion magnetic resonance imaging scans performed at around 36 weeks postmenstrual age during the infants’ routine brain imaging session before hospital discharge and 12 months AA.

Discussion

The proposed study is expected to establish the potential impact of increased maternal speech exposure on long-term language outcomes and white matter development in infants born very preterm. If successful, the findings of this study may help to guide NICU clinical practice for promoting language and brain development. This clinical trial has the potential to advance theoretical understanding of how early language exposure directly changes brain structure for later language learning.

Trial registration

NIH Clinical Trials (ClinicalTrials.gov) NCT04193579. Retrospectively registered on 10 December 2019.
Plasma interferon-alpha is associated with double-positivity for autoantibodies but is not a predictor of remission in early rheumatoid arthritis—a spin-off study of the NORD-STAR randomized clinical trial
Authors: Stockfelt Marit , Lundell Anna-Carin , Hetland Merete Lund , Østergaard Mikkel , Uhlig Till , Heiberg Marte Schrumpf , Haavardsholm Espen A. , Nurmohamed Michael T. , Lampa Jon , Nordström Dan , Petersen Kim Hørslev , Gudbjornsson Bjorn , Gröndal Gerdur , Aldridge Jonathan , Andersson Kerstin , Blennow Kaj , Zetterberg Henrik , van Vollenhoven Ronald , Rudin Anna
Published: July 2021

Background

The type I interferon (IFN) gene signature is present in a subgroup of patients with early rheumatoid arthritis (RA). Protein levels of IFNα have not been measured in RA and it is unknown whether they associate with clinical characteristics or treatment effect.

Methods

Patients with early untreated RA (n = 347) were randomized to methotrexate combined with prednisone, certolizumab-pegol, abatacept, or tocilizumab. Plasma IFNα protein levels were determined by single molecular array (Simoa) before and 24 weeks after treatment initiation and were related to demographic and clinical factors including clinical disease activity index, disease activity score in 28 joints, swollen and tender joint counts, and patient global assessment.

Results

IFNα protein positivity was found in 26% of the patients, and of these, 92% were double-positive for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). IFNα protein levels were reduced 24 weeks after treatment initiation, and the absolute change was similar irrespective of treatment. IFNα protein positivity was associated neither with disease activity nor with achievement of CDAI remission 24 weeks after randomization.

Conclusion

IFNα protein positivity is present in a subgroup of patients with early RA and associates with double-positivity for autoantibodies but not with disease activity. Pre-treatment IFNα positivity did not predict remission in any of the treatment arms, suggesting that the IFNα system is distinct from the pathways of TNF, IL-6, and T-cell activation in early RA.

A spin-off study of the NORD-STAR randomized clinical trial, NCT01491815 (ClinicalTrials), registered 12/08/2011, https://clinicaltrials.gov/ct2/show/NCT01491815.