bluuebunny/crossref_metadata_2025 huggingface dataset:
Studying the gut virome in the metagenomic era: challenges and perspectives
Authors: Garmaeva Sanzhima , Sinha Trishla , Kurilshikov Alexander , Fu Jingyuan , Wijmenga Cisca , Zhernakova Alexandra
Published: October 2019

The human gut harbors a complex ecosystem of microorganisms, including bacteria and viruses. With the rise of next-generation sequencing technologies, we have seen a quantum leap in the study of human-gut-inhabiting bacteria, yet the viruses that infect these bacteria, known as bacteriophages, remain underexplored. In this review, we focus on what is known about the role of bacteriophages in human health and the technical challenges involved in studying the gut virome, of which they are a major component. Lastly, we discuss what can be learned from studies of bacteriophages in other ecosystems.
Characterization and pathogenicity of fowl adenovirus serotype 4 isolated from eastern China
Authors: Wang Kai , Sun Haiwei , Li Yunzhang , Yang Zhiwei , Ye Jianqiang , Chen Hongjun
Published: October 2019

Background

Fowl adenovirus outbreaks have occurred in China since June 2015. This virus is an emerging infectious disease that causes hydropericardium syndrome and inclusion body hepatitis (HPS-IBH), resulting in significant economic loss to poultry farmers. Five fowl adenovirus (FAdV) strains (HN, AQ, AH726, JS07 and AH712) were isolated from Jiangsu and Anhui provinces.

Results

Phylogenetic analysis revealed that the five isolates belonged to species C fowl adenovirus serotype 4. An 11 amino-acid deletion in ORF29, relative to an older viral isolate, JSJ13, was observed for all five strains described here. In chicken experiments, 80–100% birds died after intramuscular inoculation and displayed lesions characteristic of HPS-IBH. The viral DNA copies were further detected by hexon-probe based real-time polymerase chain reaction (PCR) in the chicken samples. The viral loads and cytokine profiles were recorded in all the organs after infections. Despite minor genetic differences, the 5 strains displayed significantly different tissue tropisms and cytokine profiles.

Conclusions

Our data enhance the current understanding some of the factors involved in the pathogenicity and genetic diversity of the FAdV serotype 4 (FAdV-4) in China. Our work provides theoretical support for the prevention and control of HPS-IBH in chickens.
No evidence of avian influenza antibodies in two species of raptor nestlings inhabiting Norway
Authors: Lee Megan Marie , Jaspers Veerle L. B. , Løseth Mari E. , Briels Nathalie , Nygård Torgeir , Bustnes Jan Ove , Waugh Courtney A.
Published: October 2019

Background

Since 2016, incursions of highly pathogenic avian influenza virus (HPAIV) H5N8 clade 2.3.4.4b have caused unprecedented clinical signs and mortality in white-tailed eagles (WTE;Haliaeetus albicilla) across Europe and have been found to be infecting other raptor species, such as the northern goshawk (NG;Accipiter gentilis). Before this study, no screening of Norwegian raptors had been undertaken.

Results

Plasma samples from 43 white-tailed eagle and 29 northern goshawk nestlings, from several locations across Norway were screened for antibodies to avian influenza viruses. No antibodies, and thus, no evidence of AIV exposure, were found in these Norwegian raptors. No clinical signs of AIV were observed in 43 white tailed eagles and 29 northern goshawks.

Conclusions

There are currently no indications that white-tailed eagles and northern goshawks inhabiting Norway are threatened by the recent HPAIV outbreaks in other areas of Europe. Ongoing monitoring should, however, be maintained to detect potential future outbreaks.
Assessment of myocardial function in obstructive hypertrophic cardiomyopathy cats with and without response to medical treatment by carvedilol
Authors: Suzuki Ryohei , Mochizuki Yohei , Yuchi Yunosuke , Yasumura Yuyo , Saito Takahiro , Teshima Takahiro , Matsumoto Hirotaka , Koyama Hidekazu
Published: October 2019

Background

Inconsistency of treatment response in cats with obstructive hypertrophic cardiomyopathy is well recognized. We hypothesized that the difference in response to beta-blockers may be caused by myocardial functional abnormalities. This study was designed to compare myocardial function in cats with obstructive hypertrophic cardiomyopathy with and without response to beta-blockers. Twenty-one, client-owned, hypertrophic cardiomyopathy cats treated with carvedilol were analyzed. After carvedilol treatment, cats with decreased left ventricular outflow tract velocity were categorized as responders (n = 10); those exhibiting no response (no decrease in the left ventricular outflow tract velocity) were categorized as non-responders (n = 11). The cats were examined using layer-specific assessment of the myocardial function (whole, endocardial, and epicardial layers) longitudinally and circumferentially by two-dimensional speckle-tracking echocardiography, before and after carvedilol treatment.

Results

The non-responder cats had a significantly higher age, end-diastolic left ventricular posterior-wall thickness, peak velocity of left ventricular outflow tract, and dose of carvedilol than the responders (p = 0.04, p < 0.01, p < 0.01, and p < 0.01, respectively). The circumferential strain in the epicardial layer was lower and circumferential endocardial to epicardial strain ratio was higher in non-responders than responders (p < 0.001 and p = 0.006). According to the multivariate analysis, circumferential strain in the epicardial layer was the only independent correlate of treatment response with carvedilol.

Conclusions

Myocardial function, assessed by two-dimensional speckle-tracking echocardiography, differed in cats with hypertrophic cardiomyopathy with and without response to beta-blockers. The determination of layer-specific myocardial function may facilitate detailed pathophysiologic assessment and treatment response in cats with hypertrophic cardiomyopathy.
A comprehensive genome-wide profiling comparison between HBV and HCV infected hepatocellular carcinoma
Authors: Sun Suofeng , Li Yuan , Han Shuangyin , Jia Hongtao , Li Xiuling , Li Xiaofang
Published: October 2019

Background

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, especially in East Asia. Even with the progress in therapy, 5-year survival rates remain unsatisfied. Chronic infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV) has been epidemiologically associated with HCC and is the major etiology in the East Asian population. The detailed mechanism, especially the changes of DNA methylation and gene expression between the two types of virus-related HCC, and their contributions to the HCC development, metastasis, and recurrence remain largely unknown.

Methods

In this integrated analysis, we characterized genome-scale profiles of HBV and HCV infected HCC by comparing their gene expression pattern, methylation profiles, and copy number variations from the publicly accessible data of The Cancer Genome Atlas Program (TCGA).

Results

The HLA-A, STAT1, and OAS2 genes were highly enriched and up-regulated discovered in the HCV-infected HCC. Hypomethylation but not copy number variations might be the major factor for the up-regulation of these immune-related genes in HCV-infected HCC.

Conclusions

The results indicated the different epigenetic changes of HBV/HCV related hepatocarcinogenesis. The top up-regulated genes in HCV group were significantly clustered in the immune-related and defense response pathways. These findings will help us to understand the pathogenesis of HBV/HCV associated hepatocellular carcinoma.
Genetic and epigenetic modifications induced by chemotherapeutic drugs: human amniotic fluid stem cells as an in-vitro model
Authors: Upadhyaya Prabin , Di Serafino Alessandra , Sorino Luca , Ballerini Patrizia , Marchisio Marco , Pierdomenico Laura , Stuppia Liborio , Antonucci Ivana
Published: October 2019

Background

Bleomycin, etoposide and cisplatin (BEP) are three chemotherapeutic agents widely used individually or in combination with each other or other chemotherapeutic agents in the treatment of various cancers. These chemotherapeutic agents are cytotoxic; hence, along with killing cancerous cells, they also damage stem cell pools in the body, which causes various negative effects on patients. The epigenetic changes due to the individual action of BEP on stem cells are largely unknown.

Methods

Human amniotic fluid stem cells (hAFSCs) were treated with our in-vitro standardized dosages of BEP individually, for seven days. The cells were harvested after the treatment and extraction of DNA and RNA were performed. Real-time PCR and flow cytometry were conducted for cell markers analysis. The global DNA methylation was quantified using 5mC specific kit and promoter and CpG methylation % through bisulfite conversion and pyrosequencing. Micro- RNAs (miRNAs) were quantified with real-time qPCR.

Results

The cytotoxic nature of BEP was observed even at low dosages throughout the experiment. We also investigated the change in the expression of various pluripotent and germline markers and found a significant change in the properties of the cells after the treatments. The methylation of DNA at global, promoter and individual CpG levels largely get fluctuated due to the BEP treatment. Several tested miRNAs showed differential expression. No positive correlation between mRNA and protein expression was observed for some markers.

Conclusion

Cytotoxic chemotherapeutic agents such as BEP were found to alter stem cell properties of hAFSCs. Different methylation profiles change dynamically, which may explain such changes in cellular properties. Data also suggests that the fate of hAFSCs after treatment may depend upon the interplay between the miRNAs. Finally, our results demonstrate that hAFSCs might prove to be a suitable in-vitro model of stem cells to predict genetic and epigenetic modification due to the action of various drugs.
Liver microsystems in vitro for drug response
Authors: Lee Jyong-Huei , Ho Kuan-Lun , Fan Shih-Kang
Published: October 2019

Engineering approaches were adopted for liver microsystems to recapitulate cell arrangements and culture microenvironments in vivo for sensitive, high-throughput and biomimetic drug screening. This review introduces liver microsystems in vitro for drug hepatotoxicity, drug-drug interactions, metabolic function and enzyme induction, based on cell micropatterning, hydrogel biofabrication and microfluidic perfusion. The engineered microsystems provide varied microenvironments for cell culture that feature cell coculture with non-parenchymal cells, in a heterogeneous extracellular matrix and under controllable perfusion. The engineering methods described include cell micropatterning with soft lithography and dielectrophoresis, hydrogel biofabrication with photolithography, micromolding and 3D bioprinting, and microfluidic perfusion with endothelial-like structures and gradient generators. We discuss the major challenges and trends of liver microsystems to study drug response in vitro.
Down-regulation of long non-coding RNA SNHG14 protects against acute lung injury induced by lipopolysaccharide through microRNA-34c-3p-dependent inhibition of WISP1
Authors: Zhu Jinyuan , Bai Jijia , Wang Shaojin , Dong Hui
Published: October 2019

Background

Accumulating evidence has shown the important roles of long non-coding RNAs (lncRNAs) in acute lung injury (ALI). This study aimed to investigate the potential role of lncRNA small nucleolar RNA host gene 14 (SNHG14) in lipopolysaccharides (LPS)-induced ALI.

Methods

Expression of SNHG14, microRNA-34c-3p (miR-34c-3p) and Wnt1 inducible signaling pathway protein 1 (WISP1) in LPS-exposed mouse alveolar macrophages (MH-S) and lung tissues from mice with LPS-induced ALI was determined by reverse transcription quantitative polymerase chain reaction. The interactions among SNHG14, miR-34c-3p and WISP1 were analyzed by dual-luciferase reporter and RIP assays. Using gain-of-function or loss-of-function approaches, the contents of proinflammatory proteins were determined and MH-S cell viability was assessed to evaluate the in vitro functions of SNHG14, miR-34c-3p and WISP1, and wet/dry weight ratio and proinflammatory proteins in lung tissues were determined to assess their in vivo effects.

Results

SNHG14 and WISP1 expression was increased, while miR-34c-3p was decreased in ALI models. SNHG14 bound to miR-34c-3p, resulting in impaired miR-34c-3p-dependent down-regulation of WISP1. Both SNHG14 silencing and miR-34c-3p over-expression reduced the levels of proinflammatory proteins IL-18, IL-1β, TNF-α and IL-6 and inhibited MH-S cell viability. SNHG14 silencing or miR-34c-3p over-expression decreased the wet/dry weight ratio in lung tissues from ALI mice. The reductions induced by SNHG14 silencing or miR-34c-3p over-expression were rescued by WISP1 over-expression.

Conclusion

This study demonstrated that lncRNA SNHG14 silencing alleviated inflammation in LPS-induced ALI through miR-34c-3p-mediated inhibition of WISP1. Our findings suggest that lncRNA SNHG14 may serve as a therapeutic target for ALI.
Nanosensors and particles: a technology frontier with pitfalls
Authors: Vogel Viola
Published: October 2019

As we are approaching 20 years after the US National Nanotechnology Initiative has been announced, whereby most of that funding was spend to engineer, characterize and bring nanoparticles and nanosensors to the market, it is timely to assess the progress made. Beyond revolutionizing nonmedical applications, including construction materials and the food industry, as well as in vitro medical diagnostics, the progress in bringing them into the clinic has been far slower than expected. Even though most of the advances in nanosensor and nanoparticle research and development have been paid for by disease-oriented funding agencies, much of the gained knowledge can now be applied to treat or learn more about our environment, including water, soil, microbes and plants. As the amount of engineered nanoparticles that enter our environment is currently exponentially increasing, much tighter attention needs to be paid to assessing their health risk. This is urgent as the asbestos story told us important lessons how financial interests arising from a rapid build up of a flourishing industry has blocked and is still preventing a worldwide ban on asbestos, nearly 100 years after the first health risks were reported.
Complexity in unclassified auto-inflammatory disease: a case report illustrating the potential for disease arising from the allelic burden of multiple variants
Authors: Tucker Lori B. , Lamot Lovro , Niemietz Iwona , Chung Brian K. , Cabral David A. , Houghton Kristin , Petty Ross E. , Morishita Kimberly A. , Rice Gillian I. , Turvey Stuart E. , Gibson William T. , Brown Kelly L.
Published: October 2019

Background

Despite recent advances in the diagnosis and understanding of many autoinflammatory diseases, there are still a great number of patients with phenotypes that do not fit any clinically- and/or genetically-defined disorders.

Case presentation

We describe a fourteen-year-old boy who presented at two and a half years of age with recurrent febrile episodes. Over the course of the disease, the episodes increased in frequency and severity, with new signs and symptoms continuing to appear. Most importantly, these included skin changes, splenomegaly and transaminitis. Only partial control of the disease was achieved with anti-IL-1 therapy. Extensive investigation showed generalized inflammation without immune deficiency, with increased levels of serum amyloid A and several pro-inflammatory cytokines including interferon-γ, as well as an increased type I interferon score. Exome sequence analysis identified P369S and R408Q variants in the MEFV innate immunity regulator, pyrin (MEFV) gene and T260 M and T320 M variants in the NLR family pyrin domain containing 12 (NLRP12) gene.

Conclusion

Patients with unclassified and/or unexplained autoinflammatory syndromes present diagnostic and therapeutic challenges and collectively form a substantial part of every cohort of patients with autoinflammatory diseases. Therefore, it is important to acquire their full genomic profile through whole exome and/or genome sequencing and present their cases to a broader audience, to facilitate characterization of similar patients. A critical mass of well-characterized cases will lead to improved diagnosis and informed treatment.
The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders
Authors: Miller-Rhodes Patrick , Kong Cuicui , Baht Gurpreet S. , Saminathan Priyanka , Rodriguiz Ramona M. , Wetsel William C. , Gelbard Harris A. , Terrando Niccolò
Published: October 2019

Background

Patients with pre-existing neurodegenerative disease commonly experience fractures that require orthopedic surgery. Perioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that can result in increased 1-year mortality when superimposed on dementia. Importantly, there are no disease-modifying therapeutic options for PND. Our lab developed the “broad spectrum” mixed-lineage kinase 3 inhibitor URMC-099 to inhibit pathological innate immune responses that underlie neuroinflammation-associated cognitive dysfunction. Here, we test the hypothesis that URMC-099 can prevent surgery-induced neuroinflammation and cognitive impairment.

Methods

Orthopedic surgery was performed by fracturing the tibia of the left hindlimb with intramedullary fixation under general anesthesia and analgesia. In a pilot experiment, 9-month-old mice were treated five times with URMC-099 (10 mg/kg, i.p.), spaced 12 h apart, with three doses prior to surgery and two doses following surgery. In this experiment, microgliosis was evaluated using unbiased stereology and blood-brain barrier (BBB) permeability was assessed using immunoglobulin G (IgG) immunostaining. In follow-up experiments, 3-month-old mice were treated only three times with URMC-099 (10 mg/kg, i.p.), spaced 12 h apart, prior to orthopedic surgery. Two-photon scanning laser microscopy and CLARITY with light-sheet microscopy were used to define surgery-induced changes in microglial dynamics and morphology, respectively. Surgery-induced memory impairment was assessed using the “What-Where-When” and Memory Load Object Discrimination tasks. The acute peripheral immune response to surgery was assessed by cytokine/chemokine profiling and flow cytometry. Finally, long-term fracture healing was assessed in fracture callouses using micro-computerized tomography (microCT) and histomorphometry analyses.

Results

Orthopedic surgery induced BBB disruption and microglial activation, but had no effect on microglial process motility. Surgically treated mice exhibited impaired object place and identity discrimination in the “What-Where-When” and Memory Load Object Discrimination tasks. Both URMC-099 dosing paradigms prevented the neuroinflammatory sequelae that accompanied orthopedic surgery. URMC-099 prophylaxis had no effect on the mobilization of the peripheral innate immune response and fracture healing.

Conclusions

These findings show that prophylactic URMC-099 treatment is sufficient to prevent surgery-induced microgliosis and cognitive impairment without affecting fracture healing. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.
Characterization and pathogenicity of Vero cell-attenuated porcine epidemic diarrhea virus CT strain
Authors: Wu Yu , Li Wei , Zhou Qingfeng , Li Qunhui , Xu Zhichao , Shen Hanqin , Chen Feng
Published: October 2019

Background

Porcine epidemic diarrhea virus (PEDV) has caused enormous economic losses to the global pig industry. Currently available PEDV vaccine strains have limited protective effects against PEDV variant strains.

Methods

In this study, the highly virulent epidemic virus strain CT was serially passaged in Vero cells for up to 120 generations (P120). Characterization of the different passages revealed that compared with P10 and P64, P120 had a higher viral titer and more obvious cytopathic effects, thereby demonstrating better cell adaptability.

Results

Pathogenicity experiments using P120 in piglets revealed significant reductions in clinical symptoms, histopathological lesions, and intestinal PEDV antigen distribution; the piglet survival rate in the P120 group was 100%. Furthermore, whole-genome sequencing identified 13 amino acid changes in P120, which might be responsible for the attenuated virulence of P120.

Conclusions

Thus, an attenuated strain was obtained via cell passaging and that this strain could be used in preparing attenuated vaccines.
Multiplex PCR-based titration (MPBT) assay for determination of infectious titers of the three Sabin strains of live poliovirus vaccine
Authors: Manukyan Hasmik , Rodionova Elvira , Zagorodnyaya Tatiana , Lin Tsai-Lien , Chumakov Konstantin , Laassri Majid
Published: October 2019

Background

Conventional assays to titrate polioviruses usually test serial dilutions inoculated into replicate cell cultures to determine a 50% cytopathic endpoint, a process that is both time-consuming and laborious. Such a method is still used to measure potency of live Oral Poliovirus Vaccine during vaccine development and production and in some clinical trials. However, the conventional method is not suited to identify and titrate virus in the large numbers of fecal samples generated during clinical trials. Determining titers of each of the three Sabin strains co-existing in Oral Poliovirus Vaccine presents an additional challenge.

Results

A new assay using quantitative multiplex polymerase chain reaction as an endpoint instead of cytopathic effect was developed to overcome these limitations. In the multiplex polymerase chain reaction-based titration assay, cell cultures were infected with serial dilutions of test samples, lysed after two-day incubation, and subjected to a quantitative multiplex one-step reverse-transcriptase polymerase chain reaction. All three serotypes of poliovirus were identified in single samples and titers calculated. The multiplex polymerase chain reaction-based titration assay was reproducible, robust and sensitive. Its lower limits of titration for three Sabin strains were 1–5 cell culture 50% infectious doses per ml. We prepared different combinations of three Sabin strains and compared titers obtained with conventional and multiplex polymerase chain reaction-based titration assays. Results of the two assays correlated well and showed similar results and sensitivity. Multiplex polymerase chain reaction-based titration assay was completed in two to 3 days instead of 10 days for the conventional assay.

Conclusions

The multiplex polymerase chain reaction-based titration (MPBT) is the first quantitative assay that identifies and titrates each of several different infectious viruses simultaneously in a mixture. It is suitable to identify and titrate polioviruses rapidly during the vaccine manufacturing process as a quality control test, in large clinical trials of vaccines, and for environmental surveillance of polioviruses. The MPBT assay can be automated for high-throughput implementation and applied for other viruses including those with no cytopathic effect.
Correction to: The 2018 new definition of periprosthetic joint infection improves the diagnostic efficiency in the Chinese population
Authors: Guan Haitao , Fu Jun , Li Xiang , Chai Wei , Hao Libo , Li Rui , Zhao Jing , Chen Jiying
Published: October 2019

In the original publication of this article, [1] the affiliation of the first author Haitao Guan needs to be revised:
Correction to: Early postoperative compilations of bone filling in curettage defects
Authors: Chen Clark J. , Brien Earl W.
Published: October 2019

In the original publication of this article [1], there was a mistake in Figure 2. Figure 2a and Fig 2c should be swapped. The revised Figure 2 is shown below.
3D-tips: user-friendly mesh barrier pipette tips for 3D-spheroid culture
Authors: Chen Mo , Vial Marie-Laure , St John James A.
Published: October 2019

Background

Three dimensional (3D) cell cultures have been an area of increasing interest and relevance across several research fields including drug discovery, developmental biology and stem cell-based therapies. However, handling 3D structures can be difficult. In particular, the replacement of liquid media and reagents in which liquid is removed using pipettes is difficult to perform as the 3D spheroids can be easily aspirated into the pipette tip.

Results

We have developed the 3D-tip, a novel tool that facilitates media change and washing procedures of 3D-spheroid cultures. The 3D-tip contains a mesh with 40-μm pores allowing the aspiration of liquids including media, drugs, buffers and reagents, with the mesh acting as a barrier preventing the spheroids being aspirated into the pipette tip. After aspiration of liquids, the spheroids are gently deposited back into the culture vessel. Our results demonstrate that the 3D-tips offer superior handling of 3D-spheroid cultures in comparison to commonly used methods. We showed that the 3D-tips can easily be used on both fixed and unfixed spheroids and on cancer cell, stem cell and glial cell spheroids.

In contrast with the 50/50 media exchange method, the 3D-tips allow a complete media change with minimal loss of spheroids and without damaging their morphology. Our results showed that 86.0% of spheroids remained in the chamber after changing the media using the 3D-tips. In contrast, only 45.0% of spheroids remained using the 50/50 media exchange strategy.

In comparison with the centrifugation technique, the 3D-tips preserved spheroids whereas centrifugation led to the loss of spheroids and/or the alteration of the size and shape of the 3D cellular structures. We observed that 87.6 and 84.6% of the fixed and unfixed spheroids remained using the 3D-tip, respectively. In contrast, only 66.3% of the fixed spheroids and 36.4% of the unfixed spheroids were left using the centrifugation method. From a time perspective, the 3D-tips dramatically reduce the time taken for replacing media.

Conclusions

This novel pipette tip is suitable for high throughput screening and automation and will revolutionise the techniques used for the production and analysis of 3D spheroids.
Prevalence and root causes of surgical site infection among women undergoing caesarean section in Ethiopia: a systematic review and meta-analysis
Authors: Adane Fentahun , Mulu Abay , Seyoum Girma , Gebrie Alemu , Lake Akilog
Published: October 2019

Background

Surgical site infection is a common complication in women undergoing Caesarean section and the second most common cause of maternal mortality in obstetrics. In Ethiopia, prevalence and root causes of surgical site infection post-Caesarean section are highly variable. This systematic review and meta-analysis estimate the overall prevalence of surgical site infection and its root causes among women undergoing Caesarean section in Ethiopia.

Method

Systematic review and meta-analysis were conducted to assess the prevalence and root causes of surgical site infection in Ethiopia. The articles were searched from the databases such as Medline, Google Scholar and Science Direct. A total of 13 studies from different regions of Ethiopia reporting the prevalence and root causes of surgical site infection among women undergoing Caesarean section were included. A random effect meta-analysis model was computed to estimate the overall prevalence. In addition, the association between risk factor variables and surgical site infection related to Caesarean section were examined.

Results

Thirteen studies in Ethiopia showed that the overall prevalence of surgical site infection among women undergoing Caesarean section was 8.81% (95% CI: 6.34–11.28). Prolonged labor, prolonged rupture of membrane, presence of anemia, presence of chorioamnionitis, presence of meconium, vertical skin incision, greater than 2 cm thickness of subcutaneous tissue, and general anesthesia were significantly associated with surgical site infection post-Caesarean section.

Conclusion

Prevalence of surgical site infection among women undergoing Caesarean section was relatively higher in Ethiopians compared with the report of center of disease control guideline. Prolonged labor, prolonged rupture of membrane, presence of anemia, chorioamnionitis, presence of meconium, vertical skin incision, greater than 2 cm thickness of subcutaneous tissue and/or general anesthesia were significantly associated with surgical site infection post-Caesarean section.
Recent advances in nanotheranostics for triple negative breast cancer treatment
Authors: Thakur Vikram , Kutty Rajaletchumy Veloo
Published: October 2019

Triple-negative breast cancer (TNBC) is the most complex and aggressive type of breast cancer encountered world widely in women. Absence of hormonal receptors on breast cancer cells necessitates the chemotherapy as the only treatment regime. High propensity to metastasize and relapse in addition to poor prognosis and survival motivated the oncologist, nano-medical scientist to develop novel and efficient nanotherapies to solve such a big TNBC challenge. Recently, the focus for enhanced availability, targeted cellular uptake with minimal toxicity is achieved by nano-carriers. These smart nano-carriers carrying all the necessary arsenals (drugs, tracking probe, and ligand) designed in such a way that specifically targets the TNBC cells at site. Articulating the targeted delivery system with multifunctional molecules for high specificity, tracking, diagnosis, and treatment emerged as theranostic approach. In this review, in addition to classical treatment modalities, recent advances in nanotheranostics for early and effective diagnostic and treatment is discussed. This review highlighted the recently FDA approved immunotherapy and all the ongoing clinical trials for TNBC, in addition to nanoparticle assisted immunotherapy. Futuristic but realistic advancements in artificial intelligence (AI) and machine learning not only improve early diagnosis but also assist clinicians for their workup in TNBC. The novel concept of Nanoparticles induced endothelial leakiness (NanoEL) as a way of tumor invasion is also discussed in addition to classical EPR effect. This review intends to provide basic insight and understanding of the novel nano-therapeutic modalities in TNBC diagnosis and treatment and to sensitize the readers for continue designing the novel nanomedicine. This is the first time that designing nanoparticles with stoichiometric definable number of antibodies per nanoparticle now represents the next level of precision by design in nanomedicine.
Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer
Authors: Kowolik Claudia M. , Lin Min , Xie Jun , Overman Larry E. , Horne David A.
Published: October 2019

Background

Pancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer.

Methods

We characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo.

Results

NT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine.

Conclusions

Favorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease.
Automated volumetric breast density measures: differential change between breasts in women with and without breast cancer
Authors: Brandt Kathleen R. , Scott Christopher G. , Miglioretti Diana L. , Jensen Matthew R. , Mahmoudzadeh Amir P. , Hruska Carrie , Ma Lin , Wu Fang Fang , Cummings Steven R. , Norman Aaron D. , Engmann Natalie J. , Shepherd John A. , Winham Stacey J. , Kerlikowske Karla , Vachon Celine M.
Published: October 2019

Background

Given that breast cancer and normal dense fibroglandular tissue have similar radiographic attenuation, we examine whether automated volumetric density measures identify a differential change between breasts in women with cancer and compare to healthy controls.

Methods

Eligible cases (n = 1160) had unilateral invasive breast cancer and bilateral full-field digital mammograms (FFDMs) at two time points: within 2 months and 1–5 years before diagnosis. Controls (n = 2360) were matched to cases on age and date of FFDMs. Dense volume (DV) and volumetric percent density (VPD) for each breast were assessed using Volpara™. Differences in DV and VPD between mammograms (median 3 years apart) were calculated per breast separately for cases and controls and their difference evaluated by using the Wilcoxon signed-rank test. To simulate clinical practice where cancer laterality is unknown, we examined whether the absolute difference between breasts can discriminate cases from controls using area under the ROC curve (AUC) analysis, adjusting for age, BMI, and time.

Results

Among cases, the VPD and DV between mammograms of the cancerous breast decreased to a lesser degree (− 0.26% and − 2.10 cm3) than the normal breast (− 0.39% and − 2.74 cm3) for a difference of 0.13% (p value < 0.001) and 0.63 cm3 (p = 0.002), respectively. Among controls, the differences between breasts were nearly identical for VPD (− 0.02 [p = 0.92]) and DV (0.05 [p = 0.77]). The AUC for discriminating cases from controls using absolute difference between breasts was 0.54 (95% CI 0.52, 0.56) for VPD and 0.56 (95% CI, 0.54, 0.58) for DV.

Conclusion

There is a small relative increase in volumetric density measures over time in the breast with cancer which is not found in the normal breast. However, the magnitude of this difference is small, and this measure alone does not appear to be a good discriminator between women with and without breast cancer.
Pain REduction with bone metastases STereotactic radiotherapy (PREST): A phase III randomized multicentric trial
Authors: Cellini Francesco , Manfrida Stefania , Deodato Francesco , Cilla Savino , Maranzano Ernesto , Pergolizzi Stefano , Arcidiacono Fabio , Di Franco Rossella , Pastore Francesco , Muto Matteo , Borzillo Valentina , Donati Costanza Maria , Siepe Giambattista , Parisi Salvatore , Salatino Antonia , D’Agostino Antonino , Montesi Giampaolo , Santacaterina Anna , Fusco Vincenzo , Santarelli Mario , Gambacorta Maria Antonietta , Corvò Renzo , Morganti Alessio Giuseppe , Masiello Valeria , Muto Paolo , Valentini Vincenzo
Published: October 2019

Background

Palliative antalgic treatments represent an issue for clinical management and a challenge for scientific research. Radiotherapy (RT) plays a central role. Techniques such as stereotactic body radiotherapy (SBRT) were largely investigated in several phase 2 studies with good symptom response, becoming widely adopted. However, evidence from randomized, direct comparison of RT and SBRT is still lacking.

Methods/design

The PREST trial was designed as an interventional study without medicinal treatment. It is a phase 3, open-label, multicentric trial randomized 1:1. Inclusion criteria include painful spinal bone metastases presenting with a pain level > 4 (or > 1 if being treated with an analgesic) on the Numeric Rating Scale (NRS); expected intermediate/high prognosis (greater than 6 months) according to the Mizumoto prognostic score; low spine instability neoplastic score (SINS) sores (< 7); magnetic resonance imaging (MRI) assessment of the bulky lesion. Patients will be assigned to either standard conventional radiotherapy involving 4 Gy × 5 fractions (fx) to the whole involved vertebra or SBRT by intensity modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) involving 7 Gy × 3 fx to the whole involved vertebra + 10 Gy × 3 fx on the macroscopic lesion (gross tumor volume (GTV)). In the experimental arm, the GTV will be contoured by registration with baseline MRI.

Discussion

The primary endpoint is overall pain reduction, defined in terms of variation between baseline and 3-month evaluation; pain will be measured using the NRS. Secondary endpoints include pain control duration; retreatment rates (after a minimum interval of 1 month); local control assessed with RECIST criteria; symptom progression free survival; progression-free survival; overall survival; and quality of life (at 0, 30, and 90 days). Accrual of 330 lesions is planned. The experimental arm is expected to have an improvement in overall pain response rates of 15% with respect to the standard arm (60% according to Chow et al. (Int J Radiat Oncol Biol Phys. 82(5):1730–7, 2012)).

Trial registration

ClinicalTrials.gov, NCT03597984. Registered on July 2018.
CICAFAST: comparison of a biological dressing composed of fetal fibroblasts and keratinocytes on a split-thickness skin graft donor site versus a traditional dressing: a randomized controlled trial
Authors: Poinas Alexandra , Perrot Pierre , Lorant Judith , Nerrière Olivier , Nguyen Jean-Michel , Saiagh Soraya , Frenard Cécile , Leduc Audrey , Malard Olivier , Espitalier Florent , Duteille Franck , Chiffoleau Anne , Vrignaud Florence , Khammari Amir , Dréno Brigitte
Published: October 2019

Background

Wound repair is one of the most complex biological processes of human life. Allogeneic cell-based engineered skin substitutes provide off-the-shelf temporary wound coverage and act as biologically active dressings, releasing growth factors, cytokines and extracellular matrix components essential for proper wound healing. However, they are susceptible to immune rejection and this is their major weakness.

Thanks to their low immunogenicity and high effectiveness in regeneration, fetal skin cells represent an attractive alternative to the commonly used autologous and allogeneic skin grafts.

Methods/design

We developed a new dressing comprising a collagen matrix seeded with a specific ratio of active fetal fibroblasts and keratinocytes. These produce a variety of healing growth factors and cytokines which will increase the speed of wound healing and induce an immunotolerant state, with a slight inflammatory reaction and a reduction in pain.

The objective of this study is to demonstrate that the use of this biological dressing for wound healing at the split-thickness skin graft (STSG) donor site, reduces the time to healing, decreases other co-morbidities, such as pain, and improves the appearance of the scar.

This investigation will be conducted as part of a randomized study comparing our new biological dressing with a conventional treatment in a single patient, thus avoiding the factors that may influence the healing of a graft donor site.

Discussion

This clinical trial should enable the development of a new strategy for STSG donor-wound healing based on a regenerative dressing. The pain experienced in the first few days of STSG healing is well known due to the exposure of sensory nerve endings. Reducing this pain will also reduce analgesic drug intake and the duration of sick leave.

Our biological dressing will meet the essential need of surgeons to “re-crop” from existing donor sites, e.g., for thermal-burn patients. By accelerating healing, improving the appearance of the scar and reducing pain, we hope to improve the conditions of treatment for skin grafts.

Trial registration

ClinicalTrials.gov, ID:NCT03334656. Registered on 7 November 2017.
Association between cognitive impairment patient with solid cancer and insulin resistance
Authors: Gonda Kenji , Yaginuma Kenji , Rokkaku Yuichi , Horita Shoichiro , Maejima Yuko , Shimomura Kenju
Published: October 2019

Objectives

In an aging population, an increase in the number of elderly cancer patients with cognitive impairment is expected. The possible association between cancer and cognitive impairment is important to elucidate, because it can have a serious impact on quality of life. Here, we focused on glucose metabolism as a factor that links cancer and cognitive impairment.

Results

Thirteen subjects with solid cancers and cognitive impairment were recruited. As a control group, 14 subjects with cognitive impairment alone and 8 subjects with cancer alone were recruited. A Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and that of β-cell function (HOMA-B) were used. In comparison with patients with solid cancer alone, those with cognitive impairment alone and those with both cancer and cognitive impairment had increased HOMA-IR values. Insulin resistance was increased in patients with cognitive impairment alone and those with both cognitive impairment and solid cancer than in patients without cognitive impairment; however, β-cell function was not affected. The present data indicated that elderly cancer patients with high HOMA-IR score may be at a relatively high risk for developing cognitive impairment. Furthermore, early treatment to reduce insulin sensitivity may prevent cognitive impairment.
Evaluation of bacterial and fungal contamination of kitchens of Birjand University of Medical Sciences
Authors: Rahimi Seyyedeh Masoomeh , Ebrahimi Maryam , Barikbin Behnam , Zeinali Tayebeh
Published: October 2019

Objective

This study aims to evaluate the total bacterial and fungal count of tools, devices and surfaces of kitchens of the centers affiliated to Birjand University of Medical Sciences. In this study, 200 samples from four kitchens of Birjand University of Medical Sciences were obtained. After the preparation of serial dilutions, samples were cultured in plate count agar (PCA) plates and Sabouraud dextrose agar (SDA). After incubation at 37 and 25 °C for 24–48 and 72–96 h respectively, the microbial and fungal colonies were counted.

Results

The mean bacterial and fungal count of kitchens was 7.7 * 107 and 7.6 * 104, respectively. The highest and lowest levels of bacterial contamination were related to tools/devices and cover of tools/work clothes and the highest and lowest levels of fungal count were related to forks and spoons and the tools and devices of the storage site. The rate of contamination in the kitchens of Birjand University of Medical Sciences was relatively high. Thus, serious, continuous and accurate monitoring of the units, training of people working in all stages of cooking and disinfection the tools and devices are essential for control and prevention of disease transmission.
The dental complications of canine tooth bud removal in 2–12 years old children in Northwest Ethiopia
Authors: Teshome Amare , Assefa Berihun
Published: October 2019

Objective

Canine tooth bud removal is a process of gouging out an infant’s canine tooth buds, using unsterile tools such as Sharpe blade, garlic, or knitting needle, without anesthesia. The aim of the study was to reveal dental complications of canine tooth bud removal among children who visited the dental clinic of the University of Gondar hospital. This study was an institution-based cross-sectional conducted from January 2015 to September 2016 at the University of Gondar hospital on 2–12 years children. The tooth was assessed for whether it had previously oral mutilated or not. In addition to this, the oral cavity was evaluated for the presence of missed, malformed or normal canine.

Results

A group of 355 children aged 2–12 years was examined clinically. The mean age of the children was 7.32 ± 3.12 (SD). The prevalence of canine tooth bud removal was 86.8% which was high in 6–9 years old (54.87%) and first position children (40.26%). The most common dental complications were; malformed enamel (hypoplastic) canine (48.5%) and missed/unerupted canine (38.6%).
Selective demethylation of two CpG sites causes postnatal activation of the Dao gene and consequent removal of d-serine within the mouse cerebellum
Authors: Cuomo Mariella , Keller Simona , Punzo Daniela , Nuzzo Tommaso , Affinito Ornella , Coretti Lorena , Carella Massimo , de Rosa Valeria , Florio Ermanno , Boscia Francesca , Avvedimento Vittorio Enrico , Cocozza Sergio , Errico Francesco , Usiello Alessandro , Chiariotti Lorenzo
Published: October 2019

Background

Programmed epigenetic modifications occurring at early postnatal brain developmental stages may have a long-lasting impact on brain function and complex behavior throughout life. Notably, it is now emerging that several genes that undergo perinatal changes in DNA methylation are associated with neuropsychiatric disorders. In this context, we envisaged that epigenetic modifications during the perinatal period may potentially drive essential changes in the genes regulating brain levels of critical neuromodulators such as d-serine and d-aspartate. Dysfunction of this fine regulation may contribute to the genesis of schizophrenia or other mental disorders, in which altered levels of d-amino acids are found. We recently demonstrated that Ddo, the d-aspartate degradation gene, is actively demethylated to ultimately reduce d-aspartate levels. However, the role of epigenetics as a mechanism driving the regulation of appropriate d-ser levels during brain development has been poorly investigated to date.

Methods

We performed comprehensive ultradeep DNA methylation and hydroxymethylation profiling along with mRNA expression and HPLC-based d-amino acids level analyses of genes controlling the mammalian brain levels of d-serine and d-aspartate. DNA methylation changes occurring in specific cerebellar cell types were also investigated. We conducted high coverage targeted bisulfite sequencing by next-generation sequencing and single-molecule bioinformatic analysis.

Results

We report consistent spatiotemporal modifications occurring at the Dao gene during neonatal development in a specific brain region (the cerebellum) and within specific cell types (astrocytes) for the first time. Dynamic demethylation at two specific CpG sites located just downstream of the transcription start site was sufficient to strongly activate the Dao gene, ultimately promoting the complete physiological degradation of cerebellar d-serine a few days after mouse birth. High amount of 5′-hydroxymethylcytosine, exclusively detected at relevant CpG sites, strongly evoked the occurrence of an active demethylation process.

Conclusion

The present investigation demonstrates that robust and selective demethylation of two CpG sites is associated with postnatal activation of the Dao gene and consequent removal of d-serine within the mouse cerebellum. A single-molecule methylation approach applied at the Dao locus promises to identify different cell-type compositions and functions in different brain areas and developmental stages.