bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating the effectiveness and cost-effectiveness of establishing additional endovascular Thrombectomy stroke Centres in England: a discrete event simulation
Authors: McMeekin Peter , Flynn Darren , Allen Mike , Coughlan Diarmuid , Ford Gary A. , Lumley Hannah , Balami Joyce S. , James Martin A. , Stein Ken , Burgess David , White Phil
Published: November 2019

Background

We have previously modelled that the optimal number of comprehensive stroke centres (CSC) providing endovascular thrombectomy (EVT) in England would be 30 (net 6 new centres). We now estimate the relative effectiveness and cost-effectiveness of increasing the number of centres from 24 to 30.

Methods

We constructed a discrete event simulation (DES) to estimate the effectiveness and lifetime cost-effectiveness (from a payer perspective) using 1 year’s incidence of stroke in England. 2000 iterations of the simulation were performed comparing baseline 24 centres to 30.

Results

Of 80,800 patients admitted to hospital with acute stroke/year, 21,740 would be affected by the service reconfiguration. The median time to treatment for eligible early presenters (< 270 min since onset) would reduce from 195 (IQR 155–249) to 165 (IQR 105–224) minutes. Our model predicts reconfiguration would mean an additional 33 independent patients (modified Rankin scale [mRS] 0–1) and 30 fewer dependent/dead patients (mRS 3–6) per year. The net addition of 6 centres generates 190 QALYs (95%CI − 6 to 399) and results in net savings to the healthcare system of £1,864,000/year (95% CI -1,204,000 to £5,017,000). The estimated budget impact was a saving of £980,000 in year 1 and £7.07 million in years 2 to 5.

Conclusion

Changes in acute stroke service configuration will produce clinical and cost benefits when the time taken for patients to receive treatment is reduced. Benefits are highly likely to be cost saving over 5 years before any capital investment above £8 million is required.
In vivo immunogenicity assessment and vaccine efficacy evaluation of a chimeric tandem repeat of epitopic region of OMP31 antigen fused to interleukin 2 (IL-2) against Brucella melitensis in BALB/c mice
Authors: Nazifi Narges , Tahmoorespur Mojtaba , Sekhavati Mohammad Hadi , Haghparast Alireza , Behroozikhah Ali Mohammad
Published: November 2019

Background

Designing a potent recombinant vaccine, using the appropriate subunits with the greatest effect on stimulating the immune system, especially in the case of intracellular pathogens such as gram negativeBrucella Melitensisbacteria, is of great importance. In this study, three repeats of 27 amino acids of the immunogenic epitope derived from OMP31 antigen (3E) from theBrucella melitensis, in a protective manner against Brucellosis have been used. To fortify the delivery system of recombinant antigens, IL-2 cytokine as a molecular adjuvant was fused to recombinant constructs. Recombinant proteins were evaluated for immunological studies in a mouse model (BALB/c).

Results

The results showed that all recombinant proteins could stimulate the immune system to produce Th1 cytokines and antibodies in compare to the negative control treatments. 3E-IL2 and then OMP31-IL2 proteins stimulated higher levels of IFN-γ and IL-2 compared to the other treatments (p < 0.05). Also, the results indicated that experimental treatments produced a higher level of IgG2a isotype than IgG1 isotype. In addition, the findings of the experiment showed that the presence of chemical adjuvant (IFA) along with molecular adjuvant can play a significant role in stimulating the immune system. After determining the potency of recombinant structures, their efficacy in stimulating the immune system were also evaluated.B. melitensis M16strain was used to challenge 30 days after last immunization. The microbial load of the splenocyte in the treatments receiving chimeric proteins were significantly lower. Also, Wright serological test confirmed that these treatments had the lowest agglutination rate, as well as the positive treatment, while in the negative treatments in excess of blood serum dilutions, agglutination rate were more than 2 + .

Conclusions

3E-IL2 treatment showed the best performance compared to other recombinant proteins and could be considered as the suitable candidate for further research on the production of recombinant vaccine against Brucella.
Significant random signatures reveals new biomarker for breast cancer
Authors: Saberi Ansar Elnaz , Eslahchii Changiz , Rahimi Mahsa , Geranpayeh Lobat , Ebrahimi Marzieh , Aghdam Rosa , Kerdivel Gwenneg
Published: November 2019

Background

In 2012, Venet et al. proposed that at least in the case of breast cancer, most published signatures are not significantly more associated with outcome than randomly generated signatures. They suggested that nominalp-value is not a good estimator to show the significance of a signature. Therefore, one can reasonably postulate that some information might be present in such significant random signatures.

Methods

In this research, first we show that, using an empiricalp-value, these published signatures are more significant than their nominalp-values. In other words, the proposed empiricalp-value can be considered as a complimentary criterion for nominalp-value to distinguish random signatures from significant ones. Secondly, we develop a novel computational method to extract information that are embedded within significant random signatures. In our method, a score is assigned to each gene based on the number of times it appears in significant random signatures. Then, these scores are diffused through a protein-protein interaction network and a permutation procedure is used to determine the genes with significant scores. The genes with significant scores are considered as the set of significant genes.

Results

First, we applied our method on the breast cancer dataset NKI to achieve a set of significant genes in breast cancer considering significant random signatures. Secondly, prognostic performance of the computed set of significant genes is evaluated using DMFS and RFS datasets. We have observed that the top ranked genes from this set can successfully separate patients with poor prognosis from those with good prognosis. Finally, we investigated the expression pattern of TAT, the first gene reported in our set, in malignant breast cancer vs. adjacent normal tissue and mammospheres.

Conclusion

Applying the method, we found a set of significant genes in breast cancer, including TAT, a gene that has never been reported as an important gene in breast cancer. Our results show that the expression of TAT is repressed in tumors suggesting that this gene could act as a tumor suppressor in breast cancer and could be used as a new biomarker.
RETRACTED ARTICLE: Silencing of TRIM11 suppresses the tumorigenicity of chordoma cells through improving the activity of PHLPP1/AKT
Authors: Wang Bin , Wang Gang , Wang Qingfeng , Zhu Ziqiang , Wang Yunqing , Chen Kangwu , Yang Huilin
Published: November 2019

Background

Tripartite motif-containing protein 11 (TRIM11), a member of RING family of E3 ubiquitin ligases, is identified as an oncogene in certain human tumors. However, the detailed biological function of TRIM11 in chordoma is still unclear. The purpose of present research is to explore the role of TRIM11 in human chordoma cells.

Methods

TRIM11 was induced silencing and overexpression in human chordoma cells using RNA interference (RNAi) and lentiviral vector. qRT-PCR and western blot were used to determine gene expression in chordomas cells. Meanwhile, cell counting kit-8 (CCK-8) assay was used to examine the cell proliferation rate. Flow cytometry analysis was performed to quantify the cell apoptosis rate.

Results

We identified that TRIM11 was upregulated in chordomas tissues. Moreover, TRIM11 presented pro-proliferation and anti-apoptosis function in chordoma cells. Further, LY294002, a specific AKT inhibitor, was utilized to examine the connection between TRIM11 and AKT in human chordoma cells. Importantly, our findings elucidated that TRIM11 promoted the growth of chordoma cells and involved in AKT signaling. Much more importantly, knockdown of TRIM11 significantly upregulated the translation of PH domain leucine-rich repeats protein phosphatase 1 (PHLPP1), whereas did not affect its transcription. Results that obtained from co-immunoprecipitation (Co-IP) and ubiquitination assay demonstrated TRIM11 interacted with PHLPP1 and promoted its ubiquitination in chordoma cells. Moreover, overexpression of PHLPP1 inhibited the phosphorylation of AKT in human chordomas cells. These results suggested that TRIM11 mediated the post-translation modification of PHLPP1 and was a novel component in PHLPP1/AKT signaling pathway in human chordoma cells.

Conclusions

Taken together, the present research not only enhanced the understanding of TRIM11 but also indicated its potential target and signaling pathway in human chordoma cells.

Trial registration retrospectively registered.
The effect of ivermectin® on fertility, fecundity and mortality of Anopheles arabiensis fed on treated men in Ethiopia
Authors: Mekuriaw Wondemeneh , Balkew Meshesha , Messenger Louisa A. , Yewhalaw Delenasaw , Woyessa Adugna , Massebo Fekadu
Published: November 2019

Background

Insecticide resistance is a growing threat to malaria vector control. Ivermectin, either administered to humans or animals, may represent an alternate strategy to reduce resistant mosquito populations. The aim of this study was to assess the residual or delayed effect of administering a single oral dose of ivermectin to humans on the survival, fecundity and fertility of Anopheles arabiensis in Ethiopia.

Methods

Six male volunteers aged 25–40 years (weight range 64–72 kg) were recruited; four of them received a recommended single oral dose of 12 mg ivermectin and the other two individuals were untreated controls. A fully susceptible insectary colony of An. arabiensis was fed on treated and control participants at 1, 4, 7, 10 and 13 days post ivermectin-administration. Daily mosquito mortality was recorded for 5 days. An. arabiensis fecundity and fertility were measured from day 7 post treatment, by dissection to examine the number of eggs per mosquito, and by observing larval hatching rates, respectively.

Results

Ivermectin treatment induced significantly higher An. arabiensis mortality on days 1 and 4, compared to untreated controls (p = 0.02 and p < 0.001, respectively). However, this effect had declined by day 7, with no significant difference in mortality between treated and control groups (p = 0.06). The mean survival time of mosquitoes fed on day 1 was 2.1 days, while those fed on day 4 survived 4.0 days. Mosquitoes fed on the treatment group at day 7 and 10 produced significantly lower numbers of eggs compared to the untreated controls (p < 0.001 and p = 0.04, respectively). An. arabiensis fed on day 7 on treated men also had lower larval hatching rates than mosquitoes fed on days 10 and 13 (p = 0.003 and p = 0.001, respectively).

Conclusion

A single oral dose of ivermectin given to humans can induce mortality and reduce survivorship of An. arabiensis for 7 days after treatment. Ivermectin also had a delayed effect on fecundity of An. arabiensis that took bloodmeals from treated individuals on day 7 and 10. Additional studies are warranted using wild, insecticide-resistant mosquito populations, to confirm findings and a phase III evaluation among community members in Ethiopia is needed to determine the impact of ivermectin on malaria transmission.
The Pfs230 N-terminal fragment, Pfs230D1+: expression and characterization of a potential malaria transmission-blocking vaccine candidate
Authors: Lee Shwu-Maan , Wu Yimin , Hickey John M. , Miura Kazutoyo , Whitaker Neal , Joshi Sangeeta B. , Volkin David B. , Richter King C. , Plieskatt Jordan
Published: November 2019

Background

Control and elimination of malaria can be accelerated by transmission-blocking interventions such as vaccines. A surface antigen of Plasmodium falciparum gametocytes, Pfs230, is a leading vaccine target antigen, and has recently progressed to experimental clinical trials. To support vaccine product development, an N-terminal Pfs230 antigen was designed to increase yield, as well as to improve antigen quality, integrity, and homogeneity.

Methods

A scalable baculovirus expression system was used to express the Pfs230D1+ construct (aa 552–731), which was subsequently purified and analysed. Pfs230D1+ was designed to avoid glycosylation and protease digestion, thereby potentially increasing homogeneity and stability. The resulting Pfs230D1+ protein was compared to a previous iteration of the Pfs230 N-terminal domain, Pfs230C1 (aa 443–731), through physiochemical characterization and in vivo analysis. The induction of functional antibody responses was confirmed via the standard membrane feeding assay (SMFA).

Results

Pfs230D1+ was produced and purified to an overall yield of 23 mg/L culture supernatant, a twofold yield increase over Pfs230C1. The Pfs230D1+ protein migrated as a single band via SDS-PAGE and was detected by anti-Pfs230C1 monoclonal antibodies. Evaluation by SDS-PAGE, chromatography (size-exclusion and reversed phase) and capillary isoelectric focusing demonstrated the molecule had improved homogeneity in terms of size, conformation, and charge. Intact mass spectrometry confirmed its molecular weight and that it was free of glycosylation, a key difference to the prior Pfs230C1 protein. The correct formation of the two intramolecular disulfide bonds was initially inferred by binding of a conformation specific monoclonal antibody and directly confirmed by LC/MS and peptide mapping. When injected into mice the Pfs230D1+ protein elicited antibodies that demonstrated transmission-reducing activity, via SMFA, comparable to Pfs230C1.

Conclusion

By elimination of an O-glycosylation site, a potential N-glycosylation site, and two proteolytic cleavage sites, an improved N-terminal Pfs230 fragment was produced, termed D1+, which is non-glycosylated, homogeneous, and biologically active. An intact protein at higher yield than that previously observed for the Pfs230C1 fragment was achieved. The results indicate that Pfs230D1+ protein produced in the baculovirus expression system is an attractive antigen for transmission-blocking vaccine development.
The population randomization observation process (PROP) assessment method: using systematic habitation observations of street segments to establish household-level epidemiologic population samples
Authors: Smart Mieka , Sadler Richard , Harris Alan , Buchalski Zachary , Pearson Amber , Debra Furr-Holden C.
Published: November 2019

Background

Identifying and intervening on health disparities requires representative community public health data. For cities with high vacancy and transient populations, traditional methods of population estimation for refining random samples are not feasible. The aim of this project was to develop a novel method for systematic observations to establish community epidemiologic samples.

Results

We devised a four-step population randomization observation process for Flint, Michigan, USA: (1) Use recent total population data for community areas (i.e., neighborhoods) to establish the proportional sample size for each area, (2) Randomly select street segments of each community area, (3) Deploy raters to conduct observations about habitation for each randomly selected segment, and (4) Complete observations for second and third street segments, depending on vacancy levels. We implemented this systematic observation process on 400 randomly selected street segments. Of these, 130 (32.5%) required assessment of secondary segments due to high vacancy. Among the 130 primary segments, 28 (21.5%) required assessment of tertiary (or more) segments. For 71.5% of the 400 primary street segments, there was consensus among raters on whether the dwelling inhabited or uninhabited.

Conclusion

Houses observed with this method could have easily been considered uninhabited via other methods. This could cause residents of ambiguous dwellings (likely to be the most marginalized residents with highest levels of unmet health needs) to be underrepresented in the resultant sample.
A simple and rapid protocol for the genetic transformation of Ensete ventricosum
Authors: Matheka Jonathan , Tripathi Jaindra Nath , Merga Ibsa , Gebre Endale , Tripathi Leena
Published: November 2019

Enset (Ensete ventricosum), also known as Ethiopian banana, is a food security crop for more than 20 million people in Ethiopia. As conventional breeding of enset is very challenging, genetic engineering is an alternative option to introduce important traits such as enhanced disease resistance and nutritional value. Genetic transformation and subsequent regeneration of transgenic enset has never been reported mainly due to challenges in developing transformation protocols for this tropical species. Agrobacterium-mediated transformation could be a practical tool for the genetic improvement of enset. However, the efficiency of the transformation system depends on several parameters such as plant regeneration, genotype, explant, selection agent and Agrobacterium strains. As a first step towards the development of transgenic enset, a simple and rapid plant regeneration system was developed using multiple buds as explants. Induction and proliferation of multiple buds from shoot tip explants was achieved on Murashige and Skoog (MS) medium supplemented with 5 and 10 mg/l of 6-benzylaminopurine (BAP), respectively. Shoots were regenerated from multiple buds on MS media containing 2 mg/l BAP and 0.2% activated charcoal. Based on the optimized regeneration protocol, an Agrobacterium-mediated transformation method was developed using multiple buds as explants and the binary plasmid pCAMBIA2300-GFP containing the green florescent protein (gfp) reporter gene and neomycin phosphotransferase II (nptII) selection marker gene. Transgenic plantlets were obtained within 4 months at a frequency of about 1.25%. The transgenic lines were validated by PCR analysis using primers specific to the nptII gene. To obtain uniformly transformed plantlets, chimerism was diluted by subculturing and regenerating the transgenic shoots on a selective medium containing kanamycin (150 mg/l) for five cycles. The uniformity of the transgenic plants was confirmed by Southern blot hybridization and RT-PCR analyses on different tissues such as leaf, pseudostem and root of same transgenic plant. In the present study, we report a simple Agrobacterium-mediated transformation system for generating transgenic events of enset. To the best of our knowledge, this is the first report on the stable transformation and regeneration of transgenic events of enset. The transformation system established in this study can be used for the generation of transgenic enset with important traits such as disease resistance.
Risk factors for implant failure in reverse oblique and transverse intertrochanteric fractures treated with proximal femoral nail antirotation (PFNA)
Authors: Hao Youliang , Zhang Zhishan , Zhou Fang , Ji Hongquan , Tian Yun , Guo Yan , Lv Yang , Yang Zhongwei , Hou Guojin
Published: November 2019

Background

The incidence of intertrochanteric hip fracture is expected to increase as the global population ages. It is one of the most important causes of mortality and morbidities in the geriatric population. The incidence of reverse oblique and transverse intertrochanteric (AO/OTA 31-A3) fractures is relatively low; however, the incidence of implant failure in AO/OTA 31-A3 fractures is relatively high compared with that in AO/OTA 31-A1 and A2 fractures. To date, the risk factors for implant failure in AO/OTA 31-A3 fractures treated with proximal femoral nail antirotation (PFNA) have remained ambiguous. The purpose of this study was to identify the predictive factors of implant failure in AO/OTA 31-A3 fractures treated with PFNA.

Methods

The data of all patients who underwent surgery for trochanteric fractures at our institution between January 2006 and February 2018 were retrospectively reviewed. All AO/OTA 31-A3 fractures treated with PFNA were included. Logistic regression analysis of potential predictors of implant failure was performed. Potential predictors included age, sex, body mass index, fracture type, reduction method, status of posteromedial support and lateral femoral wall, reduction quality, tip-apex distance and position of the helical blade in the femoral head.

Results

One hundred four (9.3%) patients with AO/OTA 31-A3 fractures were identified. Forty-five patients with AO/OTA 31-A3 fractures treated with PFNA were suitable for our study. Overall, implant failure occurred in six (13.3%) of forty-five patients. Multivariate analysis identified poor reduction quality (OR, 28.70; 95% CI, 1.91–431.88; p = 0.015) and loss of posteromedial support (OR, 18.98; 95% CI, 1.40–257.08; p = 0.027) as factors associated with implant failure.

Conclusions

Poor reduction quality and loss of posteromedial support are predictors of implant failure in reverse oblique and transverse intertrochanteric fractures treated with PFNA.
The effect of impulsivity and inhibitory control deficits in the saccadic behavior of premanifest Huntington’s disease individuals
Authors: Júlio Filipa , Caetano Gina , Januário Cristina , Castelo-Branco Miguel
Published: November 2019

Background

This study aims to test response inhibition in premanifest Huntington’s disease individuals (Pre-HD), in the context of a saccadic paradigm with working memory demands and fronto-executive load as a way to measure inhibitory control deficits and impulsive behavior in Huntington’s disease (HD).

Methods

The oculomotor function of 15 Pre-HD and 22 Control individuals was assessed using an experimental paradigm comprising four horizontal saccadic tasks: prosaccade (PS), antisaccade (AS), 1- or 2-back memory prosaccade (MPS), and 1- or 2-back memory antisaccade (MAS). Success rate, latency, directional and timing errors were calculated for each task. A comprehensive battery of neuropsychological tests was also used to assess the overall cognitive functioning of study participants. Statistical correlations between oculomotor, clinical and cognitive measures were computed for the Pre-HD group.

Results

Pre-HD participants showed reduced success rate in the AS task, increased direction errors in the AS and MAS tasks and decreased latency in the MAS task when compared to Controls, despite presenting similar executive and memory scores in the conventional neuropsychological tests applied. Significant associations were identified between specific AS and MAS parameters and disease-related measures, cognitive skills and other oculomotor results of Pre-HD participants.

Conclusions

Our results show that oculomotor performance in premanifest Huntington’s disease deteriorates once inhibitory control, working memory and/or fronto-executive load are added to the task. A more automatic pattern of performance, including a faster response time and directionally erroneous eye movements were detected in the oculomotor behavior of the Pre-HD group—these alterations were significantly correlated with disease stage and cognitive status. Our saccadic paradigm was able to capture impulsivity and inhibitory control deficits in a group of Pre-HD individuals on average far from symptom onset, thus holding the potential to identify the earliest disease-related changes.
A hospital-based cancer registry in Luanda, Angola: the Instituto Angolano de Controlo do Cancer (IACC) Cancer registry
Authors: Miguel Fernando , Bento Maria José , de Lacerda Gonçalo Forjaz , Weiderpass Elisabete , Santos Lúcio Lara
Published: November 2019

Background

The Instituto Angolano de Controlo do Cancer (IACC) Cancer Registry in Luanda, Angola is the most ancient and organized hospital-based cancer registry in Angola and provides data on cancer cases treated in several hospital facilities in Luanda.

Methods

Newly-diagnosed cancer cases (2012–2016) of IACC were collected. A total of 6638 malignant neoplasms were recorded. After excluding duplicates, missing data and non-melanoma skin cancers cases, a final number of 5609 cancer cases was considered valid for analysis.

Results

From 5609 new cases, 2059 were males and 3550 females. Of all cases, 9.7% was in children below the age of 15 years. Most of the cases were residents from the Luanda district. The five most common cancers for all periods were breast (21.4%), cervix (16.8%), prostate (7.1%), non-Hodgkin lymphoma (4.5%) and Kaposi sarcoma (4.3%). For men, 19.3% of the cancers were prostate, 7.5% Kaposi sarcoma and 7.5% non-Hodgkin lymphoma. Cancers of the breast and cervix together accounted 60% of all cancers in females. Comparison of our data onto the 5 most frequent tumours, by sex, according to GLOBOCAN 2018 estimations for Angola, highlights the potential deviation from reality that estimates may have and reinforces the urgent need to build a truly population-based cancer registry in Luanda.

Conclusion

To accomplish that task, it is mandatory to implement a more rigorous quality control program at the hospital-based cancer registry at IACC and to optimize the network of health institutions that actively working on and contributing to the cancer registry, in Luanda.
Curcumin derivative WZ35 inhibits tumor cell growth via ROS-YAP-JNK signaling pathway in breast cancer
Authors: Wang Lihua , Wang Canwei , Tao Zheying , Zhao Liqian , Zhu Zheng , Wu Wencan , He Ye , Chen Hong , Zheng Bin , Huang Xiangjie , Yu Yun , Yang Linjun , Liang Guang , Cui Ri , Chen Tongke
Published: November 2019

Background

Breast cancer is the most prevalent cancer among women worldwide. WZ35, an analog of curcumin, has been demonstrated to remarkably improve the pharmacokinetic profiles in vivo compared with curcumin. WZ35 exhibits promising antitumor activity in gastric cancer, HCC, colon cancer. However, antitumor effects of WZ35 in breast cancer and its underlying molecular mechanisms remain unclear.

Methods

CCK8, Flow cytometry and transwell assays were used to measure cell proliferation, cell cycle arrest, apoptosis, cell migration and invasion. We constructed xenograft mouse model and lung metastasis model to assess the antitumor activities of WZ35 in vivo. To explore the underlying molecular mechanisms of WZ35, we performed a series of overexpression and knockdown experiments. The cellular oxygen consumption rates (OCRs) was measured to assess mitochondrial dysfunction.

Results

We found that treatment of breast cancer cells with WZ35 exerts stronger anti-tumor activities than curcumin both in vitro and in vivo. Mechanistically, our research showed that WZ35 induced reactive oxygen species (ROS) generation and subsequent YAP mediated JNK activation in breast cancer cells. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP and JNK activation. In addition, ROS mediated YAP and JNK activation induced mitochondrial dysfunction in breast cancer cells.

Conclusion

Our study showed that novel anti-cancer mechanisms of WZ35 in breast cancer cells and ROS-YAP-JNK pathway might be a potential therapeutic target for the treatment of breast cancer patients.
Upregulation of CENPM promotes hepatocarcinogenesis through mutiple mechanisms
Authors: Xiao Yusha , Najeeb Rahmathullah Mohamed , Ma Dong , Yang Kang , Zhong Qiu , Liu Quanyan
Published: November 2019

Background

Hepatocellular carcinoma (HCC) still remains a dominating medical challenge in early diagnosis and clinical therapy. Centromere protein M (CENPM) has been proved to be over-expressed in HCC tissues, but carcinogenic mechanism of CENPM contributing to liver cancer is poorly understood.

Methods

In this study, we first explored mRNA and protein levels of CENPM in HCC samples, matching adjacent non-tumor tissues and six hepatoma cell lines by polymerase chain reaction (PCR), western blotting and immunohistochemistry (IHC). Clinical data of HCC patients downloaded from The Cancer Genome Atlas (TCGA) were also analyzed. The character of CENPM concerned with HCC progression through several functional experimentations in vitro and in vivo was researched. Bioinformatics was carried out to further discover biological functions of CENPM.

Results

CENPM was positively up-regulated in HCC and connected with a poor prognosis. Silencing CENPM repressed cell proliferation in vivo and in vitro, and knock-down CENPM inhibited cell migration and invasion. Additionally, depletion of CENPM can promote cell apoptosis and arrested cell cycle. Furthermore, single-gene gene set enrichment analysis (GSEA) analysis indicated that CENPM was linked to the P53 signaling pathway and cell cycle pathway, and our research supported this prediction. Finally, we also found that miR-1270 was a negative regulator and participated in post-transcriptional regulation of CENPM, and hepatitis B virus X protein (HBx) can promote hepatocellular carcinoma by suppressing miR1270.

Conclusion

CENPM was closely associated with HCC progression and it could be considered as a new possible biomarker along with a therapeutic target for HCC.
Targeting the Formyl Peptide Receptor type 1 to prevent the adhesion of ovarian cancer cells onto mesothelium and subsequent invasion
Authors: Minopoli Michele , Botti Giovanni , Gigantino Vincenzo , Ragone Concetta , Sarno Sabrina , Motti Maria Letizia , Scognamiglio Giosuè , Greggi Stefano , Scaffa Cono , Roca Maria Serena , Stoppelli Maria Patrizia , Ciliberto Gennaro , Losito Nunzia Simona , Carriero Maria Vincenza
Published: November 2019

Background

The biological behavior of epithelial ovarian cancer (EOC) is unique since EOC cells metastasize early to the peritoneum. Thereby, new anti-target agents designed to block trans-coelomic dissemination of EOC cells may be useful as anti-metastatic drugs. The Urokinase Plasminogen Activator Receptor (uPAR) is overexpressed in EOC tissues, and its truncated forms released in sera and/or ascitic fluid are associated with poor prognosis and unfavorable clinical outcome. We documented that uPAR triggers intra-abdominal dissemination of EOC cells through the interaction of its 84–95 sequence with the Formyl Peptide Receptor type 1 (FPR1), even as short linear peptide Ser-Arg-Ser-Arg-Tyr (SRSRY). While the pro-metastatic role of uPAR is well documented, little information regarding the expression and role of FPR1 in EOC is currently available.

Methods

Expression levels of uPAR and FPR1 in EOC cells and tissues were assessed by immunofluorescence, Western blot, or immunohystochemistry. Cell adhesion to extra-cellular matrix proteins and mesothelium as well as mesothelium invasion kinetics by EOC cells were monitored using the xCELLigence technology or assessed by measuring cell-associated fluorescence. Cell internalization of FPR1 was identified on multiple z-series by confocal microscopy. Data from in vitro assays were analysed by one-way ANOVA and post-hoc Dunnett t-test for multiple comparisons. Tissue microarray data were analyzed with the Pearson’s Chi-square (χ2) test.

Results

Co-expression of uPAR and FPR1 by SKOV-3 and primary EOC cells confers a marked adhesion to vitronectin. The extent of cell adhesion decreases to basal level by pre-exposure to anti-uPAR84–95 Abs, or to the RI-3 peptide, blocking the uPAR84–95/FPR1 interaction. Furthermore, EOC cells exposed to RI-3 or desensitized with an excess of SRSRY, fail to adhere also to mesothelial cell monolayers, losing the ability to cross them. Finally, primary and metastatic EOC tissues express a high level of FPR1.

Conclusions

Our findings identify for the first time FPR1 as a potential biomarker of aggressive EOC and suggests that inhibitors of the uPAR84–95/FPR1 crosstalk may be useful for the treatment of metastatic EOC.
Clarithromycin synergizes with cisplatin to inhibit ovarian cancer growth in vitro and in vivo
Authors: Zhou Bo , Xia Meng , Wang Bin , Thapa Niresh , Gan Lijuan , Sun Chaoyang , Guo Ensong , Huang Jia , Lu Yulan , Cai Hongbin
Published: November 2019

Background

Cisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment often occurs in epithelial ovarian cancer, and effective and practical methods for overcoming this obstacle are urgently needed. The study aimed to demonstrate the synergistic effect of clarithromycin (CAM) with cisplatin to inhibit ovarian carcinoma cells growth in vitro and in vivo.

Results

We performed CCK-8 assay to detect apoptosis rates in response to CAM alone or in combination with cisplatin, which were further confirmed by Annexin V and PI staining methods and western blotting. Mechanistically, CAM could reduce endogenous antioxidant enzyme expression and increase the levels of reactive oxygen species (ROS) to augment the cytotoxic effect of cisplatin. Meanwhile, a tumor xenograft model in athymic BALB/c-nude mice demonstrated that CAM combined with cisplatin resulted in reduced tumor growth and weight compared with cisplatin alone.

Conclusion

Collectively, our results indicate that CAM works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.
CRUP: a comprehensive framework to predict condition-specific regulatory units
Authors: Ramisch Anna , Heinrich Verena , Glaser Laura V. , Fuchs Alisa , Yang Xinyi , Benner Philipp , Schöpflin Robert , Li Na , Kinkley Sarah , Römer-Hillmann Anja , Longinotto John , Heyne Steffen , Czepukojc Beate , Kessler Sonja M. , Kiemer Alexandra K. , Cadenas Cristina , Arrigoni Laura , Gasparoni Nina , Manke Thomas , Pap Thomas , Pospisilik John A. , Hengstler Jan , Walter Jörn , Meijsing Sebastiaan H. , Chung Ho-Ryun , Vingron Martin
Published: November 2019

We present the software Condition-specific Regulatory Units Prediction (CRUP) to infer from epigenetic marks a list of regulatory units consisting of dynamically changing enhancers with their target genes. The workflow consists of a novel pre-trained enhancer predictor that can be reliably applied across cell types and species, solely based on histone modification ChIP-seq data. Enhancers are subsequently assigned to different conditions and correlated with gene expression to derive regulatory units. We thoroughly test and then apply CRUP to a rheumatoid arthritis model, identifying enhancer-gene pairs comprising known disease genes as well as new candidate genes.
Transcriptomic analysis of reproductive damage in the epididymis of male Kunming mice induced by chronic infection of Toxoplasma gondii PRU strain
Authors: Zheng Yu-Xiang , Zhang Xiu-Xiang , Hernandez Jorge A. , Mahmmod Yasser S. , Huang Wan-Yi , Li Gui-Feng , Wang Ya-Pei , Zhou Xue , Li Xiu-Ming , Yuan Zi-Guo
Published: November 2019

Background

Some researchers have reported that Toxoplasma gondii can cause serious reproductive impairment in male animals. Specifically, T. gondii destroy the quality of sperm in the epididymis, which affects their sexual ability. However, among such studies, none have investigated the male reproductive transcriptome. Therefore, to investigate the relationship between T. gondii and sperm maturation, we infected mice with T. gondii prugniaud (PRU) strain and performed transcriptome sequencing of the epididymis.

Results

Compared with the control group, 431 upregulated and 229 downregulated differentially expressed genes (DEGs) were found (P-value < 0.05, false discovery rate (FDR) < 0.05 and |log2 (fold change)| ≥ 1). According to results of a bioinformatics analysis, Gene Ontology (GO) function is divided into three categories: cellular component, molecular function and biological process. Upon performing GO analysis, we found that some DEGs correlated with an integral part of membrane, protein complex, cell surface, ATP binding, immune system process, signal transduction and metabolic process which are responsible for the epididymal injury. DEGs were mapped to 101 unique KEGG pathways. Pathways such as cytokine-cytokine receptor interaction, glycolysis/gluconeogenesis and apoptosis are closely related to sperm quality. Moreover, Tnfsf10 and spata18 can damage the mitochondria in sperm, which decreases sperm motility and morphology.

Conclusions

We sequenced the reproductive system of male mice chronically infected with T. gondii, which provides a new direction for research into male sterility caused by Toxoplasma infection. This work provides valuable information and a comprehensive database for future studies of the interaction between T. gondii infection and the male reproductive system.
Initial loss to follow up among tuberculosis patients: the role of Ward-Based Outreach Teams and short message service (SMS) technology (research proposal)
Authors: Mwansa-Kambafwile Judith R. M. , Chasela Charles , Ismail Nazir , Menezes Colin
Published: November 2019

Introduction

Tuberculosis (TB) is a problem in South Africa. Initial loss to follow up (LTFU) among TB patients is high varying between 14.9 and 18%. Some of the reasons for this are: lack of proper communication between patient and staff on next steps after testing, not aware that results are ready; and other competing priorities. Receiving reminder messages that result is ready is an intervention that can be explored to reduce initial LTFU. This can be through either receiving a note from the Ward-Based Outreach Teams (WBOTs) or via short message service (SMS) advising the patient to collect test result at the facility. This proposal aims to assess the effectiveness of WBOTs or SMS technology in reducing TB initial LTFU.

Methods

This will be a mixed methods approach. In depth interviews with WBOT Managers and TB Program Managers will be conducted. Focus group discussions with WBOT members will also be conducted. Two interventions (enhanced WBOTs/SMS technology) will be tested using a 3 arm randomized controlled trial (standard of care, SMS technology or enhanced WBOTs). The WBOTs will deliver paper note reminders while SMS intervention will entail sending reminder SMS messages to patients as soon as TB results are ready.
Lower-body positive pressure diminishes surface blood flow reactivity during treadmill walking
Authors: Tajino Junichi , Ito Akira , Torii Yusuke , Tsuchimoto Koji , Iijima Hirotaka , Zhang Xiangkai , Tanima Momoko , Yamaguchi Shoki , Ieki Hiroshi , Kakinoki Ryosuke , Kuroki Hiroshi
Published: November 2019

Objective

The purpose of this study was to determine the effects of the lower-body positive pressure on surface blood flow during standing still and treadmill walking to explore cardiovascular safety for application to rehabilitation treatment. Thirteen healthy volunteers participated in the experiment and surface blood flows were measured in the forehead, thigh, calf, and the top of the foot during standing still and walking under various pressure conditions (0 kPa, 5 kPa, and 6.7 kPa).

Results

Lower-body positive pressure decreased the blood flow in the forehead and the thigh during walking (p < .05 for each), whereas an increasing trend in blood flow was observed during standing still (p < .05). Furthermore, in the forehead and thigh, the extent of blood flow increase at the onset of walking was found to decrease in accordance with the applied pressure (p < .01 for each). These findings suggest that during walking, lower-body positive pressure modulates the blood flow, which implies safeness of this novel apparatus for use during orthopedic rehabilitation treatment.
Cell cycle dynamics during diapause entry and exit in an annual killifish revealed by FUCCI technology
Authors: Dolfi Luca , Ripa Roberto , Antebi Adam , Valenzano Dario Riccardo , Cellerino Alessandro
Published: November 2019

Background

Annual killifishes are adapted to surviving and reproducing over alternating dry and wet seasons. During the dry season, all adults die and desiccation-resistant embryos remain encased in dry mud for months or years in a state of diapause where their development is halted in anticipation of the months that have to elapse before their habitats are flooded again. Embryonic development of annual killifishes deviates from canonical teleost development. Epiblast cells disperse during epiboly, and a “dispersed phase” precedes gastrulation. In addition, annual fish have the ability to enter diapause and block embryonic development at the dispersed phase (diapause I), mid-somitogenesis (diapause II) and the final phase of development (diapause III). Developmental transitions associated with diapause entry and exit can be linked with cell cycle events. Here we set to image this transition in living embryos.

Results

To visibly explore cell cycle dynamics during killifish development in depth, we created a stable transgenic line inNothobranchius furzerithat expresses two fluorescent reporters, one for the G1phase and one for the S/G2phases of the cell cycle, respectively (Fluorescent Ubiquitination-based Cell Cycle Indicator, FUCCI). Using this tool, we observed that, during epiboly, epiblast cells progressively become quiescent and exit the cell cycle. All embryos transit through a phase where dispersed cells migrate, without showing any mitotic activity, possibly blocked in the G1phase (diapause I). Thereafter, exit from diapause I is synchronous and cells enter directly into the S phase without transiting through G1. The developmental trajectories of embryos entering diapause and of those that continue to develop are different. In particular, embryos entering diapause have reduced growth along the medio-lateral axis. Finally, exit from diapause II is synchronous for all cells and is characterized by a burst of mitotic activity and growth along the medio-lateral axis such that, by the end of this phase, the morphology of the embryos is identical to that of direct-developing embryos.

Conclusions

Our study reveals surprising levels of coordination of cellular dynamics during diapause and provides a reference framework for further developmental analyses of this remarkable developmental quiescent state.
Prosthetic rehabilitation with fixed prosthesis of a 5-year-old child with Hypohidrotic Ectodermal Dysplasia and Oligodontia: a case report
Authors: AlNuaimi Reema , Mansoor Mohammad
Published: November 2019

Background

Ectodermal dysplasia is a rare genetic disorder that affects ectodermally derived structures, including teeth, nails, hair, and sweat glands. Hypohidrotic ectodermal dysplasia is the most common type, with oligodontia being the most striking dental feature. Prosthetic rehabilitation in children with ectodermal dysplasia is an important step toward improving their overall quality of life. The fixed prosthesis has the advantages of being more stable in the mouth with good child compliance and a good aesthetic outcome.

Case presentation

Our patient was a 5-year-old Middle Eastern boy with oligodontia caused by ectodermal dysplasia. He was managed by fabrication of an upper functional space maintainer and a lower fixed partial denture to restore occlusion, masticatory function, aesthetics, and overall quality of life.

Conclusions

The use of the fixed prosthesis in children is a new and evolving treatment modality that resolves many of the issues caused by removable prostheses. It accommodates jaw growth in the mandible, reduces the need to remake the prosthesis, and has an overall better aesthetic outcome.
Construction of a family of non-stationary biorthogonal wavelets
Authors: Zhang Baoxing , Zheng Hongchan , Zhou Jie , Pan Lulu
Published: November 2019

The family of exponential pseudo-splines is the non-stationary counterpart of the pseudo-splines and includes the exponential B-spline functions as special members. Among the family of the exponential pseudo-splines, there also exists the subclass consisting of interpolatory cardinal functions, which can be obtained as the limits of the exponentials reproducing subdivision. In this paper, we mainly focus on this subclass of exponential pseudo-splines and propose their dual refinable functions with explicit form of symbols. Based on this result, we obtain the corresponding biorthogonal wavelets using the non-stationary Multiresolution Analysis (MRA). We verify the stability of the refinable and wavelet functions and show that both of them have exponential vanishing moments, a generalization of the usual vanishing moments. Thus, these refinable and wavelet functions can form a non-stationary generalization of the Coifman biorthogonal wavelet systems constructed using the masks of the D–D interpolatory subdivision.
Factor structure of the Night Eating Diagnostic Questionnaire (NEDQ) and an evaluation of the diagnostic criteria of the night eating syndrome
Authors: Nolan Laurence J. , Geliebter Allan
Published: November 2019

Background

The Night Eating Diagnostic Questionnaire (NEDQ) is a validated assessment of the night eating syndrome (NES) based on the proposed diagnostic criteria. While past results show that NEDQ is associated with psychopathology and body mass index (BMI), the relationships between the proposed NES diagnostic criteria and psychopathology and BMI have not been investigated. Thus, the relationships between the proposed NES diagnostic criteria and factors previously associated with NES, namely depression, “food addiction” (FA), sleep quality, and BMI were examined. Finally, the NEDQ factor structure was examined for the first time in order to determine whether the NEDQ is assessing NES appropriately.

Methods

The NEDQ, depression, sleep quality, and FA questionnaires were administered to a sample of older community members (n = 468) and a student sample (n = 254). Principal Components Analysis (PCA) was performed to examine the factor structure of the NEDQ. The relationships between the proposed diagnostic criteria and depression, sleep quality, FA, and BMI were examined using multiple regression.

Results

The proposed NES criteria were highly intercorrelated. PCA revealed a single factor solution for the NEDQ. In the community sample, depression was associated with the presence of five of nine proposed diagnostic criteria while poor sleep quality and FA were associated with the presence of seven and six criteria respectively. In the community sample, only the sleep problems and impairment/distress criteria were positively associated with BMI. In the student sample, fewer criteria were associated with psychopathology, and no criteria were associated with BMI.

Conclusions

These findings support the proposed criteria for diagnosis of NES. All proposed criteria were associated with at least one psychopathology measure. BMI was only associated with the sleep problems and impairment/distress criteria in the community sample. The PCA finding of a single factor indicates that the NEDQ is a cohesive assessment of NES, and that the NEDQ is a good measure of NES criteria.
Region-specific interneuron demyelination and heightened anxiety-like behavior induced by adolescent binge alcohol treatment
Authors: Rice James , Coutellier Laurence , Weiner Jeffrey L. , Gu Chen
Published: November 2019

Adolescent binge drinking represents a major public health challenge and can lead to persistent neurological and mental conditions, but the underlying pathogenic mechanisms remain poorly understood. Using a mouse model of adolescent binge ethanol treatment (ABET), we found that this treatment induced behavioral changes associated with demyelination in different brain regions. After ABET, adolescent mice exhibited anxiogenic behaviors with no change in locomotion on the elevated plus maze, and impaired spatial memory indicated by a significant reduction in spontaneous alternation in the Y maze test. Both effects persisted into adulthood. Anatomical studies further showed that ABET induced a significant reduction of parvalbumin-positive (PV+) GABAergic interneurons and myelin density in the hippocampus and medial prefrontal cortex (mPFC). While these deficits in PV+ interneurons and myelin persisted into early adulthood in the hippocampus, the myelin density recovered in the mPFC. Moreover, whereas ABET mainly damaged myelin of PV+ axons in the hippocampus, it primarily damaged myelin of PV-negative axons in the mPFC. Thus, our findings reveal that an adolescent binge alcohol treatment regimen disrupts spatial working memory, increases anxiety-like behaviors, and exerts unique temporal and spatial patterns of gray matter demyelination in the hippocampus and mPFC.