bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular characterization of hepatitis C virus in liver disease patients in Botswana: a retrospective cross-sectional study
Authors: Bhebhe Lynnette , Anderson Motswedi , Souda Sajini , Choga Wonderful T. , Zumbika Edward , Shaver Zachary M. , Mbangiwa Tshepiso , Phinius Bonolo B. , Banda Chabeni C. , Melamu Pinkie , Musonda Rosemary M. , Essex Max , Blackard Jason T. , Moyo Sikhulile , Gaseitsiwe Simani
Published: October 2019

Background

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease globally. Direct acting antivirals (DAAs) have proven effective in curing HCV. However, the current standard of care (SOC) in Botswana remains PEGylated interferon-α (IFN-α) with ribavirin. Several mutations have been reported to confer resistance to interferon-based treatments. Therefore, there is a need to determine HCV genotypes in Botswana, as these data will guide new treatment guidelines and understanding of HCV epidemiology in Botswana.

Methods

This was a retrospective cross-sectional pilot study utilizing plasma obtained from 55 participants from Princess Marina Hospital in Gaborone, Botswana. The partial core region of HCV was amplified, and genotypes were determined using phylogenetic analysis.

Results

Four genotype 5a and two genotype 4v sequences were identified. Two significant mutations – K10Q and R70Q – were observed in genotype 5a sequences and have been associated with increased risk of hepatocellular carcinoma (HCC), while R70Q confers resistance to interferon-based treatments.

Conclusion

Genotypes 5a and 4v are circulating in Botswana. The presence of mutations in genotype 5 suggests that some patients may not respond to IFN-based regimens. The information obtained in this study, in addition to the World health organization (WHO) recommendations, can be utilized by policy makers to implement DAAs as the new SOC for HCV treatment in Botswana.
Paranasal sinus air suction for immediate pain relief of acute migraine – a randomized, double blind pilot study
Authors: Bandara S. M. R. , Samita S. , Kiridana A. M. , Ralapanawa D. M. P. U. K. , Herath H. M. M. T. B.
Published: October 2019

Background

Migraine is a primary headache disorder, which cause significant disability in adolescence. This double blind, randomized clinical trial assessed the immediate effects of suction of paranasal sinus air during an acute migraine episode.

Methods

A randomized, double blind study was conducted with 56 selected Sri Lankan school children of 16–19 years of age. Participants who met International Headache Society criteria for migraine (with or without aura) were included in the study. Subjects were randomly allocated into 2 groups where one group was subjected to three intermittent 10 sec paranasal air suctions with a ten sec suction free interval between two suctions for each nostril and the other group was subjected to placebo air suction (no paranasal air suction) in similar arrangement. Severity of headache and sub–orbital tenderness before and after suction were recorded using standard pain rating scale.

Results

After dropouts, treated and placebo groups consisted of 27 and 23 subjects respectively. The mean headache pain score drop in the treated group was significantly higher compared to that of the control group. Moreover, there was a difference in the treatment response between the types of headache (with or without aura). With respect to tenderness there was a statistically significant drop in the treated group compared to the control. In general, airflow rates in left and right nostrils were different in these subjects. However such difference was not seen in the tenderness on two sides. Nevertheless it was revealed that airflow rate has a slight negative correlation with the tenderness irrespective of the side.

Conclusion

Sixty–second paranasal air suction can provide an immediate pain relief for acute migraine in adolescents. We did not assess pain outcomes beyond 60 s, but the initial responses suggests the need to further study the efficacy of paranasal suction in migraine. A further study is suggested to evaluate the acute effects, efficacy and side effects of paranasal air suction using follow up over a prolong period.

Trial registration

Sri Lanka Clinical Trials Registry SLCTR/2017/018, 29 Jun 2017. Retrospectively registered.
Estimating the pattern of causes of death in Papua New Guinea
Authors: Kitur Urarang , Adair Tim , Riley Ian , Lopez Alan D.
Published: October 2019

Background

Papua New Guinea (PNG) is a diverse country with high mortality and evidence of increased prevalence of non-communicable diseases (NCDs), but there is no reliable cause of death (COD) data because civil registration is insufficient and routine health data comprise only a small proportion of deaths. This study aims to estimate cause-specific mortality fractions (CSMFs) for five broad groups of causes (endemic infections, emerging infections, endemic NCDs, emerging NCDs and injuries), by sex for each of PNG’s provinces.

Methods

CSMFs are calculated as the average of estimates obtained from: (1) Empirical cause method: Utilising available Verbal Autopsy (VA) data and Discharge Health Information System (DHIS) data, and applying statistical models of community versus facility CODs; and (2) Expected cause patterns method: Utilising existing estimates of mortality levels in each province and statistical models of the relationship between all-cause and cause-specific mortality using Global Burden of Disease (GBD) data.

Results

An estimated 41% of male and 49% of female deaths in PNG are due to infectious, maternal (female only), neonatal and nutritional causes. Furthermore, 45% of male and 42% of female deaths arise from NCDs. Infectious diseases, maternal, neonatal and nutritional conditions account for more than half the deaths in a number of provinces, including lower socioeconomic status provinces of Gulf and Sandaun, while provinces with higher CSMFs from emerging NCDs (e.g. ischemic heart disease, stroke) tend to be those where socioeconomic status is comparatively high (e.g. National Capital District, Western Highlands Province, Manus Province, New Ireland Province and East New Britain Province). Provinces with the highest estimated proportion of deaths from emerging infectious diseases are readily accessible by road and have the highest rates of sexually transmitted infections (STIs), while provinces with the highest CSMFs from endemic infectious, maternal, neonatal and nutritional causes are geographically isolated, have high malaria and high all-cause mortality.

Conclusions

Infectious, maternal, neonatal and nutritional causes continue to be an important COD in PNG, and are likely to be higher than what is estimated by the GBD. Nonetheless, there is evidence of the emergence of NCDs in provinces with higher socioeconomic status. The introduction of routine VA for non-facility deaths should improve COD data quality to support health policy and planning to control both infectious and NCDs.
Materials for pulpotomy in immature permanent teeth: a systematic review and meta-analysis
Authors: Chen Yuan , Chen Xinlei , Zhang Yali , Zhou Fangjie , Deng Jiaxin , Zou Jing , Wang Yan
Published: October 2019

Background

Pulpotomy is one of the most widely used methods in preserving vital pulp in teeth, which is of great significance in achieving continue root formation in immature permanent teeth suffering from dental caries or trauma. The aim of this meta-analysis and systemic review is to synthesize the available evidences to compare different pulpotomy dressing agents for pulpotomy treatment in immature permanent teeth.

Methods

Electronic databases including MEDLINE (via Pubmed), EMBASE, the Cochrane library (CENTRAL) and the clinicaltrials.gov database were searched. The references of all included articles or relevant reviews were cross-checked. Only randomized controlled trials (RCTs) comparing two or more pulp dressing agent in permanent teeth with open apex would be included. Also, the studies should have at least 6 months of follow-up, report clinical and radiographic success in detail and publish in English.

Results

Five RCTs were included for a systematic review, and all of them had a high risk of bias. There is little difference in success rate between mineral trioxide aggregate (MTA) and calcium hydroxide (CH) at 6-month follow-up (risk ratio (RR) 1; 95% confidence interval (CI) 0.94 to 1.06) and 12-month follow-up (RR 1.04; 95% CI 0.96 to 1.13). There is no difference between MTA versus platelet-rich fibrin and MTA versus calcium-enriched mixture (CEM). There is only weak evidence of increased success rate in using MTA and triple antibiotic paste (TAP) rather than abscess remedy.

Conclusions

Based on the present evidence, similar success rates with MTA were found between the dressing agents CH, CEM, RPF and TAP as pulpotomy-dressing agents in the treatment of immature permanent teeth. More high-quality RCTs are needed in this field in future studies.
Stigma among healthcare workers towards hepatitis B infection in Bangalore, India: a qualitative study
Authors: van der Scheun F. C. , Nagelkerke M. C. M. , Kilaru A. , Shridhar V. , Prasad R. , van der Werf T. S.
Published: October 2019

Background

With about 50 million people infected with hepatitis B (HBV) in India the burden of disease is high. Stigma has been identified to have a major negative impact on screening, diagnosis and treatment of hepatitis B patients. The aim of this study was to assess the stigma in nurses and physicians in Bangalore, India; studies on stigma in HBV have only been published outside of India.

Methods

Semi-structured in-depth-interviews were conducted in the period of March 20th and April 16th 2018 to study stigma and other problems in the care of hepatitis B patients. Stigma was pragmatically defined as a mark of disgrace associated with having a hepatitis B infection. Thirty physicians and nurses in different clinics and hospitals across the city of Bangalore were selected by purposeful sampling and snowball effect until theoretical saturation was reached.

Results

The following themes were identified during the interviews: feelings when treating a patient; pregnancy and marriage; confidentiality; morality; improvement in care and the difference with HIV. The most stigma was discovered in the theme morality. The majority of our participants mentioned lack of awareness as biggest obstacle in health care of hepatitis B patients.

Conclusions

This is the first qualitative study in India exploring hepatitis B stigma among health care workers. Stigma was found in certain themes, such as morality. Though, no unwillingness to treat was found. There was a general lack of awareness amongst patients according to our participants and could jeopardize proper treatment. These results will further help in developing strategies to tackle hepatitis B in India.
Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines
Authors: Liu Ningbo , Wang Yong Antican , Sun Yunguang , Ecsedy Jeffrey , Sun Jifeng , Li Xue , Wang Ping
Published: October 2019

Background

In mammalian cells, Aurora serine/threonine kinases (Aurora A, B, and C) are expressed in a cell cycle-dependent fashion as key mitotic regulators required for the maintenance of chromosomal stability. Aurora-A (AURKA) has been proven to be an oncogene in a variety of cancers; however, whether its expression relates to patient survival and the association with radiotherapy remains unclear in non-small cell lung cancer (NSCLC).

Methods

Here, we first analyzed AURKA expression in 63 NSCLC tumor samples by immunohistochemistry (IHC) and used an MTS assay to compare cell survival by targeting AURKA with MLN8237 (Alisertib) in H460 and HCC2429 (P53-competent), and H1299 (P53-deficient) cell lines. The radiosensitivity of MLN8237 was further evaluated by clonogenic assay. Finally, we examined the effect of combining radiation and AURKA inhibition in vivo with a xenograft model and explored the potential mechanism.

Results

We found that increased AURKA expression correlated with decreased time to progression and overall survival (p = 0.0447 and 0.0096, respectively). AURKA inhibition using 100 nM MLN8237 for 48 h decreases cell growth in a partially P53-dependent manner, and the survival rates of H460, HCC2429, and H1299 cells were 56, 50, and 77%, respectively. In addition, the survival of H1299 cells decreased 27% after ectopic restoration of P53 expression, and the radiotherapy enhancement was also influenced by P53 expression (DER H460 = 1.33; HCC2429 = 1.35; H1299 = 1.02). Furthermore, tumor growth of H460 was delayed significantly in a subcutaneous mouse model exposed to both MLN8237 and radiation.

Conclusions

Taken together, our results confirmed that the expression of AURKA correlated with decreased NSCLC patient survival, and it might be a promising inhibition target when combined with radiotherapy, especially for P53-competent lung cancer cells. Modulation of P53 function could provide a new option for reversing cell resistance to the AURKA inhibitor MLN8237, which deserves further investigation.
In silico-guided engineering of Pseudomonas putida towards growth under micro-oxic conditions
Authors: Kampers Linde F. C. , van Heck Ruben G. A. , Donati Stefano , Saccenti Edoardo , Volkers Rita J. M. , Schaap Peter J. , Suarez-Diez Maria , Nikel Pablo I. , Martins dos Santos Vitor A. P.
Published: October 2019

Background

Pseudomonas putida is a metabolically versatile, genetically accessible, and stress-robust species with outstanding potential to be used as a workhorse for industrial applications. While industry recognises the importance of robustness under micro-oxic conditions for a stable production process, the obligate aerobic nature of P. putida, attributed to its inability to produce sufficient ATP and maintain its redox balance without molecular oxygen, severely limits its use for biotechnology applications.

Results

Here, a combination of genome-scale metabolic modelling and comparative genomics is used to pinpoint essential $$\text {O}_{2}$$

O
2

-dependent processes. These explain the inability of the strain to grow under anoxic conditions: a deficient ATP generation and an inability to synthesize essential metabolites. Based on this, several P. putida recombinant strains were constructed harbouring acetate kinase from Escherichia coli for ATP production, and a class I dihydroorotate dehydrogenase and a class III anaerobic ribonucleotide triphosphate reductase from Lactobacillus lactis for the synthesis of essential metabolites. Initial computational designs were fine-tuned by means of adaptive laboratory evolution.

Conclusions

We demonstrated the value of combining in silico approaches, experimental validation and adaptive laboratory evolution for microbial design by making the strictly aerobic Pseudomonas putida able to grow under micro-oxic conditions.
Methodological limitations in experimental studies on symptom development in individuals with idiopathic environmental intolerance attributed to electromagnetic fields (IEI-EMF) – a systematic review
Authors: Schmiedchen Kristina , Driessen Sarah , Oftedal Gunnhild
Published: October 2019

Background

Hypersensitivity to electromagnetic fields (EMF) is a controversial condition. While individuals with idiopathic environmental intolerance attributed to electromagnetic fields (IEI-EMF) claim to experience health complaints upon EMF exposure, many experimental studies have found no convincing evidence for a physical relation. The aim of this systematic review was to evaluate methodological limitations in experimental studies on symptom development in IEI-EMF individuals that might have fostered false positive or false negative results. Furthermore, we compared the profiles of these limitations between studies with positive and negative results.

Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guided the methodological conduct and reporting. Eligible were blinded experimental studies that exposed individuals with IEI-EMF to different EMF exposure levels and queried the development of symptoms during or after each exposure trial. Strengths and limitations in design, conduct and analysis of individual studies were assessed using a customized rating tool.

Results

Twenty-eight studies met the eligibility criteria and were included in this review. In many studies, both with positive and negative results, we identified methodological limitations that might have either fostered false or masked real effects of exposure. The most common limitations were related to the selection of study participants, the counterbalancing of the exposure sequence and the effectiveness of blinding. Many studies further lacked statistical power estimates. Methodically sound studies indicated that an effect of exposure is unlikely.

Conclusion

Overall, the evidence points towards no effect of exposure. If physical effects exist, previous findings suggest that they must be very weak or affect only few individuals with IEI-EMF. Given the evidence that the nocebo effect or medical/mental disorders may explain the symptoms in many individuals with IEI-EMF, additional research is required to identify the various factors that may be important for developing IEI-EMF and for provoking the symptoms. We recommend the identification of subgroups and exploring IEI-EMF in the context of other idiopathic environmental intolerances. If further experimental studies are conducted, they should preferably be performed at the individual level. In particular, to increase the likelihood of detecting hypersensitive individuals, if they exist, we encourage researchers to achieve a high credibility of the results by minimizing sources of risk of bias and imprecision.
What do Accredited Social Health Activists need to provide comprehensive care that incorporates non-communicable diseases? Findings from a qualitative study in Andhra Pradesh, India
Authors: Abdel-All Marwa , Abimbola Seye , Praveen D. , Joshi Rohina
Published: October 2019

Background

The Indian National Program for Cardiovascular Disease, Diabetes, Cancer and Stroke (NPCDCS) was introduced to provide non-communicable disease (NCD) care through primary healthcare teams including Accredited Social Health Activists (ASHAs). Since ASHAs are being deployed to provide NCD care on top of their regular work for the first time, there is a need to understand the current capacity and challenges faced by them.

Methods

A desktop review of NPCDCS and ASHA policy documents was conducted. This was followed by group discussions with ASHAs, in-depth interviews with their supervisors and medical officers and group discussions with community members in Guntur, Andhra Pradesh, India. The multi-stakeholder data were analysed for themes related to needs, capacity, and challenges of ASHAs in providing NCD services.

Results

This study identified three key themes—first, ASHAs are unrecognised as part of the formal NPCDCS service delivery team. Second, they are overburdened, since they deliver several NPCDCS activities without receiving training or remuneration. Third, they aspire to be formally recognised as employees of the health system. However, ASHAs are enthusiastic about the services they provide and remain an essential link between the health system and the community.

Conclusion

ASHAs play a key role in providing comprehensive and culturally appropriate care to communities; however, they are unrecognised and overburdened and aspire to be part of the health system. ASHAs have the potential to deliver a broad range of services, if supported by the health system appropriately.

Trial registration

The study was registered with “Clinical Trials Registry – India” (identifier CTRI/2018/03/012425).
Better transport accessibility, better health: a health economic impact assessment study for Melbourne, Australia
Authors: Brown Vicki , Barr Alison , Scheurer Jan , Magnus Anne , Zapata-Diomedi Belen , Bentley Rebecca
Published: October 2019

Background

Physical inactivity is a global public health problem, partly due to urbanization and increased use of passive modes of transport such as private motor vehicles. Improving accessibility to public transport could be an effective policy for Governments to promote equity and efficiency within transportation systems, increase population levels of physical activity and reduce the negative externalities of motor vehicle use. Quantitative estimates of the health impacts of improvements to public transport accessibility may be useful for resource allocation and priority-setting, however few studies have been published to inform this decision-making. This paper aims to estimate the physical activity, obesity, injury, health and healthcare cost-saving outcomes of scenario-based improvements to public transport accessibility in Melbourne, Australia.

Methods

Baseline and two hypothetical future scenario estimates of improved public transport accessibility for Melbourne, Australia, were derived using a spatial planning and decision tool designed to simulate accessibility performance (the Spatial Network Analysis for Multimodal Urban Transport Systems (SNAMUTS)). Public transport related physical activity was quantified by strata of age group and sex from Melbourne travel survey data (VISTA survey) and used with the SNAMUTS Composite Index to estimate input data for health impact modelling for the Melbourne population aged 20–74 years. A proportional multi-state, multiple cohort lifetable Markov model quantified the potential health gains and healthcare cost-savings from estimated changes in physical activity, body weight and injuries related to walking to access/egress public transport under two scenarios: (S1) public transport accessibility under current policy directions, and (S2) multi-directional, high-frequency network improvements.

Results

Multi-directional, high-frequency improvements to the public transport network (S2) resulted in significantly greater health and economic gains than current policy directions (S1) in relation to physical activity (mean 6.4 more MET minutes/week), body weight (mean 0.05 kg differential), health-adjusted life years gained (absolute difference of 4878 HALYs gained) and healthcare cost-savings (absolute difference of AUD43M), as compared to business as usual under both scenarios (n = 2,832,241 adults, over the lifecourse).

Conclusions

Based on our conservative analyses, improving accessibility to public transport will improve population health by facilitating physical activity and lead to healthcare cost savings compared with business-as-usual. These wider health benefits should be better considered in transport planning and policy decisions.
A rare simultaneous coexistence of epithelioid gastrointestinal stromal tumors and schwannoma in the stomach: a case report
Authors: Li Yuxin , Teng Yongliang , Wei Xiaofei , Tian Zhuang , Cao Yuqing , Liu Xiaona , Duan Xiumei
Published: October 2019

Background

Gastrointestinal stromal tumors (GISTs), a type of mesenchymal tumor in the gastrointestinal tract, are believed to be closely associated with PDGFRA and C-KIT mutations. Schwannoma in the stomach, which is an unusual location, is a rare disorder. The simultaneous occurrence of the two diseases is rarer than metachronous occurrences, and its pathological characteristics have not been reported to date. We present a case report on a patient with simultaneous coexistence of gastric schwannoma and GISTs.

Case presentation

A 39-year-old female visited our hospital complaining of intermittent abdominal pain for the previous 3 months. CT revealed a 3.4 cm slight homogeneous enhancement in the lesser curvature of the stomach; the mass was nodular soft tissue, which was removed by radical surgery. Two solid tumors with different volumes were located in the stomach. Histologically and immunohistochemically different, the larger tumor consisted of spindle cells surrounded by a peripheral lymphoid cuff, and was positive for S-100. The larger tumor was therefore classified as a gastric schwannoma. The smaller tumor was composed of medium-sized round, oval cells with amphiphilic granular cytoplasm; vacuolization was also observed. The tumor cells were positive for DOG1 and sporadically positive for CD34 and CD117. Hence, the smaller tumor was diagnosed as epithelioid GISTs. Sanger sequencing revealed that the GIST tumor cells contained a deletion mutation (c.2527_2538 del12,843–846del4), which was located in exon 18 of PDGFRA.

Conclusion

GISTs combined with gastric schwannoma are a considerably rare subgroup of gastric tumors. Related clinical research is comparatively weak, and the mechanism remains unknown. We reviewed related articles to provide knowledge to improve the correct identification, diagnosis and management of patients with gastric cancer. All pathologists involved in the diagnosis and clinicians involved in the treatment should be aware of this new kind of disease pattern to improve their understanding of the disease.
Stereotactic ablative radiotherapy versus conventionally fractionated radiotherapy in the treatment of hepatocellular carcinoma with portal vein invasion: a retrospective analysis
Authors: Yang Jen-Fu , Lo Cheng-Hsiang , Lee Meei-Shyuan , Lin Chun-Shu , Dai Yang-Hong , Shen Po-Chien , Chao Hsing-Lung , Huang Wen-Yen
Published: October 2019

Background

This study aimed to compare the clinical outcomes of stereotactic ablative radiotherapy (SABR) and conventionally fractionated radiotherapy (CFRT) in hepatocellular carcinoma (HCC) patients with portal vein invasion (PVI).

Methods

HCC patients with PVI treated with radiotherapy from 2007 to 2016 were analysed. CFRT was administered at a median dose of 51.5 Gy (interquartile range, 45–54 Gy) with 1.8–3 Gy per fraction. SABR was administered at a median dose of 45 Gy (interquartile range, 40–48 Gy) with 6–12.5 Gy per fraction. Treatment efficacy, toxicity, and associated predictors were assessed.

Results

Among the 104 evaluable patients (45 in the SABR group and 59 in the CFRT group), the overall response rate (ORR, complete and partial response) was significantly higher in the SABR group than the CFRT group (62.2% vs. 33.8%, p = 0.003). The 1-year overall survival (OS) rate (34.9% vs. 15.3%, p = 0.012) and in-field progression-free survival (IFPS) rate (69.6% vs. 32.2%, p = 0.007) were also significantly higher in the SABR vs. CFRT group. All 3 rates remained higher in the SABR group after propensity score matching. Multivariable analysis identified SABR and a biologically effective dose ≥65 Gy as favourable predicators of OS. There was no difference between treatment groups in the incidence of radiation-induced liver disease or increase of Child-Pugh score ≥ 2 within 3 months of radiotherapy.

Conclusions

SABR was superior to CFRT in terms of ORR, OS, and IFPS. We suggest that SABR should be the preferred technique for HCC patients with PVI.
Maintenance chemotherapy using S-1 following definitive chemoradiotherapy in patients with N3 nasopharyngeal carcinoma
Authors: Zong Jingfeng , Xu Hanchuan , Chen Bijuan , Guo Qiaojuan , Xu Yun , Chen Chuanben , Weng Youliang , Zheng Wei , Pan Jianji , Lin Shaojun
Published: October 2019

Background

Patients with N3 stage nasopharyngeal carcinoma (NPC) are at high risk for treatment failure. This study aims to assess the efficacy of maintenance chemotherapy (MC) using S-1 (MC-S1), a novel oral fluoropyrimidine agent, following definitive chemoradiotherapy (CRT) using intensity-modulated radiotherapy (IMRT) in patients with N3 nasopharyngeal carcinoma (N3-NPC).

Methods

A retrospective review was conducted for all N3-NPC treated with CRT with MC (CRT-MC) or without MC (CRT-non-MC) during 2014–2016. Toxicities with MC were recorded. Overall survival (OS), locoregional failure-free survival (LFFS) and distant metastasis free survival (DMFS) were compared between CRT-MC vs. CRT-non-MC cohorts.

Results

A total of 130 N3 patients were identified, of whom 21 (16.2%) were treated with CRT-MC, and 109 (83.8%) with CRT-non-MC. Patient characteristics did not significantly differ between the CRT-MC and CRT-non-MC groups, with the exception of the number of cycles of neoadjuvant chemotherapy. Following IMRT 69 patients achieved a complete response (CR) (CRT-MC: 10; CRT-non-MC: 59), 61 had a partial response (PR) (11 vs. 50), and none maintained stable disease (SD) or developed progression of disease (PD). After a median follow-up of 41 months for surviving patients, a significant differences in OS (76.3% vs. 95.2%, p = 0.046) and DMFS (70.3% vs. 90.5%, p = 0.043) but not LFFS (84.9% vs. 100%, p = 0.091) at 3 years were observed between the CRT-non-MC and CRT-MC groups. Skin hyperpigmentation, leucopenia, fatigue, neutropenia, anorexia and nausea were the common but not severe (grade 1–2) toxicities of MC.

Conclusions

Using MC-S1 in N3-NPC patients following IMRT achieved superior survival to the CRT-non-MC patients. The toxicities of MC-S1 were mild and tolerable. Further clinical trials are required to evaluate the efficacy of MC-S1 in N3-NPC patients.
Hybrid procedure for treating adult congenital heart disease with valvular heart disease in two patients
Authors: Li Chun-sheng , Lu Zhong , Song Xiao-rong , Yan Zhong-ya
Published: October 2019

Background

The traditional approach for adult congenital heart disease combined with valvular disease is surgical treatment under cardiopulmonary bypass (CPB). This approach has a high incidence of postoperative complications, especially in patients with pulmonary hypertension and old age. We present two patients in whom the hybrid procedure was used to treat congenital malformations, followed by valve formation and replacement surgery.

Case presentation

A 63-year-old man had a muscular ventricular septal defect complicated by mitral regurgitation and a 57-year-old man had patent ductus arteriosus complicated by aortic stenosis. In both of the patients, the congenital malformation was successfully treated by the hybrid procedure, followed by valve repair or replacement. Both patients had no complications. A post-procedure echocardiogram showed no residual shunt across the duct.

Conclusions

Our findings suggest that the hybrid procedure is a useful alternative for treating adult congenital heart disease with valvular heart disease. This procedure reduces the surgical incision and difficulty of surgery, shortens the CPB time, avoids residual leakage after surgery, and reduces recovery and hospitalization times.
Controlling the laxative abuse of anorexia nervosa patients with the Serigaya Methamphetamine Relapse Prevention Program workbook: a case report
Authors: Toyoshima Kuniyoshi , Kusumi Ichiro
Published: October 2019

Background

There is no consensus on effective treatment for laxative abuse in patients with eating disorders. Here, we report the case of a patient with laxative abuse who showed some improvement through an intervention based on the Matrix model.

Case presentation

A woman diagnosed with anorexia nervosa-binge eating/purging type (AN-BP) steadfastly denied laxative abuse and would not admit to suffering from an eating disorder. This led to low motivation for undergoing conventional psychotherapy, psychoeducation, and cognitive behavioral therapy. These were ineffective and followed by repeated cycles of hospitalization and discharge. The patient’s general condition, as depicted by her laboratory and clinical parameters, deteriorated due to the medical complications resulting from laxative abuse.

Focusing on laxative abuse, we considered an intervention for drug addiction. Because the patient could maintain a diet diary and acknowledged laxative abuse as a drug addiction, we introduced the Serigaya Methamphetamine Relapse Prevention Program (SMARPP) workbook as a self-administered treatment. The patient meticulously completed the treatment and experienced a gradual improvement in laxative abuse. She has not been re-hospitalized in 4 years, currently performs household chores, and demonstrates improved social function.

Conclusions

In patients with AN-BP, the SMARPP workbook may be effective in treating laxative abuse.
RUNX1 mutations promote leukemogenesis of myeloid malignancies in ASXL1-mutated leukemia
Authors: Bera Rabindranath , Chiu Ming-Chun , Huang Ying-Jung , Lin Tung-Huei , Kuo Ming-Chung , Shih Lee-Yung
Published: October 2019

Background

Additional sex combs-like 1 (ASXL1) mutations have been described in all forms of myeloid neoplasms including chronic myelomonocytic leukemia (CMML) and associated with inferior outcomes, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) remains poorly understood. Transformation of CMML to secondary AML (sAML) is one of the leading causes of death in CMML patients. Previously, we observed that transcription factor RUNX1 mutations (RUNX1-MT) coexisted with ASXL1-MT in CMML and at myeloid blast phase of chronic myeloid leukemia. The contribution of RUNX1 mutations in the pathogenesis of myeloid transformation in ASXL1-mutated leukemia, however, remains unclear.

Methods

To evaluate the leukemogenic role of RUNX1-MT in ASXL1-mutated cells, we co-expressed RUNX1-MT (R135T) and ASXL1-MT (R693X) in different cell lines and performed immunoblot, co-immunoprecipitation, gene expression microarray, quantitative RT-PCR, cell proliferation, differentiation, and clonogenic assays for in vitro functional analyses. The in vivo effect was investigated using the C57BL/6 mouse bone marrow transplantation (BMT) model.

Results

Co-expression of two mutant genes increased myeloid stem cells in animal model, suggesting that cooperation of RUNX1 and ASXL1 mutations played a critical role in leukemia transformation. The expression of RUNX1 mutant in ASXL1-mutated myeloid cells augmented proliferation, blocked differentiation, and increased self-renewal activity. At 9 months post-BMT, mice harboring combined RUNX1 and ASXL1 mutations developed disease characterized by marked splenomegaly, hepatomegaly, and leukocytosis with a shorter latency. Mice transduced with both ASXL1 and RUNX1 mutations enhanced inhibitor of DNA binding 1 (ID1) expression in the spleen, liver, and bone marrow cells. Bone marrow samples from CMML showed that ID1 overexpressed in coexisted mutations of RUNX1 and ASXL1 compared to normal control and either RUNX1-MT or ASXL1-MT samples. Moreover, the RUNX1 mutant protein was more stable than WT and increased HIF1-α and its target ID1 gene expression in ASXL1 mutant cells.

Conclusion

The present study demonstrated the biological and functional evidence for the critical role of RUNX1-MT in ASXL1-mutated leukemia in the pathogenesis of myeloid malignancies.
Galectin-1 promotes hepatocellular carcinoma and the combined therapeutic effect of OTX008 galectin-1 inhibitor and sorafenib in tumor cells
Authors: Leung Zoe , Ko Frankie Chi Fat , Tey Sze Keong , Kwong Ernest Man Lok , Mao Xiaowen , Liu Bonnie Hei Man , Ma Angel Po Yee , Fung Yi Man Eva , Che Chi-Ming , Wong Danny Ka Ho , Lai Ching Lung , Ng Irene Oi-Lin , Yam Judy Wai Ping
Published: October 2019

Background

Galectins are beta-galactose specific binding proteins. In human cancers, including hepatocellular carcinoma (HCC), galectin-1 (Gal-1) is often found to be overexpressed. In order to combat the dismal diagnosis and death rates of HCC, gene silencing and targeted inhibition of Gal-1 was investigated for its improved therapeutic potential.

Methods

Cellular and secretory Gal-1 levels were analyzed using HCC clinical samples. The study of Gal-1 was carried by both knockdown and overexpression approaches. The stable clones were tested by in vitro assays and in vivo experiments. Mass spectrometry was used to identify downstream targets of Gal-1. The upstream regulator of Gal-1, microRNA-22 (miR-22) was characterized by functional assays. The therapeutic effect of inhibiting Gal-1 was also analyzed.

Results

Gal-1 overexpression was observed in HCC and correlated with aggressive clinicopathological features and poorer survival. The loss of Gal-1 resulted in hindered cell migration, invasion and anchorage independent growth. This was also observed in the animal models, in that when Gal-1 was knocked down, there were fewer lung metastases. Proteomic profiling of control and Gal-1 knockdown cells identified that the level of retention in endoplasmic reticulum 1 (RER1) was suppressed when Gal-1 level was reduced. The cell motility of Gal-1 knockdown cells was enhanced upon the rescue of RER1 expression. In HCC tissues, Gal-1 and RER1 expressions displayed a significant positive correlation. The upstream regulator of Gal-1, miR-22 was observed to be underexpressed in HCC tissues and negatively correlated with Gal-1. Silencing of miR-22 resulted in the upregulation of Gal-1 and enhanced cell growth, migration and invasion. However, such enhancement was abolished in cells treated with OTX008, an inhibitor of Gal-1. Combinational treatment of OTX008 and sorafenib significantly reduced tumor growth and size.

Conclusions

Gal-1 overexpression was detected in HCC and this played a role in promoting tumorigenic processes and metastasis. The function of Gal-1 was found to be mediated through RER1. The correlations between miR-22, Gal-1 and RER1 expressions demonstrated the importance of miR-22 regulation on Gal-1/RER1 oncogenic activity. Lastly, the combinational treatment of OTX008 and sorafenib proved to be an improved therapeutic option compared to when administering sorafenib alone.
Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51
Authors: Lee Jung Ok , Kang Min Ju , Byun Won Seok , Kim Shin Ae , Seo Il Hyeok , Han Jeong Ah. , Moon Ji Wook , Kim Ji Hae , Kim Su Jin , Lee Eun Jung , In Park Serk , Park Sun Hwa , Kim Hyeon Soo
Published: October 2019

Background

Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported.

Methods

Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed.

Results

Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo.

Conclusions

Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.
Retrotransposon gag-like 1 (RTL1) and the molecular evolution of self-targeting imprinted microRNAs
Authors: Mainieri Avantika , Haig David
Published: October 2019

Background

Transcription of the antisense strand ofRTL1produces a sense mRNA that is targeted for degradation by antisense microRNAs transcribed from the sense strand. Translation of the mRNA produces a retrotransposon-derived protein that is implicated in placental development. The sense and antisense transcripts are oppositely imprinted: sense mRNAs are expressed from the paternally-derived chromosome, antisense microRNAs from the maternally-derived chromosome.

Results

Two microRNAs at theRTL1locus, miR-431 and the rodent-specific miR-434, are derived from within tandem repeats. We present an evolutionary model for the establishment of a new self-targeting microRNA derived from within a tandem repeat that inhibits production of RTL1 protein when maternally-derived in heterozygotes but not when paternally-derived.

Conclusions

The interaction of sense and antisense transcripts can be interpreted as a form of communication between maternally-derived and paternally-derivedRTL1alleles that possesses many of the features of a greenbeard effect. This interaction is evolutionary stable, unlike a typical greenbeard effect, because of the necessary complementarity between microRNAs and mRNA transcribed from opposite strands of the same double helix. We conjecture that microRNAs and mRNA cooperate to reduce demands on mothers when an allele is paired with itself in homozygous offspring.

Reviewers

This article was reviewed by Eugene Berezikov and Bernard Crespi.
Multi-center screening of the Pathogen Box collection for schistosomiasis drug discovery
Authors: Maccesi Martina , Aguiar Pedro H. N. , Pasche Valérian , Padilla Melody , Suzuki Brian M. , Montefusco Sandro , Abagyan Ruben , Keiser Jennifer , Mourão Marina M. , Caffrey Conor R.
Published: October 2019

Background

Over the past five years, as a public service to encourage and accelerate drug discovery for diseases of poverty, the Medicines for Malaria Venture (MMV) has released box sets of 400 compounds named the Malaria, Pathogen and Stasis Boxes. Here, we screened the Pathogen Box against the post-infective larvae (schistosomula) of Schistosoma mansoni using assays particular to the three contributing institutions, namely, the University of California San Diego (UCSD) in the USA, the Swiss Tropical and Public Health Institute (Swiss TPH) in Switzerland, and the Fundação Oswaldo Cruz (FIOCRUZ) in Brazil. With the same set of compounds, the goal was to determine the degree of inter-assay variability and identify a core set of active compounds common to all three assays. New drugs for schistosomiasis would be welcome given that current treatment and control strategies rely on chemotherapy with just one drug, praziquantel.

Methods

Both the UCSD and Swiss TPH assays utilize daily observational scoring methodologies over 72 h, whereas the FIOCRUZ assay employs XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) at 72 h to measure viability as a function of NAD+/NADH redox state. Raw and transformed data arising from each assay were assembled for comparative analysis.

Results

For the UCSD and Swiss TPH assays, there was strong concordance of at least 87% in identifying active and inactive compounds on one or more of the three days. When all three assays were compared at 72 h, concordance remained a robust 74%. Further, robust Pearsonʼs correlations (0.48–0.68) were measured between the assays. Of those actives at 72 h, the UCSD, Swiss TPH and FIOCRUZ assays identified 86, 103 and 66 compounds, respectively, of which 35 were common. Assay idiosyncrasies included the identification of unique compounds, the differential ability to identify known antischistosomal compounds and the concept that compounds of interest might include those that increase metabolic activity above baseline.

Conclusions

The inter-assay data generated were in good agreement, including with previously reported data. A common set of antischistosomal molecules for further exploration has been identified.
From the feces to the genome: a guideline for the isolation and preservation of Strongyloides stercoralis in the field for genetic and genomic analysis of individual worms
Authors: Zhou Siyu , Harbecke Dorothee , Streit Adrian
Published: October 2019

Strongyloidiasis is a soil-borne helminthiasis, which, in spite of the up to 370 million people currently estimated to be infected with its causing agent, the nematodeStrongyloides stercoralis, is frequently overlooked. Recent molecular taxonomic studies conducted in Southeast Asia and Australia, showed that dogs can carry the same genotypes ofS. stercoralisthat also infect humans, in addition to a presumably dog-specificStrongyloidesspecies. This suggests a potential for zoonotic transmission ofS. stercoralisfrom dogs to humans. Although naturalS. stercoralisinfections have not been reported in any host other than humans, non-human primates and dogs, other as yet unidentified animal reservoirs cannot be excluded. Molecular studies also showed that humans carry rather different genotypes ofS. stercoralis. As a result, their taxonomic status and the question of whether they differ in their pathogenic potential remains open. It would therefore be very important to obtain molecular genetic/genomic information aboutS. stercoralispopulations from around the world. One way of achieving this (with little additional sampling effort) would be that people encounteringS. stercoralisin the process of their diagnostic work preserve some specimens for molecular analysis. Here we provide a guideline for the isolation, preservation, genotyping at the nuclear18SrDNA and the mitochondrialcox1 loci, and for whole genome sequencing of singleS. stercoralisworms. Since in many cases the full analysis is not possible or desired at the place and time whereS. stercoralisare found, we emphasize when and how samples can be preserved, stored and shipped for later analysis. We hope this will benefit and encourage researchers conducting field studies or diagnostics to collect and preserveS. stercoralisfor molecular genetic/genomic analyses and either analyze them themselves or make them available to others for further analysis.