bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving lung cancer risk stratification leveraging whole transcriptome RNA sequencing and machine learning across multiple cohorts
Authors: Choi Yoonha , Qu Jianghan , Wu Shuyang , Hao Yangyang , Zhang Jiarui , Ning Jianchang , Yang Xinwu , Lofaro Lori , Pankratz Daniel G. , Babiarz Joshua , Walsh P. Sean , Billatos Ehab , Lenburg Marc E. , Kennedy Giulia C. , McAuliffe Jon , Huang Jing
Published: October 2020

Background

Bronchoscopy for suspected lung cancer has low diagnostic sensitivity, rendering many inconclusive results. The Bronchial Genomic Classifier (BGC) was developed to help with patient management by identifying those with low risk of lung cancer when bronchoscopy is inconclusive. The BGC was trained and validated on patients in the Airway Epithelial Gene Expression in the Diagnosis of Lung Cancer (AEGIS) trials. A modern patient cohort, the BGC Registry, showed differences in key clinical factors from the AEGIS cohorts, with less smoking history, smaller nodules and older age. Additionally, we discovered interfering factors (inhaled medication and sample collection timing) that impacted gene expressions and potentially disguised genomic cancer signals.

Methods

In this study, we leveraged multiple cohorts and next generation sequencing technology to develop a robust Genomic Sequencing Classifier (GSC). To address demographic composition shift and interfering factors, we synergized three algorithmic strategies: 1) ensemble of clinical dominant and genomic dominant models; 2) development of hierarchical regression models where the main effects from clinical variables were regressed out prior to the genomic impact being fitted in the model; and 3) targeted placement of genomic and clinical interaction terms to stabilize the effect of interfering factors. The final GSC model uses 1232 genes and four clinical covariates – age, pack-years, inhaled medication use, and specimen collection timing.

Results

In the validation set (N = 412), the GSC down-classified low and intermediate pre-test risk subjects to very low and low post-test risk with a specificity of 45% (95% CI 37–53%) and a sensitivity of 91% (95%CI 81–97%), resulting in a negative predictive value of 95% (95% CI 89–98%). Twelve percent of intermediate pre-test risk subjects were up-classified to high post-test risk with a positive predictive value of 65% (95%CI 44–82%), and 27% of high pre-test risk subjects were up-classified to very high post-test risk with a positive predictive value of 91% (95% CI 78–97%).

Conclusions

The GSC overcame the impact of interfering factors and achieved consistent performance across multiple cohorts. It demonstrated diagnostic accuracy in both down- and up-classification of cancer risk, providing physicians actionable information for many patients with inconclusive bronchoscopy.
Predicting miRNA-disease associations using a hybrid feature representation in the heterogeneous network
Authors: Liu Minghui , Yang Jingyi , Wang Jiacheng , Deng Lei
Published: October 2020

Background

Studies have found that miRNAs play an important role in many biological activities involved in human diseases. Revealing the associations between miRNA and disease by biological experiments is time-consuming and expensive. The computational approaches provide a new alternative. However, because of the limited knowledge of the associations between miRNAs and diseases, it is difficult to support the prediction model effectively.

Methods

In this work, we propose a model to predict miRNA-disease associations, MDAPCOM, in which protein information associated with miRNAs and diseases is introduced to build a global miRNA-protein-disease network. Subsequently, diffusion features and HeteSim features, extracted from the global network, are combined to train the prediction model by eXtreme Gradient Boosting (XGBoost).

Results

The MDAPCOM model achieves AUC of 0.991 based on 10-fold cross-validation, which is significantly better than that of other two state-of-the-art methods RWRMDA and PRINCE. Furthermore, the model performs well on three unbalanced data sets.

Conclusions

The results suggest that the information behind proteins associated with miRNAs and diseases is crucial to the prediction of the associations between miRNAs and diseases, and the hybrid feature representation in the heterogeneous network is very effective for improving predictive performance.
ADAM17 promotes the invasion of hepatocellular carcinoma via upregulation MMP21
Authors: Xiang Yuqi , Liu Liyu , Wang Ying , Li Bo , Peng Jinwu , Feng Deyun
Published: October 2020

Background

The upregulation of ADAM17 has been reported to be associated with invasion and metastasis in various tumors, however the molecular mechanism of ADAM17 in the progression of hepatocellular carcinoma (HCC) remain to be clarified. Human matrix metalloproteinase 21 (MMP21), the newest member of the MMP gene family, has been suggested to play an important role in embryogenesis and tumor progression. So far, nothing is known about the relationship between ADAM17 and MMP21.

Methods

In this study, the expression level of ADAM17 and MMP21 in HCC tissues was measured by immunohistochemistry. The Scratch wounding assay and Transwell were used to identify the invasion and metastasis ability. ELISA was used to evaluate the production of MMP21. Coimmunoprecipitation experiments demonstrated a direct association between ADAM17 and MMP21. HPLC was used to confirmed that ADAM17 participated in the maturation of MMP21.

Results

Our present data indicated that ADAM17 and MMP21 was significantly upregulated in human HCC tissues. Knockdown of ADAM17 in HCC inhibited cell invasion and metastasis. Moreover, ADAM17 regulates the secretion and expression of MMP21. Furthermore we discovered a direct association between ADAM17 and MMP21, and we also found MMP21 prodomain could be cleaved by ADAM17.

Conclusion

Our data suggest that ADAM17 plays an important role in the development of HCC invasion and metastasis and this function may be implement by MMP21.
Dimethyl fumarate reduces TNF and Plasmodium falciparum induced brain endothelium activation in vitro
Authors: Mita-Mendoza Neida K. , Magallon-Tejada Ariel , Parmar Priyanka , Furtado Raquel , Aldrich Margaret , Saidi Alex , Taylor Terrie , Smith Joe , Seydel Karl , Daily Johanna P.
Published: October 2020

Background

Cerebral malaria (CM) is associated with morbidity and mortality despite the use of potent anti-malarial agents. Brain endothelial cell activation and dysfunction from oxidative and inflammatory host responses and products released by Plasmodium falciparum-infected erythrocytes (IE), are likely the major contributors to the encephalopathy, seizures, and brain swelling that are associated with CM. The development of adjunctive therapy to reduce the pathological consequences of host response pathways could improve outcomes. A potentially protective role of the nuclear factor E2-related factor 2 (NRF2) pathway, which serves as a therapeutic target in brain microvascular diseases and central nervous system (CNS) inflammatory diseases such as multiple sclerosis was tested to protect endothelial cells in an in vitro culture system subjected to tumour necrosis factor (TNF) or infected red blood cell exposure. NRF2 is a transcription factor that mediates anti-oxidant and anti-inflammatory responses.

Methods

To accurately reflect clinically relevant parasite biology a unique panel of parasite isolates derived from patients with stringently defined CM was developed. The effect of TNF and these parasite lines on primary human brain microvascular endothelial cell (HBMVEC) activation in an in vitro co-culture model was tested. HBMVEC activation was measured by cellular release of IL6 and nuclear translocation of NFκB. The transcriptional and functional effects of dimethyl fumarate (DMF), an FDA approved drug which induces the NRF2 pathway, on host and parasite induced HBMVEC activation was characterized. In addition, the effect of DMF on parasite binding to TNF stimulated HBMVEC in a semi-static binding assay was examined.

Results

Transcriptional profiling demonstrates that DMF upregulates the NRF2-Mediated Oxidative Stress Response, ErbB4 Signaling Pathway, Peroxisome Proliferator-activated Receptor (PPAR) Signaling and downregulates iNOS Signaling and the Neuroinflammation Signaling Pathway on TNF activated HBMVEC. The parasite lines derived from eight paediatric CM patients demonstrated increased binding to TNF activated HBMVEC and varied in their binding and activation of HBMVEC. Overall DMF reduced both TNF and CM derived parasite activation of HBMVEC.

Conclusions

These findings provide evidence that targeting the NRF2 pathway in TNF and parasite activated HBMVEC mediates multiple protective pathways and may represent a novel adjunctive therapy to improve infection outcomes in CM.
Hepatitis B virus infection among people who use drugs in Iran: a systematic review, meta-analysis, and trend analysis
Authors: Rostam-Abadi Yasna , Rafiemanesh Hossein , Gholami Jaleh , Shadloo Behrang , Amin-Esmaeili Masoumeh , Rahimi-Movaghar Afarin
Published: October 2020

Background

People who use drugs (PWUD) are considered as one of the main at-risk populations for Hepatitis B virus (HBV) infection. We conducted a systematic review on the prevalence of HBV infection among PWUD in Iran.

Methods

Consistent with PRISMA guideline, international (Medline, Web of Science, Scopus, and Embase) and national (Scientific Information Database) databases were searched using a comprehensive search strategy up to September 2019. The retrieved records were reviewed, and experts were contacted for unpublished studies. Studies on Iranian PWUD reporting HBV surface Antigen (HBsAg) prevalence among people who inject drugs (PWID) and non-injecting PWUD were included. HBsAg prevalence was pooled for PWID and non-injecting PWUD and for other subgroups using random-effects model meta-analysis. The trend of HBV prevalence over time was investigated using meta-regression analysis.

Results

Overall, 35 studies reported data on HBV infection among PWID (33 studies) and non-injecting PWUD (11 studies). The pooled prevalence of HBsAg among PWID was 4.8% (95% CI 3.7–6.2). The only risk factor significantly associated with the odds of positive HBsAg in PWID was the previous history of imprisonment (OR 1.72, 95% CI 1.29–2.30, p value = 0.000). The pooled estimate of HBsAg among non-injecting PWUD was 2.9% (95% CI 2.5–3.2). Time trend analyses showed significant decrease in HBV prevalence among PWID reaching from 8.2% (95% CI 3.9–16.5) in 2004–2006 to 3.1% (95% CI 2.3–4.1) in 2016 and later (b = -0.07; p value = 0.05). No significant trend was detected for non-injecting PWUD.

Conclusion

The prevalence of HBV infection among non-injecting PWUD and even PWID was not considerably higher than the Iranian general population. This might be the result of extensive harm reduction interventions in Iran. However, it seems that there are subgroups of PWID, who do not adequately benefit from existing harm reduction interventions. Future programs should more specifically target these high-risk groups.
In vivo vaccination with cell line-derived whole tumor lysates: neoantigen quality, not quantity matters
Authors: Salewski Inken , Gladbach Yvonne Saara , Kuntoff Steffen , Irmscher Nina , Hahn Olga , Junghanss Christian , Maletzki Claudia
Published: October 2020

Background

Cancer vaccines provide a complex source of neoantigens. Still, increasing evidence reveals that the neoantigen quality rather than the quantity is predictive for treatment outcome.

Methods

Using the preclinical Mlh1−/− tumor model, we performed a side-by side comparison of two autologous cell-line derived tumor lysates (namely 328 and A7450 T1 M1) harboring different tumor mutational burden (TMB; i.e. ultra-high: 328; moderate-high: A7450 T1 M1). Mice received repetitive prophylactic or therapeutic applications of the vaccine. Tumor incidence, immune responses and tumor microenvironment was examined.

Results

Both tumor cell lysates delayed tumor formation in the prophylactic setting, with the A7450 T1 M1 lysate being more effective in decelerating tumor growth than the 328 lysate (median overall survival: 37 vs. 25 weeks). Comparable results were achieved in therapeutic setting and could be traced back to antigen-driven immune stimulation. Reactive T cells isolated from A7450 T1 M1-treated mice recognized autologous Mlh1−/− tumor cells in IFNγ ELISpot, but likewise YAC-1 cells, indicative for stimulation of both arms of the immune system. By deciphering local effects, vaccines shaped the tumor microenvironment differently. While A7450 T1 M1 prophylactically vaccinated tumors harbored low numbers of myeloid-derived suppressor cells (MDSC) and elevated CD8-T cell infiltrates, vaccination with the 328 lysate evoked MDSC infiltration. Similar effects were seen in the therapeutic setting with stable disease induction only upon A7450 T1 M1 vaccination. Untangling individual response profiles revealed strong infiltration with LAG3+ and PD-L1+ immune cells when treatments failed, but almost complete exclusion of checkpoint-expressing lymphocytes in long-term survivors.

Conclusions

By applying two tumor cell lysates we demonstrate that neoantigen quality outranks quantity. This should be considered prior to designing cancer vaccine-based combination approaches.
Resveratrol mediates mechanical allodynia through modulating inflammatory response via the TREM2-autophagy axis in SNI rat model
Authors: Wang Yaping , Shi Yu , Huang Yongquan , Liu Wei , Cai Guiyuan , Huang Shimin , Zeng Yanyan , Ren Siqiang , Zhan Hongrui , Wu Wen
Published: October 2020

Background

Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms.

Methods

A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence.

Results

The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia.

Conclusions

Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.
These legs were made for propulsion: advancing the diagnosis and treatment of post-stroke propulsion deficits
Authors: Awad Louis N. , Lewek Michael D. , Kesar Trisha M. , Franz Jason R. , Bowden Mark G.
Published: October 2020

Advances in medical diagnosis and treatment have facilitated the emergence of precision medicine. In contrast, locomotor rehabilitation for individuals with acquired neuromotor injuries remains limited by the dearth of (i) diagnostic approaches that can identify the specific neuromuscular, biomechanical, and clinical deficits underlying impaired locomotion and (ii) evidence-based, targeted treatments. In particular, impaired propulsion by the paretic limb is a major contributor to walking-related disability after stroke; however, few interventions have been able to target deficits in propulsion effectively and in a manner that reduces walking disability. Indeed, the weakness and impaired control that is characteristic of post-stroke hemiparesis leads to heterogeneous deficits that impair paretic propulsion and contribute to a slow, metabolically-expensive, and unstable gait. Current rehabilitation paradigms emphasize the rapid attainment of walking independence, not the restoration of normal propulsion function. Although walking independence is an important goal for stroke survivors, independence achieved via compensatory strategies may prevent the recovery of propulsion needed for the fast, economical, and stable gait that is characteristic of healthy bipedal locomotion. We posit that post-stroke rehabilitation should aim to promote independent walking, in part, through the acquisition of enhanced propulsion. In this expert review, we present the biomechanical and functional consequences of post-stroke propulsion deficits, review advances in our understanding of the nature of post-stroke propulsion impairment, and discuss emerging diagnostic and treatment approaches that have the potential to facilitate new rehabilitation paradigms targeting propulsion restoration.
A neglected problem in the utilization of free anterolateral thigh flap toward reconstructing complicated wounds of extremities: the obliteration of deep dead space
Authors: Ren Gao-hong , Xiang Da-yong , Wu Xiao-hu , Chen Yun-biao , Li Runguang
Published: October 2020

Background

Deep dead space may be thought as an independent risk factor of the poor infection control after flap reconstruction in complex limb wounds. But it can be easily neglected. The conventional skin flap and musculocutaneous flap are difficult to obliterate the deep dead space in irregular shape effectively. It was investigated that the clinical application of chimeric anterolateral thigh perforator flap in the treatment of complex wounds complicated with deep dead space of the extremities in the paper.

Methods

Fifty-six cases complicated with deep dead space wounds were registered in group. Following thorough debridement and treatment with VSD, the granulation tissues grew with well-controlled infection. And then the chimeric anterolateral thigh perforator flap was used to obliterate the deep dead space and repair the wounds. The postoperative flap survival and infection conditions were evaluated.

Results

Overall, the infection was effectively controlled, without persistent exudation or sinus tract formation after wound healing. While 5 cases lost to follow-up, the remaining 51 cases were followed up until 15 months on average. Generally, the affected extremities recovered satisfactorily with normal appearances and texture of the flaps, along with normal functions. Importantly, no recurrence of infection was observed.

Conclusion

During the grafting of chimeric perforator flap pedicled with lateral thigh muscle flap, the muscle flap is recommended to obliterate the deep dead space while the skin flap is being used to cover the wound. The combination of these two technologies performed well in the repair and reconstruction of the complex wounds of the extremities, possessing potential for broader clinical application.
Correlation of the anatomical sacral slope with pelvic incidence in female patients with developmental hip dysplasia: a retrospective cross-sectional study
Authors: Imai Norio , Suzuki Hayato , Sakagami Atsushi , Hirano Yuki , Endo Naoto
Published: October 2020

Background

The anatomical sacral slope is considered as an anatomical pelvic parameter independent of femoral head centers for measurement of anatomical sacral slope and was previously described to strongly correlate with pelvic incidence on a two-dimensional examination of healthy subjects. However, the correlation between anatomical sacral slope and pelvic incidence was unclear in patients with developmental dysplasia of the hip. This study aimed to examine the correlation between anatomical sacral slope and other spinopelvic parameters by analyzing plain radiographs of female patients with developmental dysplasia of the hip.

Methods

Eighty-four women with developmental dysplasia of the hip were examined. Lumbar lordosis, thoracic kyphosis, pelvic incidence, sacral slope, and anatomical sacral slope (the angle formed by the straight line of the S1 superior endplate and a line at a right angle to the anterior pelvic plane) were determined by analyzing plain radiographs. The correlations were examined by Pearson’s correlation coefficients, and intra- and inter-rater intraclass correlation coefficients were evaluated for reliability.

Results

A strong correlation was observed between pelvic incidence and anatomical sacral slope (r = 0.725, p < 0.001). In addition, the correlation between anatomical sacral slope and lumbar lordosis was similar to that between pelvic incidence and lumbar lordosis (r = 0.661, p < 0.001, and r = 0.554, p < 0.001, respectively). The intra-rater intraclass correlation coefficient values were 0.869 and 0.824 for anatomical sacral slope and pelvic incidence, respectively. Furthermore, the inter-rater intraclass correlation coefficient values were 0.83 and 0.685 for anatomical sacral slope and pelvic incidence, respectively.

Conclusions

We observed that the strong correlation between anatomical sacral slope and pelvic incidence in patients with developmental dysplasia of the hip was equal to that in normal healthy subjects. The correlation between anatomical sacral slope and lumbar lordosis was equal to that between pelvic incidence and lumbar lordosis. Additionally, the intraclass correlation coefficient values for the anatomical sacral slope were slightly higher than those for pelvic incidence. Thus, we conclude that anatomical sacral slope can be considered as a helpful anatomical pelvic parameter that is a substitute for pelvic incidence not only in normal healthy subjects, but also in patients with developmental dysplasia of the hip.
UBE2T-regulated H2AX monoubiquitination induces hepatocellular carcinoma radioresistance by facilitating CHK1 activation
Authors: Sun Jingyuan , Zhu Zhenru , Li Wenwen , Shen Mengying , Cao Chuanhui , Sun Qingcan , Guo Zeqin , Liu Li , Wu Dehua
Published: October 2020

Background

Radioresistance is the major obstacle in radiation therapy (RT) for hepatocellular carcinoma (HCC). Dysregulation of DNA damage response (DDR), which includes DNA repair and cell cycle checkpoints activation, leads to radioresistance and limits radiotherapy efficacy in HCC patients. However, the underlying mechanism have not been clearly understood.

Methods

We obtained 7 pairs of HCC tissues and corresponding non-tumor tissues, and UBE2T was identified as one of the most upregulated genes. The radioresistant role of UBE2T was examined by colony formation assays in vitro and xenograft tumor models in vivo. Comet assay, cell cycle flow cytometry and γH2AX foci measurement were used to investigate the mechanism by which UBE2T mediating DDR. Chromatin fractionation and immunofluorescence staining were used to assess cell cycle checkpoint kinase 1(CHK1) activation. Finally, we analyzed clinical data from HCC patients to verify the function of UBE2T.

Results

Here, we found that ubiquitin-conjugating enzyme E2T (UBE2T) was upregulated in HCC tissues, and the HCC patients with higher UBE2T levels exhibited poorer outcomes. Functional studies indicated that UBE2T increased HCC radioresistance in vitro and in vivo. Mechanistically, UBE2T-RNF8, was identified as the E2-E3 pair, physically bonded with and monoubiquitinated histone variant H2AX/γH2AX upon radiation exposure. UBE2T-regulated H2AX/γH2AX monoubiquitination facilitated phosphorylation of CHK1 for activation and CHK1 release from the chromatin to cytosol for degradation. The interruption of UBE2T-mediated monoubiquitination on H2AX/γH2AX, including E2-enzyme-deficient mutation (C86A) of UBE2T and monoubiquitination-site-deficient mutation (K119/120R) of H2AX, cannot effectively activate CHK1. Moreover, genetical and pharmacological inhibition of CHK1 impaired the radioresistant role of UBE2T in HCC. Furthermore, clinical data suggested that the HCC patients with higher UBE2T levels exhibited worse response to radiotherapy.

Conclusion

Our results revealed a novel role of UBE2T-mediated H2AX/γH2AX monoubiquitination on facilitating cell cycle arrest activation to provide sufficient time for radiation-induced DNA repair, thus conferring HCC radioresistance. This study indicated that disrupting UBE2T-H2AX-CHK1 pathway maybe a promising potential strategy to overcome HCC radioresistance.
Prognostic value of kallikrein-related peptidase 7 (KLK7) mRNA expression in advanced high-grade serous ovarian cancer
Authors: Gong Weiwei , Liu Yueyang , Diamandis Eleftherios P. , Kiechle Marion , Bronger Holger , Dorn Julia , Dreyer Tobias , Magdolen Viktor
Published: October 2020

Background

High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer. A growing body of evidence suggests tumor-supporting roles of several members of the kallikrein-related peptidase (KLK) family, including KLK5 and KLK7, in this cancer subtype. In normal physiology, KLK5 and KLK7 are the major proteases involved in skin desquamation. Moreover, in several cancer types KLK5 and KLK7 co-expression has been observed. Recently, we have shown that elevated KLK5 mRNA levels are associated with an unfavorable prognosis in HGSOC. Therefore, the aim of this study was to investigate the clinical significance of KLK7 mRNA expression and to explore its relation to KLK5 levels in HGSOC.

Methods

mRNA expression levels of KLK7 were quantified by qPCR in a well-characterized patient cohort afflicted with advanced high-grade serous ovarian cancer (FIGO III/IV, n = 139). Previously determined KLK5 mRNA as well as KLK5 and KLK7 antigen concentrations were used to evaluate the relationship between the expression patterns of both factors on the mRNA as well as protein level in tumor tissue of HGSOC patients.

Results

There were strong, significant positive correlations between KLK5 and KLK7 both at the mRNA and the protein level, suggesting coordinate expression of these proteases in HGSOC. In univariate analyses, elevated KLK7 levels as well as the combination of KLK5 + KLK7 (high and/or high versus low/low) were significantly associated with worse progression-free survival (PFS). High mRNA expression levels of KLK7 and the combination of KLK5 and KLK7 showed a trend towards significance for overall survival (OS). In multivariate analyses, KLK7 mRNA expression represented an unfavorable, statistically significant independent predictor for PFS and OS.

Conclusions

The findings imply that both increased KLK5 and KLK7 mRNA expression levels represent unfavorable prognostic biomarkers in advanced high-grade serous ovarian cancer, whereby multivariate analyses indicate that KLK7 mRNA exhibits a stronger predictive value as compared to KLK5 mRNA and the combination of KLK5 and KLK7.
Resilience in a prehospital setting - a new focus for future research?
Authors: Jeppesen Elisabeth , Wiig Siri
Published: October 2020

Background

Handling and initiating of treatment in a prehospital setting are complex processes that involve many treatment options and include several parts of the chain of survival. Capacity to adapt to unexpected changes in the patients’ conditions or in the surroundings is a prerequisite for patient safety. Outside the healthcare sector, safety science is moving from an approach focused on the analysis and management of error (Safety I) to instead understanding the inherent properties of safety systems (Safety II). In healthcare the attention to why service providers are able to succeed under challenging conditions remains sparse. The aim of this commentary is to give a better understanding of how the concept and inclusion of resilience can inspire a new approach for future research in prehospital settings. So far, most resilience studies have been conducted in emergency departments while the role of contextual factors and adaptations in a prehospital setting has remained unexplored.

Main body

In contrast to traditional research on healthcare quality and safety, which tends to focus on failures, resilience research is interested in examining the overwhelming majority of healthcare processes with successful outcomes, to determine how high-quality patient care is generated. Resilience is conceptualized as a proactive ability to adjust to potentially harmful influences and challenges rather than to resist them. To better understand and promote resilience, there is a need to explore the underlying mechanisms of adaptation, trade-offs and improvisation that occur in the emergency chain. Attention to how people respond to disruptions, challenges and opportunities is vital. There are factors, recognized and unidentified, influencing adaptation, trade-offs and improvisation. Influencing factors at different levels could be of particular value to increase knowledge to better understand resilience in a practical perspective. As prehospital work conditions are highly unpredictable and diverse, learning through everyday work could be of great value if the experiences are transferred and integrated in training and simulation.

Conclusions

Empirical research is of crucial importance to build and support resilient systems and processes in a prehospital setting. We need a new framework and a new approach to how research on this topic is conducted and to support resilient performance. This should involve identifying factors that promote resilience, both on individual-, team- and system- levels.
Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia
Authors: Tuazon Anna Marie De Asis , Lott Paul , Bohórquez Mabel , Benavides Jennyfer , Ramirez Carolina , Criollo Angel , Estrada-Florez Ana , Mateus Gilbert , Velez Alejandro , Carmona Jenny , Olaya Justo , Garcia Elisha , Polanco-Echeverry Guadalupe , Stultz Jacob , Alvarez Carolina , Tapia Teresa , Ashton-Prolla Patricia ,   Brazilian Familial Cancer Network, Alemar Barbara , Netto Cristina Brinckmann Oliveira , Carraro Dirce Maria , Vargas Fernando Regla , da Silva Gustavo Stumpf , Nascimento Ivana Lúcia Oliveira , de Souza Kelly Rose Lobo , Achatz Maria Isabel , Moreira Miguel Angelo Martins , Torrales Maria Betânia , Pimenta Maristela , Machado-Lopes Taisa Manuela Bonfim , Vega Ana , Lazaro Conxi , Tornero Eva , Martinez-Bouzas Cristina , Infante Mar , De La Hoya Miguel , Diez Orland , Browning Brian L. ,   COLUMBUS Consortium, Bolaños Fernando , Murillo Raúl , Sánchez Yesid , Sanabria Carolina , Serrano Martha Lucia , Suarez John Jairo , Rannala Bruce , Teixeira Manuel R. , Carvallo Pilar , Echeverry Magdalena , Carvajal-Carmona Luis G.
Published: October 2020

Background

The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry.

Methods

BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia.

Results

The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period.

Conclusions

Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening.
Suicide Reduction in Schizophrenia via Exercise (SUnRISE): study protocol for a multi-site, single-blind, randomized clinical trial of aerobic exercise for suicide risk reduction in individuals with schizophrenia
Authors: Beck-Felts Katie , Goodman Marianne , Ospina Luz H. , Wall Melanie , McEvoy Joseph , Jarskog Lars F. , Ballon Jacob S. , Bartels Matthew N. , Buchsbaum Richard , Sloan Richard P. , Stroup T. Scott , Kimhy David
Published: October 2020

Background

Suicide risk among individuals with schizophrenia (SZ) is intractably high, with over 40% of individuals attempting to take their own lives during their lifetime and an estimated 5–10% completing suicide. At present, available pharmacological and psychotherapeutic treatments offer limited risk reduction benefits, and thus, there remains an urgent need to explore novel interventions that will ameliorate this risk. Aerobic exercise (AE) has been shown to improve a number of predictors of suicide risk (e.g., depressed mood, sleeping difficulties). As individuals with SZ display a highly sedentary lifestyle, AE may reduce suicide risk.

Methods

Employing a multi-site, single-blind, randomized clinical trial design, we will examine the impact of AE on risk for suicide and related variables in individuals with SZ. Participants will be randomized to one of two 12-week exercise interventions: AE or a stretching and toning (ST) control intervention. Primary outcome measures will include suicide risk (Columbia Suicide Severity Rating Scale, C-SSRS) and aerobic fitness (VO2max), along with additional measures of suicide risk, mood, emotion regulation, sleep, cognition, and physical activity, with assessments completed at baseline and after 6 and 12 weeks of interventions.

Discussion

It is hypothesized that AE will reduce suicide risk among individuals with SZ. This study may offer support for a more efficacious treatment method for this population in addition to the pre-existing pharmacological and psychotherapeutic treatment regimens.

Trial registration

Clinicaltrials.gov,NCT03270098. Registered on September 1, 2017.
The epigenetic implication in coronavirus infection and therapy
Authors: Atlante Sandra , Mongelli Alessia , Barbi Veronica , Martelli Fabio , Farsetti Antonella , Gaetano Carlo
Published: October 2020

Epigenetics is a relatively new field of science that studies the genetic and non-genetic aspects related to heritable phenotypic changes, frequently caused by environmental and metabolic factors. In the host, the epigenetic machinery can regulate gene expression through a series of reversible epigenetic modifications, such as histone methylation and acetylation, DNA/RNA methylation, chromatin remodeling, and non-coding RNAs. The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, and spread worldwide, causes it. COVID-19 severity and consequences largely depend on patient age and health status. In this review, we will summarize and comparatively analyze how viruses regulate the host epigenome. Mainly, we will be focusing on highly pathogenic respiratory RNA virus infections such as coronaviruses. In this context, epigenetic alterations might play an essential role in the onset of coronavirus disease complications. Although many therapeutic approaches are under study, more research is urgently needed to identify effective vaccine or safer chemotherapeutic drugs, including epigenetic drugs, to cope with this viral outbreak and to develop pre- and post-exposure prophylaxis against COVID-19.
Correction to: Structural alterations and markers of endothelial activation in pulmonary and bronchial arteries in fatal asthma
Authors: Rossi Renata Calciolari , Annoni Raquel , Ferreira Diogenes Seraphim , da Silva Luiz Fernando Ferraz , Mauad Thais
Published: October 2020

An amendment to this paper has been published and can be accessed via the original article.
Brown adipose tissue uptake of triglyceride-rich lipoprotein-derived fatty acids in diabetic or obese mice under different temperature conditions
Authors: Paulus Andreas , Drude Natascha , van Marken Lichtenbelt Wouter , Mottaghy Felix M. , Bauwens Matthias
Published: October 2020

Background

In vivo imaging of glucose analogue 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) via positron emission tomography (PET) is the current gold standard to visualize and assess brown adipose tissue (BAT) activity. However, glucose metabolism is only a part of the metabolic activity of BAT. [18F]FDG-PET has been shown in clinical trials to often fail to visualize BAT under insulin-resistant conditions associated with aging and weight gain. We employed a novel developed triglyceride-based tracer to visualize BATs metabolic activity under different temperature conditions as well as under diabetic and obese conditions in preclinical models.

Results

[18F]BDP-TG-chylomicron-like particles visualized BAT in control, streptozocin-induced diabetes and obese mice. Increased BAT tracer uptake was found in control mice acutely exposed to cold but not in cold-acclimated animals. Diabetes did not remove BAT tracer uptake, but did limit BAT tracer uptake to levels of control mice housed at 21 °C. In obese animals, BAT tracer uptake was significantly reduced, although the stimulating effect of cold exposure could still be noted.

Conclusion

BAT was visualized in control, diabetic and obese conditions. Streptozocin-induced diabetes, but not obesity, inhibited the stimulatory effect of cold exposure.
Environmental exposures and health behavior in association with mental health: a study design
Authors: Hautekiet Pauline , Nawrot Tim S. , Demarest Stefaan , Van der Heyden Johan , Van Overmeire Ilse , De Clercq Eva M. , Saenen Nelly D.
Published: October 2020

Background

Air pollution, green space and smoking are known to affect human health. However, less is known about their underlying biological mechanisms. One of these mechanisms could be biological aging. In this study, we explore the mediation of biomarkers of exposure and biological aging to explain the associations between environmental exposures, health behavior and mental health.

Methods

The study population of this cross-sectional study (n = 1168) is a subsample of the Belgian 2018 Health Interview Survey (BHIS). Mental health indicators including psychological and severe psychological distress, life satisfaction, vitality, eating disorders, suicidal ideation, subjective health and depressive and anxiety disorders, demographics and health behavior such as smoking are derived from the BHIS. Urine and blood samples are collected to measure respectively the biomarkers of exposure (urinary black carbon (BC) and (hydroxy)cotinine) and the biomarkers of biological aging (mitochondrial DNA content (mtDNAc) and telomere length (TL)). Recent and chronic exposure (μg/m3) to nitrogen dioxide (NO2), particulate matter ≤2.5 μm (PM2.5) and ≤ 10 μm (PM10) and BC at the participants’ residence are modelled using a high resolution spatial temporal interpolation model. Residential green space is defined in buffers of different size (50 m – 5000 m) using land cover data in ArcGIS 10 software. For the statistical analysis multivariate linear and logistic regressions as well as mediation analyses are used taking into account a priori selected covariates and confounders.

Results

As this study combined data of BHIS and laboratory analyses, not all data is available for all participants. Therefore, data analyses will be conducted on different subsets. Data on air pollution and green space exposure is available for all BHIS participants. Questions on smoking and mental health were answered by respectively 7829 and 7213 BHIS participants. For biomarker assessment, (hydroxy) cotinine, urinary BC and the biomarkers of biological aging are measured for respectively 1130, 1120 and 985 participants.

Conclusion

By use of personal markers of air pollution and smoking, as well as biological aging, we will gain knowledge about the association between environmental exposures, health behavior, and the mental health status. The results of the study can provide insights on the health of the Belgian population, making it a nationwide interesting study.
Mapping current and potential future distributions of the oak tree (Quercus aegilops) in the Kurdistan Region, Iraq
Authors: Khwarahm Nabaz R.
Published: October 2020

Background

The oak tree (Quercus aegilops) comprises ~ 70% of the oak forests in the Kurdistan Region of Iraq (KRI). Besides its ecological importance as the residence for various endemic and migratory species,Q. aegilopsforest also has socio-economic values—for example, as fodder for livestock, building material, medicine, charcoal, and firewood. In the KRI,Q. aegilopshas been degrading due to anthropogenic threats (e.g., shifting cultivation, land use/land cover changes, civil war, and inadequate forest management policy) and these threats could increase as climate changes. In the KRI and Iraq as a whole, information on current and potential future geographical distributions ofQ. aegilopsis minimal or not existent. The objectives of this study were to (i) predict the current and future habitat suitability distributions of the species in relation to environmental variables and future climate change scenarios (Representative Concentration Pathway (RCP) 2.6 2070 and RCP8.5 2070); and (ii) determine the most important environmental variables controlling the distribution of the species in the KRI. The objectives were achieved by using the MaxEnt (maximum entropy) algorithm, available records ofQ. aegilops, and environmental variables.

Results

The model demonstrated that, under the RCP2.6 2070 and RCP8.5 2070 climate change scenarios, the distribution ranges ofQ. aegilopswould be reduced by 3.6% (1849.7 km2) and 3.16% (1627.1 km2), respectively. By contrast, the species ranges would expand by 1.5% (777.0 km2) and 1.7% (848.0 km2), respectively. The distribution of the species was mainly controlled by annual precipitation. Under future climate change scenarios, the centroid of the distribution would shift toward higher altitudes.

Conclusions

The results suggest (i) a significant suitable habitat range of the species will be lost in the KRI due to climate change by 2070 and (ii) the preference of the species for cooler areas (high altitude) with high annual precipitation. Conservation actions should focus on the mountainous areas (e.g., by establishment of national parks and protected areas) of the KRI as climate changes. These findings provide useful benchmarking guidance for the future investigation of the ecology of the oak forest, and the categorical current and potential habitat suitability maps can effectively be used to improve biodiversity conservation plans and management actions in the KRI and Iraq as a whole.
“Show this thread”: policing, disruption and mobilisation through Twitter. An analysis of UK law enforcement tweeting practices during the Covid-19 pandemic
Authors: Nikolovska Manja , Johnson Shane D. , Ekblom Paul
Published: October 2020

Crisis and disruption are often unpredictable and can create opportunities for crime. During such times, policing may also need to meet additional challenges to handle the disruption. The use of social media by officials can be essential for crisis mitigation and crime reduction. In this paper, we study the use of Twitter for crime mitigation and reduction by UK police (and associated) agencies in the early stages of the Covid-19 pandemic. Our findings suggest that whilst most of the tweets from our sample concerned issues that were not specifically about crime, especially during the first stages of the pandemic, there was a significant increase in tweets about fraud, cybercrime and domestic abuse. There was also an increase in retweeting activity as opposed to the creation of original messages. Moreover, in terms of the impact of tweets, as measured by the rate at which they are retweeted, followers were more likely to ‘spread the word’ when the tweet was content-rich (discussed a crime specific matter and contained media), and account holders were themselves more active on Twitter. Considering the changing world we live in, criminal opportunity is likely to evolve. To help mitigate this, policy makers and researchers should consider more systematic approaches to developing social media communication strategies for the purpose of crime mitigation and reduction during disruption and change more generally. We suggest a framework for so doing.
Survey on Van Gogh’s early painting technique through the non-invasive and multi analytical study of Head of peasant
Authors: Defeyt Catherine , Marechal Dominique , Vandepitte Francisca , Strivay David
Published: October 2020

The strong lighting of the face against a dark background, the bold brushstroke and the model’s expressiveness that characterize Van Gogh’s Head of peasant, belonging to the Royal Museums of Fine Arts of Belgium collections, are typical features found in the peasant heads studies painted in Nuenen, in March–April 1885, in prevision of the well-known The Potato Eaters. However, this oil painting additionally testifies of Van Gogh’s early experiments in regards with the laws of colors, the flesh rendering and portraying models under artificial light. In order to collect material and technical information revealing how the painter practically handled these issues, the Brussels peasant head has been investigated in situ by complementary non-invasive imaging and analytical methods. While the identified pigments strictly reflect Van Gogh’s palette in Nuenen, relevant outcomes regarding the flesh tones composition, the rendered forceful expression of the figure, the effect of a face painted by lamplight, and the use of simultaneous color contrasts were achieved.
A survey of methods supporting cyber situational awareness in the context of smart cities
Authors: Neshenko Nataliia , Nader Christelle , Bou-Harb Elias , Furht Borko
Published: October 2020

A modern urban infrastructure no longer operates in isolation, but instead, leverages the latest technologies to collect, process, and distribute aggregated knowledge in order to improve the quality of the provided services and promote the efficiency of resource consumption. This technological development, however, manifests in the form of new vulnerabilities and a plethora of attack vectors. In the same context, the ambiguity of ever-evolving cyber threats and their debilitating consequences introduce new barriers for decision-makers. Therefore, cyber situational awareness of smart cities emerges as a mission-critical task that requires support methods for effective and timely decision-making. In this article, we investigate the threat landscape of smart cities, survey and reveal the progress in data-driven methods for situational awareness and evaluate their effectiveness when addressing various cyber threats. We draw several potential research directions that aim at advancing cyber situational awareness in the context of smart cities.