bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-tumor effects of mevalonate pathway inhibition in ovarian cancer
Authors: Göbel Andy , Zinna Valentina M. , Dell’Endice Stefania , Jaschke Nikolai , Kuhlmann Jan Dominik , Wimberger Pauline , Rachner Tilman D.
Published: July 2020

Background

Ovarian cancer remains the most fatal gynecological malignancy. Current therapeutic options are limited due to late diagnosis in the majority of the cases, metastatic spread to the peritoneal cavity and the onset of chemo-resistance. Thus, novel therapeutic approaches are required. Statins and amino-bisphosphonates are inhibitors of the mevalonate pathway, which is a fundamental pathway of cellular metabolism, essential for cholesterol production and posttranslational protein farnesylation and geranylgeranylation. While this pathway has emerged as a promising treatment target in several human malignancies, its potential as a therapeutic approach in ovarian cancer is still not fully understood.

Methods

Human ovarian cancer cell lines (IGROV-1, A2780, A2780cis) were treated with increasing concentrations (0.5-100 μM) of statins (simvastatin, atorvastatin, rosuvastatin) and zoledronic acid. Effects on cell vitality and apoptosis were assessed using Cell Titer Blue®, Caspase 3/7 Glo®, clonogenic assays as well as cleaved poly (ADP-ribose) polymerase (cPARP) detection. The inhibition of the mevalonate pathway was confirmed using Western Blot of unprenylated Ras and Rap1a proteins. Quantitative real-time PCR and ELISA were used to analyze modulations on several key regulators of ovarian cancer tumorigenesis.

Results

The treatment of IGROV-1 and A2780 cells with statins and zoledronic acid reduced vitality (by up to 80%;p < 0.001) and induced apoptosis by up to 8-folds (p < 0.001) in a dose-dependent fashion. Rescue experiments using farnesyl pyrophosphate or geranylgeranyl pyrophosphate evidenced that blocked geranylgeranylation is the major underlying mechanism of the pro-apoptotic effects. Gene expression of the tumor-promoting cytokines and mediators, such as transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), interleukin (IL)-8, and IL-6 were significantly suppressed by statins and zoledronic acid by up to 90% (p < 0.001). For all readouts, simvastatin was most potent of all agents used. Cisplatin-resistant A2780cis cells showed a relative resistance to statins and zoledronic acid. However, similar to the effects in A2780 cells, simvastatin and zoledronic acid significantly induced caspase 3/7 activation (6-folds;p < 0.001).

Conclusion

Our in vitro findings point to promising anti-tumor effects of statins and zoledronic acid in ovarian cancer and warrant additional validation in preclinical and clinical settings.
Questioning the IGF1 receptor’s assigned role in CRC – a case for rehabilitation?
Authors: Heckl Steffen M. , Pellinghaus Marie , Behrens Hans-Michael , Krüger Sandra , Schreiber Stefan , Röcken Christoph
Published: July 2020

Background

The insulin-like growth factor 1 receptor (IGF1R) is suspected to be involved in colorectal carcinogenesis and has been associated with worse survival in colorectal cancer (CRC). We hypothesized that the alleged suspect might be in truth beyond any suspicion. We investigated if the expression of the IGF1R in CRC correlates with (1) clinicopathological patient characteristics, including survival, and hence is involved in colon cancer biology; (2) the expression of the IGF1R in CRC is linked to the expression of the insulin receptor (IR).

Methods

We evaluated 4497 CRC samples from 1499 patients for the expression of IGF1R in tumor cells by immunohistochemistry. Cytoplasmic (cCC-IGF1R) and membranous (mCC-IGF1R) immunostaining was evaluated by employing a modified HistoScore (HScore), which was dichotomized into low or high IGF1R expressions. The IGF1R status was correlated with clinicopathological patient characteristics, survival and the IR expression status.

Results

cCC-IGF1R and mCC-IGF1R (HScore> 0) were found in 85.4 and 60.8% of all CRCs. After dichotomization of the HScores, 54.9 and 48.6% were classified as cCC-IGF1R-high and mCC-IGF1R-high, respectively. IGF1R was associated with tumor localization, local tumor growth, lymphatic vessel invasion, grading, mismatch repair protein expression status and IR-expression. We found no significant association with overall or tumor-specific survival, with a tendency for an even improved overall survival for cCC-IGF1R.

Conclusions

IGF1R expression is frequent and biologically relevant in CRC, but does not correlate with patient survival. The IGF1R might be beyond suspicion in CRC after all.
Both p53 codon 72 Arg/Arg and pro/Arg genotypes in glioblastoma multiforme are associated with a better prognosis in bevacizumab treatment
Authors: Shen Chiung-Chyi , Cheng Wen-Yu , Lee Chung-Hsin , Dai Xue-Jun , Chiao Ming-Tsang , Liang Yea-Jiuen , Hsieh Wan-Yu , Mao Tsuo-Fei , Lin Guo-Shi , Chen Shou-Ren , Liu Bai-Shuan , Chen Jun-Peng
Published: July 2020

Background

It has previously been shown that bevacizumab, when added to chemotherapy, improved overall survival in several cancers. In glioblastoma multiforme (GBM), bevacizumab increased progression-free survival and it is widely used for tumor recurrence, though it has failed to improve overall survival (OS) in controlled trials. However, an effective biomarker for predicting the prognosis of bevacizumab treatment has yet to be identified. This study, therefore, aimed to retrospectively analyze the polymorphisms of p53 codon 72 and the clinical characteristics of GBM specimens from Taiwanese patients.

Methods

The polymorphisms of p53 codon 72 in 99 patients with GBM treated at Taichung Veterans General Hospital in Taiwan from 2007 to 2017 were analyzed using direct DNA sequencing and PCR-RFLP analysis.

Results

We found that among these GBM patients, the distribution of codon 72 polymorphisms was 28.3% for proline homozygotes (Pro/Pro), 38.4% for arginine homozygotes (Arg/Arg), and 33.3% for proline/arginine heterozygotes (Pro/Arg). Although the polymorphisms of p53 codon 72 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Pro genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone.

Conclusions

This pilot study suggests that both the Arg/Arg and Arg/Pro genotypes of p53 codon 72 polymorphism may have value as independent prognostic or predictive parameters for bevacizumab treatment response and failure. Relatedly, the results of the study further demonstrate the utility of stratifying GBM patients according to bevacizumab sensitivity.
Unusual non-nanophthalmic uveal effusion syndrome with histologically normal scleral architecture: a case report
Authors: Kaewsangthong Kasama , Thoongsuwan Somanus , Uiprasertkul Mongkol , Phasukkijwatana Nopasak
Published: July 2020

Background

To report an unusual case of non-nanophthalmic uveal effusion syndrome (UES) with histologically normal sclera but responsive to scleral resection.

Case presentation

A73-year-old man presented with a bullous retinal detachment without ciliochoroidal detachment on funduscopic examination of the right eye. The axial length of both eyes was normal. Extensive investigations for possible causes of exudative retinal detachment were performed with unremarkable results except for choroidal hyperpermeability on indocyanine green angiography (ICGA). Ultrasound biomicroscopy (UBM) revealed scleral thickening with peripheral choroidal elevation leading to the diagnosis of UES.

Partial thickness sclerectomy and sclerotomy was performed resulting in complete retinal reattachment, reduction of choroidal hyperpermeability on ICGA and improvement of visual acuity. However, histological studies of the excised sclera revealed no scleral architectural changes or abnormal deposits.

Conclusions

The diagnosis of UES in non-nanophthalmic eyes is challenging. Thorough systemic and ocular investigations are critical to rule out other etiologies. UBM can be helpful to evaluate scleral thickness and anterior choroid in equivocal cases. Our case was unique in that, although the sclera was thick, no abnormal microscopic scleral architecture could be identified. Misdiagnosis may lead to different surgical procedures such as vitrectomy resulting in unfavorable outcomes.
Facilitating factors and barriers to accessibility and utilization of kangaroo mother care service among parents of low birth weight infants in Mangochi District, Malawi: a qualitative study
Authors: Mathias Christina T. , Mianda Solange , Ginindza Themba G.
Published: July 2020

Background

Kangaroo Mother Care (KMC) is one of the interventions widely used in low-income countries to manage Low Birth Weight Infants (LBWIs), a global leading cause of neonatal and child mortality. LBWI largely contributes to neonatal mortality in Malawi despite the country strengthening and implementing KMC, nationwide, to enhance the survival of LBWIs. This qualitative study aimed to assess the facilitating factors and barriers to accessibility and utilization of KMC service by the parent of low birth weight infants (PLBWIs) in Mangochi District, Malawi.

Methods

Two focused group discussions assessed factors facilitating and hindering the accessibility and utilization of KMC service were conducted in April 2018 that reached out to (N = 12) participants; (n:6) PLBWI practicing KMC at Mangochi district hospital (MDH) referred from four health facilities and (n:6) high-risk pregnant mothers (HRPMs) visiting antenatal care (ANC) clinic at MDH. The availability of KMC at MDH was assessed using KMC availability checklist. The study used purposive, convenient and simple random sampling to identify eligible participants. Thematic analysis was used to analyze the findings.

Results

Sixteen themes emerged on facilitating factors and barriers to accessibility and utilization of KMC service by the PLBWIs. The identified themes included; availability of KMC providers, social factor (social support and maternal love), timing of KMC information, knowledge on KMC, health linkage systems, recognition of LBWIs, safety on the use of KMC, preference of LBWI’s care practice, lived experience on KMC practice, KMC expert clients, perceived causes of LBWI births, cultural/traditional factors, religious beliefs, health-seeking behavior, women empowerment and quality of care.

Conclusions

Although KMC was available in some of the health facilities, integration of KMC messages in ANC guidelines, community awareness and in sensitization of any health intervention may enhance KMC accessibility and utilization by the targeted population.
Factors affecting bone maturation in Chinese girls aged 4–8 years with isolated premature thelarche
Authors: Su Huiping , Su Zhe , Pan Lili , Wang Li , Xu Zhongwei , Peng Gang , Li Xianglei
Published: July 2020

Background

In isolated premature thelarche (IPT) girls, bone age (BA) is considered consistent with chronological age. However, some IPT girls confirmed by gonadotropin-releasing hormone (GnRH) stimulation test could show another trend. We analysed BA and possible potentiating factors in a selected group of girls aged 4–8 years with IPT.

Methods

IPT girls confirmed by GnRH stimulation test aged 4–8 years hospitalized from January 2015 to April 2018 at Shenzhen Children’s Hospital were included in this retrospective study. They were divided into two groups with advanced BA of 2 years as the cut-off. Body mass index (BMI) and hormone levels were the main outcome measures, and regression analysis was used to identify independent risk factors. IPT girls were divided into subgroups according to the levels of BMI standard deviation score (SDS), insulin-like growth factor-1 (IGF-1) SDS and dehydroepiandrosterone sulfate (DHEAS) SDS for comparisons of advanced BA.

Results

Overall, 423 subjects were included and classified into the advanced BA group (48.7%, n = 206) and control group (51.3%, n = 217). The advanced BA group had significantly higher BMI SDS, serum DHEAS SDS, IGF-1 SDS, androstenedione and fasting insulin and significantly lower sex hormone binding globulin (all p < 0.001). Serum IGF-1 SDS (OR = 1.926, p<0.001), BMI SDS (OR = 1.427, p = 0.001) and DHEAS SDS (OR = 1.131, p = 0.005) were independent risk factors for significantly advanced BA. In the multiple linear regression model, serum IGF-1 SDS, BMI SDS and DHEAS SDS were the strongest predictors of advanced BA, accounting for 19.3% of the variance. According to BMI, 423 patients were classified into three groups: normal weight (56.03%, n = 237), overweight (19.15%, n = 81) and obesity (24.82%, n = 105). The proportion of advanced BA in obesity group was significantly higher than those of normal weight and overweight groups (χ2 = 18.088, p<0.001). In the subgroup with normal weight, higher serum IGF-1 SDS (p = 0.009) and DHEAS SDS (p = 0.003) affected BA advancement independent of BMI SDS.

Conclusions

Girls with IPT confirmed by GnRH stimulation test aged 4–8 years might have significantly advanced BA. Obesity was highly associated with advanced BA. Age-specific serum IGF-1 SDS and DHEAS SDS were risk factors for BA advancement independent of BMI.
An integrated community mental healthcare program to reduce suicidal ideation and improve maternal mental health during the postnatal period: the findings from the Nagano trial
Authors: Tachibana Yoshiyuki , Koizumi Noriaki , Mikami Masashi , Shikada Kana , Yamashita Sayaka , Shimizu Mieko , Machida Kazuyo , Ito Hiroto
Published: July 2020

Background

During the perinatal period, suicides are more likely to occur in those with depression and who are not receiving active treatment at the time of death. Suicide is a common outcome in people with suicide ideation. We developed an intervention program taking care of comprehensive perinatal maternal mental healthcare to prevent suicide ideation. We hypothesized that our intervention program could reduce postnatal suicide ideation and improve maternal mental health.

Methods

We performed a controlled trial to examine the usual postnatal care plus a maternal suicide prevention program (the intervention group) compared with usual postnatal care alone, which comprised home visits by public health nurses without mental health screening (the control group) in Nagano city, Japan. In total, 464 women were included; 230 were allocated to the control group and 234 to the intervention group. The intervention had three components: 1) all the women received postnatal mental health screening by public health nurses who completed home visits during the neonatal period, 2) the intervention was administered by a multidisciplinary clinical network, and 3) systematic follow-up sheets were used to better understand bio–psycho–social characteristics of both the mothers and their infants and develop responsive care plans. We measured the participants’ mental health at 3–4 months postpartum (T1) and 7–8 months postpartum (T2) using the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS).

Results

Suicidal ideation was significantly lower in the intervention group compared with the control group at T1 (p = 0.014); however, this significant between-group difference did not continue to T2 (p = 0.111). We measured the intervention effects on maternal mental health using the total score of the EPDS, which was significantly improved in the intervention group compared with the control group at T1. Here, the significant difference continued to T2 (p = 0.049).

Conclusions

Our results indicate that our program may reduce maternal suicidal ideation at 3–4 months postnatally and improve women’s mental health during the postnatal periods of 3–4 to 7–8 months. Postnatal maternal mental healthcare, including services to reduce suicide ideation, should be included as an important component of general postnatal care.

Trial registration

Name of registry: A multidisciplinary intervention program for maternal mental health in perinatal periods.

UMIN Clinical Trials Registry number: UMIN000033396.

Registration URL: https://upload.umin.ac.jp/cgibin/ctr/ctr_view_reg.cgi?recptno=R000038076

Registration date: July 15, 2018.

Registration timing: retrospective.
Community knowledge and practices regarding antibiotic use in rural Mozambique: where is the starting point for prevention of antibiotic resistance?
Authors: Cambaco Olga , Alonso Menendez Yara , Kinsman John , Sigaúque Betuel , Wertheim Heiman , Do Nga , Gyapong Margaret , John-Langba Johannes , Sevene Esperança , Munguambe Khátia
Published: July 2020

Background

Antibiotic misuse and other types of unnecessary use of antibiotics can contribute to accelerate the process of antibiotic resistance, which is considered a global concern, mostly affecting low-and middle-income countries (LMICs). In Mozambique there is limited evidence on community knowledge and practices regarding antibiotics and antibiotic resistance. As part of the ABACUS project, this paper describes knowledge and practices of antibiotic use among the general population in the semi-rural district of Manhiça to inform evidence-based communication intervention strategies for safer antibiotic use.

Methods

The study was conducted in Manhiça, a semi-rural district of Southern Mozambique. Sixteen in-depth interviews and four focus group discussions (FGDs) were conducted with community members to explore lay knowledge and practices regarding antibiotics and awareness of antibiotic resistance. The qualitative data was analysed using a combination of content and thematic analysis. The SRQR guidelines for reporting qualitative studies was performed.

Results

Although participants did not hold any consistent knowledge of antibiotics, their visual recognition of amoxicillin (distinct red yellow capsule) was acceptable, but less so for different types and brands of antibiotics. The majority of participants were aware of the term ‘antibiotic’, yet the definition they gave was rarely backed by biomedical knowledge. Participants associated antibiotics with certain colours, shapes and health conditions. Participants reported common habits that may contribute to resistance: not buying the full course, self-medication, sharing medicines and interruption of treatment. Most had never heard of the term ‘antibiotic resistance’ but were familiar with the phenomenon. They often understood the term ‘resistance’ as treatment failure and likened ‘resistance’ to non-compliance, ineffective medication, disease resistance or to an inability of the physical body to respond to it.

Conclusion

There is a broad understanding of the importance of medication compliance but not specifically of antibiotic resistance. In addition, there is a recognized gap between knowledge of responsible drug compliance and actual behaviour. Future qualitative research is required to further explore what determines this behaviour. The existing ability to visually identify amoxicillin by its distinct red and yellow appearance is informative for future awareness and behavioural change campaigns that may incorporate visual aids of antibiotics.
eHealth technologies assisting in identifying potential adverse interactions with complementary and alternative medicine (CAM) or standalone CAM adverse events or side effects: a scoping review
Authors: Ng Jeremy Y. , Mooghali Maryam , Munford Vanessa
Published: July 2020

Background

While there are several existing eHealth technologies for drug-drug interactions and stand-alone drug adverse effects, it appears that considerably less attention is focussed on that of complementary and alternative medicine (CAM). Despite poor knowledge of their potential interactions and side effects, many patients use CAM. This justifies the need to identify what eHealth technologies are assisting in identifying potential 1) adverse drug interactions with CAM, 2) adverse CAM-CAM interactions or 3) standalone CAM adverse events or side effects.

Methods

A scoping review was conducted to identify eHealth technologies assisting in identifying potential adverse interactions with CAM or standalone CAM adverse events or side effects, following Arksey and O’Malley’s five-stage scoping review framework. MEDLINE, EMBASE, and AMED databases and the Canadian Agency for Drugs and Technologies in Health website were systematically searched. Eligible articles had to have assessed or referenced an eHealth technology assisting in identifying potential one or more of the three aforementioned items. We placed no eligibility restrictions on type of eHealth technology.

Results

Searches identified 3467 items, of which 2763 were unique, and 2674 titles and abstracts were eliminated, leaving 89 full-text articles to be considered. Of those, 48 were not eligible, leaving a total of 41 articles eligible for review. From these 41 articles, 69 unique eHealth technologies meeting our eligibility criteria were identified. Themes which emerged from our analysis included the following: the lack of recent reviews of CAM-related healthcare information; a large number of databases; and the presence of government adverse drug/event surveillance.

Conclusions

The present scoping review is the first, to our knowledge, to provide a descriptive map of the literature and eHealth technologies relating to our research question. We highlight that while an ample number of resources are available to healthcare providers, researchers, and patients, we caution that the quality and update frequency for many of these resources vary widely, and until formally assessed, remain unknown. We identify that a need exists to conduct an updated and systematically-searched review of CAM-related healthcare or research resources, as well as develop guidance documents associated with the development and evaluation of CAM-related eHealth technologies.
Students’ perceptions of the educational environment at King Abdulaziz University Faculty of Dentistry (KAUFD): a cross sectional study
Authors: Sabbagh Heba J. , Bakhaider Hanin A. , Abokhashabah Hesham M. , Bader Mohammed U.
Published: July 2020

Background

Prior research studies have found that dental students’ educational environment has an impact on their academic achievement. Therefore, the aim of this cross-sectional study was to assess dental students’ perceptions of the educational environment at King Abdulaziz University Faculty of Dentistry (KAUFD) in Saudi Arabia.

Methods

Second-, third-, and fourth-year dental students at KAUFD, responded to the Dundee Ready Education Environment Measure (DREEM) in October 2017. It consists of five subscales: students’ perceptions of learning, students’ perceptions of teachers, students’ academic self-perceptions, students’ perceptions of the atmosphere, and students’ social self-perceptions. The overall mean value was calculated.

Results

A total of 217 dental students responded to the questionnaire (92 males, 125 females); the response rate was 43.40%. The overall mean DREEM score was 125, which is considered “more positive than negative.” The mean DREEM score was higher for females (128.73) than for males (120.13). Third-year students (137.99) obtained higher mean scores compared to fourth-year (121.42) and fifth-year students (115.94).

Conclusions

Dental students’ perceptions of the educational environment at KAUFD support the findings of national and international studies. Students in the preclinical dental academic year (third year) obtained the highest DREEM score, when compared to those who belonged to the clinical academic years. Therefore, a personal development program and good support systems must be emphasized for clinical-year students.
How interprofessional education could benefit the future of healthcare – medical students’ perspective
Authors: Choudhury Regwaan Imtiaz , Salam Muhammed Aizaz us , Mathur Jai , Choudhury Sharfraz Riaz
Published: July 2020

As British medical students, we believe the impact that interprofessional education can have upon the future of healthcare to be a positive one. This is if it is implemented in health professions’ pre-registration curricula worldwide. Our motivations for producing this article stem from our own experiences with IPE or rather our limited experiences during our medical school journey. We have exemplified the UK’s NHS to demonstrate how IPE would positively impact a nation’s healthcare system. With patient safety, patient experience and the economical functioning of the NHS always pertaining mainstream topics of discussion within the healthcare field, the need for improved interprofessional cohesion is now more important than ever before; especially with an increasingly demanding population. Through this article, we deeply analyse and expand upon the significance IPE has in enhancing interprofessional interactions at a pre-registration stage, in preparation for work within the NHS.
Availability, accessibility, and quality of adolescent Sexual and Reproductive Health (SRH) services in urban health facilities of Rwanda: a survey among social and healthcare providers
Authors: Ndayishimiye Pacifique , Uwase Rosine , Kubwimana Isabelle , Niyonzima Jean de la Croix , Dzekem Dine Roseline , Nyandwi Jean Baptiste , Ntokamunda Kadima Justin
Published: July 2020

Background

Adolescents are still getting pregnant and contracting Human Immunodeficiency Virus (HIV) and Sexually Transmitted Infections (STIs) in Rwanda as elsewhere. Quality and comprehensive SRH services and information for adolescents is valuable for adolescents’ wellbeing. This study aimed at understanding SRH services providers’ viewpoints on accessibility, availability, and quality of SRH services provided to adolescents in selected cities of Rwanda.

Method

The study was a descriptive cross-sectional survey conducted between May 2018 and May 2019 in six selected cities of Rwanda using a mixed-methods approach. A checklist was used to collect data from 159 conveniently selected SRH services providers. The survey tool was validated. SPSS version 20 was used to describe quantitative data and ATLAS TI version 5.2 was used to code and analyze the qualitative data thematically.

Results

Qualitatively, health care providers reported that the availability of adolescent SRHS are satisfactory with access to accurate SRH information, contraceptive methods, prevention and management of STIs and HIV services, and counselling. However, the accessibility of some services remains limited. According to respondents, some products such as female condoms are less in demand and often expire before they can be distributed. One nurse clarified that they render services at a low price if an adolescent has insurance medical coverture. Religious leaders and family members may hinder adolescents from health-seeking behavior by promoting abstinence and discouraging use of protective means. Quantitatively, we found that 94.3% of health facilities provide information to adolescents on SRH services that were available and 51.6% affirmed delivering services at a low cost. Only 57.2% of respondents mentioned that adolescents are involved in designing the feedback mechanisms at their facilities.

Conclusion

SRH services in Rwanda are available for the general population and are not specifically designed for adolescents. These SRH services seem to be fairly accessible to adolescents with insufficient quality as adolescents themselves do not get to be fully involved in service provision among other aspects of quality SRH as stated by the World Health Organization (WHO). Therefore, there is a need to improve the present quality of these services to meet adolescents’ needs in an urban setting.
A simple threat-detection strategy in mice
Authors: Yang Xing , Liu Qingqing , Zhong Jinling , Song Ru , Zhang Lin , Wang Liping
Published: July 2020

Background

Avoiding danger and accessing environmental resources are two fundamental, yet conflicting, survival instincts across species. To maintain a balance between these instincts, animals must efficiently distinguish approaching threats from low-threat cues. However, little is known about the key visual features that animals use to promptly detect such imminent danger and thus facilitate an immediate and appropriate behavioral response.

Results

We used an automatic behavior detection system in mice to quantify innate defensive behaviors, including freezing, flight, and rearing, to a series of looming visual stimuli with varying expanding speeds and varying initial and final sizes. Looming visual stimuli within a specific “alert range” induced flight behavior in mice. Looming stimuli with an angular size of 10–40° and an expanding speed of 57–320°/s were in this range. Stimuli with relatively low expanding speeds tended to trigger freezing behavior, while those with relatively high expanding speeds tended to trigger rearing behavior. If approaching objects are in this “alert range,” their visual features will trigger a flight response; however, non-threatening objects, based on object size and speed, will not.

Conclusions

These results indicate a simple strategy in mice that is used to detect predators and suggest countermeasures that predators may have taken to overcome these defensive strategies.
Analysis of exosomal circRNAs upon irradiation in pancreatic cancer cell repopulation
Authors: Chen Yi-yun , Jiang Ming-jie , Tian Ling
Published: July 2020

Background

Pancreatic cancer is one of the most malignant tumors. However, radiotherapy can lead to tumor recurrence, which is caused by the residual surviving cells repopulation stimulated by some molecular released from dying cells. Exosomes may mediate cell-cell communication and transfer kinds of signals from the dying cells to the surviving cells for stimulating tumor repopulation. Circular RNAs (circRNAs) may be one vital kind of exosomal cargos involving in modulating cancer cell repopulation.

Methods

Next generation sequencing (NGS) and bioinformatics were performed to analyze and annotate the expression and function of exosome-derived circRNAs in pancreatic cancer cells after radiation. Four circRNAs were chosen for qRT-PCR analysis to validate the sequencing results.

Results

In this study, 3580 circRNAs were annotated in literatures and circBase among 12,572 identified circRNAs. There were 196 filtered differentially expressed circRNAs (the up-regulation and down-regulation respectively is 182 and 14, fold change > 2, p-value < 0.05). Regulation of metabolic process and lysine degradation were the main enriched biological processes and pathway according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.

Conclusions

The hsa_circ_0002130-hsa_miR_4482-3p-NBN interaction network suggested potential sponging miRNA and target mRNA. Our results provided potential functions of circRNAs to explore molecular mechanisms and therapeutic targets in pancreatic cancer cell repopulation upon irradiation.
LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes
Authors: Zhou Cefan , Yi Changhua , Yi Yongxiang , Qin Wenying , Yan Yanan , Dong Xueying , Zhang Xuewen , Huang Yuan , Zhang Rui , Wei Jie , Ali Declan William , Michalak Marek , Chen Xing-Zhen , Tang Jingfeng
Published: July 2020

Background

Pancreatic cancer is one of the most lethal malignancies and has an extremely poor diagnosis and prognosis. The development of resistance to gemcitabine is still a major challenge. The long noncoding RNA PVT1 was reported to be involved in carcinogenesis and chemoresistance; however, the mechanism by which PVT1 regulates the sensitivity of pancreatic cancer to gemcitabine remains poorly understood.

Methods

The viability of pancreatic cancer cells was assessed by MTT assay in vitro and xenograft tumor formation assay in vivo. The expression levels of PVT1 and miR-619-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blotting analysis and qRT-PCR were performed to assess the protein and mRNA levels of Pygo2 and ATG14, respectively. Autophagy was explored via autophagic flux detection under confocal microscopy and autophagic vacuole investigation under transmission electron microscopy (TEM). The functional role and mechanism of PVT1 were further investigated by gain- and loss-of-function assays in vitro.

Results

In the present study, we demonstrated that PVT1 was up-regulated in gemcitabine-resistant pancreatic cancer cell lines. Gain- and loss-of-function assays revealed that PVT1 impaired sensitivity to gemcitabine in vitro and in vivo. We further found that PVT1 up-regulated the expression of both Pygo2 and ATG14 and thus regulated Wnt/β-catenin signaling and autophagic activity to overcome gemcitabine resistance through sponging miR-619-5p. Moreover, we discovered three TCF/LEF binding elements (TBEs) in the promoter region of PVT1, and activation of Wnt/β-catenin signaling mediated by the up-regulation of Pygo2 increased PVT1 expression by direct binding to the TBE region. Furthermore, PVT1 was discovered to interact with ATG14, thus promoting assembly of the autophagy specific complex I (PtdIns3K-C1) and ATG14-dependent class III PtdIns3K activity.

Conclusions

These data indicate that PVT1 plays a critical role in the sensitivity of pancreatic cancer to gemcitabine and highlight its potential as a valuable target for pancreatic cancer therapy.
A comparative study on normal and obese mice indicates that the secretome of mesenchymal stromal cells is influenced by tissue environment and physiopathological conditions
Authors: Ayaz-Guner Serife , Alessio Nicola , Acar Mustafa B. , Aprile Domenico , Özcan Servet , Di Bernardo Giovanni , Peluso Gianfranco , Galderisi Umberto
Published: July 2020

Background

The term mesenchymal stromal cells (MSCs) designates an assorted cell population comprised of stem cells, progenitor cells, fibroblasts, and stromal cells. MSCs contribute to the homeostatic maintenance of many organs through paracrine and long-distance signaling.

Tissue environment, in both physiological and pathological conditions, may affect the intercellular communication of MSCs.

Methods

We performed a secretome analysis of MSCs isolated from subcutaneous adipose tissue (sWAT) and visceral adipose tissue (vWAT), and from bone marrow (BM), of normal and obese mice.

Results

The MSCs isolated from tissues of healthy mice share a common core of released factors: components of cytoskeletal and extracellular structures; regulators of basic cellular functions, such as protein synthesis and degradation; modulators of endoplasmic reticulum stress; and counteracting oxidative stress. It can be hypothesized that MSC secretome beneficially affects target cells by the horizontal transfer of many released factors. Each type of MSC may exert specific signaling functions, which could be determined by looking at the many factors that are exclusively released from every MSC type.

The vWAT-MSCs release factors that play a role in detoxification activity in response to toxic substances and drugs. The sWAT-MSC secretome contains proteins involved in in chondrogenesis, osteogenesis, and angiogenesis. Analysis of BM-MSC secretome revealed that these cells exert a signaling function by remodeling extracellular matrix structures, such as those containing glycosaminoglycans. Obesity status profoundly modified the secretome content of MSCs, impairing the above-described activity and promoting the release of inflammatory factors.

Conclusion

We demonstrated that the content of MSC secretomes depends on tissue microenvironment and that pathological condition may profoundly alter its composition.
Prevalence of antibodies against a cyclic peptide mimicking the FG loop of the human papillomavirus type 16 capsid among Tunisian women
Authors: Hassen Elham , Bansal Devendra , Ghdira Randa , Chaieb Anouar , Khairi Hedi , Zakhama Abdelfattah , Remadi Sami , Hoebeke Johan , Sultan Ali A. , Chouchane Lotfi
Published: July 2020

Background

In the past decade, cervical cancer has gone from being the second to the fourth most common cancer in women worldwide, but remains the second most common in developing countries. This cancer is most commonly caused by high-risk types of human papillomavirus (HPV), mainly type 16 (HPV16), which are sexually transmitted. This study aimed to investigate the usefulness of a cyclic synthetic peptide designed from the major L1 capsid protein of HPV16 for detecting anti-HPV16 antibodies.

Methods

We designed and synthetized a peptide that corresponds to the full sequence of the surface-exposed FG loop. We tested the antigenicity of the linear and the cyclic peptides against HPV16 L1 monoclonal antibodies. We used ELISA to detect anti-peptide antibodies in sera and cervical secretions of 179 Tunisian women, and we applied polymerase chain reaction and direct sequencing methods to detect and genotype HPV DNA.

Results

Both the linear and the cyclic peptides were recognized by the same neutralizing monoclonal antibodies, but the cyclic peptide was more reactive with human sera. The prevalence of the anti-peptide antibodies in sera was higher in women with low-grade squamous intraepithelial lesions (LGSIL) than in women with high-grade squamous intraepithelial lesions (HGSIL) (44% and 15%, respectively). This contrasts with HPV16 DNA prevalence. Compared to women from the general population, systemic IgG prevalence was significantly higher among sex workers (25%; P = 0.002) and women with LGSIL (44%; P = 0.001). In addition, systemic IgA and cervical IgG prevalence was higher among sex workers only (P = 0.002 and P = 0.001, respectively). We did not observe anti-peptide IgG antibodies in women with a current HPV16 infection.

Conclusion

Anti-peptide IgG in sera or in cervical secretions could be markers of an effective natural immunization against HPV16. This may open novel perspectives for monitoring vaccinated women and for the design of synthetic peptide-based vaccines.
The generic Informed Consent Service gICS®: implementation and benefits of a modular consent software tool to master the challenge of electronic consent management in research
Authors: Rau Henriette , Geidel Lars , Bialke Martin , Blumentritt Arne , Langanke Martin , Liedtke Wenke , Pasewald Sandra , Stahl Dana , Bahls Thomas , Maier Christian , Prokosch Hans-Ulrich , Hoffmann Wolfgang
Published: July 2020

Background

Defining and protecting participants’ rights is the aim of several ethical codices and legal regulations. According to these regulations, the Informed Consent (IC) is an inevitable element of research with human subjects. In the era of “big data medicine”, aspects of IC become even more relevant since research becomes more complex rendering compliance with legal and ethical regulations increasingly difficult.

Methods

Based on literature research and practical experiences gathered by the Institute for Community Medicine (ICM), University Medicine Greifswald, requirements for digital consent management systems were identified.

Results

To address the requirements, the free-of-charge, open-source software “generic Informed Consent Service” (gICS®) was developed by ICM to provide a tool to facilitate and enhance usage of digital ICs for the international research community covering various scenarios. gICS facilitates IC management based on IC modularisation and supports various workflows within research, including (1) electronic depiction of paper-based consents and (2) fully electronic consents. Numerous projects applied gICS and documented over 336,000 ICs and 2400 withdrawals since 2014.

Discussion

Since the consent’s content is a prerequisite for securing participants’ rights, application of gICS is no guarantee for legal compliance. However, gICS supports fine-granular consents and accommodation of differentiated consent states, which can be directly exchanged between systems, allowing automated data processing.

Conclusion

gICS simplifies and supports sustained IC management as a major key to successfully conduct studies and build trust in research with human subjects. Therefore, interested researchers are invited to use gICS and provide feedback for further improvements.
A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1
Authors: Singh Hina , Ojeda-Juárez Daniel , Maung Ricky , Shah Rohan , Roberts Amanda J. , Kaul Marcus
Published: July 2020

Background

HIV-1 infection remains a major public health concern despite effective combination antiretroviral therapy (cART). The virus enters the central nervous system (CNS) early in infection and continues to cause HIV-associated neurocognitive disorders (HAND). The pathogenic mechanisms of HIV-associated brain injury remain incompletely understood. Since HIV-1 activates the type I interferon system, which signals via interferon-α receptor (IFNAR) 1 and 2, this study investigated the potential role of IFNAR1 in HIV-induced neurotoxicity.

Methods

We cross-bred HIVgp120-transgenic (tg) and IFNAR1 knockout (IFNAR1KO) mice. At 11–14 months of age, we performed a behavioral assessment and subsequently analyzed neuropathological alterations using deconvolution and quantitative immunofluorescence microscopy, quantitative RT-PCR, and bioinformatics. Western blotting of brain lysates and an in vitro neurotoxicity assay were employed for analysis of cellular signaling pathways.

Results

We show that IFNAR1KO results in partial, sex-dependent protection from neuronal injury and behavioral deficits in a transgenic model of HIV-induced brain injury. The IFNAR1KO rescues spatial memory and ameliorates loss of presynaptic terminals preferentially in female HIVgp120tg mice. Similarly, expression of genes involved in neurotransmission reveals sex-dependent effects of IFNAR1KO and HIVgp120. In contrast, IFNAR1-deficiency, independent of sex, limits damage to neuronal dendrites, microgliosis, and activation of p38 MAPK and restores ERK activity in the HIVgp120tg brain. In vitro, inhibition of p38 MAPK abrogates neurotoxicity caused similarly by blockade of ERK kinase and HIVgp120.

Conclusion

Our findings indicate that IFNAR1 plays a pivotal role in both sex-dependent and independent processes of neuronal injury and behavioral impairment triggered by HIV-1.
Correction to: LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions
Authors: Desimmie Belete Ayele , Schrijvers Rik , Demeulemeester Jonas , Borrenberghs Doortje , Weydert Caroline , Thys Wannes , Vets Sofie , Van Remoortel Barbara , Hofkens Johan , De Rijck Jan , Hendrix Jelle , Bannert Norbert , Gijsbers Rik , Christ Frauke , Debyser Zeger
Published: July 2020

An amendment to this paper has been published and can be accessed via the original article.
Correction to: HIV-1 IN/Pol recruits LEDGF/p75 into viral particles
Authors: Desimmie Belete Ayele , Weydert Caroline , Schrijvers Rik , Vets Sofie , Demeulemeester Jonas , Proost Paul , Paron Igor , De Rijck Jan , Mast Jan , Bannert Norbert , Gijsbers Rik , Christ Frauke , Debyser Zeger
Published: July 2020

An amendment to this paper has been published and can be accessed via the original article.
Depression is associated with efavirenz-containing treatments in newly antiretroviral therapy initiated HIV patients in Ecuador
Authors: Checa Alejandro , Castillo Alberto , Camacho Malena , Tapia William , Hernandez Isabel , Teran Enrique
Published: July 2020

Background

It is well known that people living with HIV (PLWH) is in higher risk for the development of depression and it has also been suggested that the use of efavirenz into the antiretroviral regimens increases even that risk.

Objective

To evaluate the effect of efavirenz-containing antiretroviral regimens on the development of depression in newly ART initiated HIV patients in Ecuador.

Methods

In a prospective cohort study from June 2016 to May 2017, all newly HIV diagnosed patients at the HIV/AIDS Unit of the Hospital Eugenio Espejo in Quito, Ecuador were evaluated using the Hamilton Rating Scale for Depression followed by a second assessment 8–12 weeks after antiretroviral therapy containing efavirenz was initiated.

Results

A total of 79 patients, mainly males younger than 35 years were studied. Majority of them were on TDF/FTC/EFV. Initial score in Hamilton Rating Scale revealed that less than 30% had no depression symptoms while almost 40% had mild depression. However, in the second assessment, 22.6% of the subjects had a score in the Hamilton Rating Scale compatible with severe or very severe depression (RR 1.58, 95% CI 1.09 to 2.28; p = 0.05).

Conclusion

In our cohort study, depression was much higher in patients on Efavirenz-containing treatments. Therefore, assessment for depression must be essential as part of follow-up in these patients.
Mindfulness-based programs for substance use disorders: a systematic review of manualized treatments
Authors: Korecki J. Richard , Schwebel Frank J. , Votaw Victoria R. , Witkiewitz Katie
Published: July 2020

Background

Substance use disorders are prevalent and returning to substance use (i.e., relapse) following treatment is common, underscoring the need for effective treatments that will help individuals maintain long-term reductions in substance use. Mindfulness-based interventions (MBIs) have been increasingly developed and evaluated for the treatment of substance use disorders. The aim of this article was to update a systematic review conducted by Li et al. in 2017 on the outcomes of randomized control trials of MBIs for substance use disorders. In addition, we provided a session-by-session examination of the most widely used MBI protocols.

Methods

We conducted a comprehensive literature search of the PubMed, PsycINFO, and Web of Science databases from January of 2016 through April of 2020. Studies were included based on the following criteria: 1) examined the effects of an MBI, 2) employed a randomized controlled trial design with repeated measures, including secondary data analyses of randomized controlled trials, and 3) enrolled participants seeking treatment for substance use disorders.

Results

The search identified 902 publications and 30 studies were eligible for inclusion and data extraction. MBIs appear to be as effective as existing evidence-based treatments for substance use disorders at reducing the frequency and quantity of alcohol and drug use, substance-related problems, craving for substance use, and at increasing the rate of abstinence.

Conclusions

Future directions include additional large scale randomized controlled trials, investigation of the most suitable settings and protocols, examination of patient populations that may benefit most from MBIs, and dissemination and implementation research.