bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein tyrosine kinase 2: a novel therapeutic target to overcome acquired EGFR-TKI resistance in non-small cell lung cancer
Authors: Tong Xuexia , Tanino Ryosuke , Sun Rong , Tsubata Yukari , Okimoto Tamio , Takechi Mayumi , Isobe Takeshi
Published: December 2019

Background

Protein tyrosine kinase 2 (PTK2) expression has been reported in various types of human epithelial cancers including lung cancer; however, the role of PTK2 in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has not been elucidated. We previously reported that pemetrexed-resistant NSCLC cell line PC-9/PEM also acquired EGFR-TKI resistance with constitutive Akt activation, but we could not find a therapeutic target.

Methods

Cell viability in EGFR-mutant NSCLC cell lines was measured by the WST-8 assay. Phosphorylation antibody array assay for receptor tyrosine kinases was performed in PC-9 and PC-9/PEM cell lines. We evaluated the efficacy of EGFR and PTK2 co-inhibition in EGFR-TKI-resistant NSCLC in vitro. Oral defactinib and osimertinib were administered in mice bearing subcutaneous xenografts to evaluate the efficacy of the treatment combination in vivo. Both the PTK2 phosphorylation and the treatment combination efficacy were evaluated in erlotinib-resistant EGFR-mutant NSCLC cell lines.

Results

PTK2 was hyperphosphorylated in PC-9/PEM. Defactinib (PTK2 inhibitor) and PD173074 (FGFR inhibitor) inhibited PTK2 phosphorylation. Combination of PTK2 inhibitor and EGFR-TKI inhibited Akt and induced apoptosis in PC-9/PEM. The combination treatment showed improved in vivo therapeutic efficacy compared to the single-agent treatments. Furthermore, erlotinib-resistant NSCLC cell lines showed PTK2 hyperphosphorylation. PTK2 inhibition in the PTK2 hyperphosphorylated erlotinib-resistant cell lines also recovered EGFR-TKI sensitivity.

Conclusion

PTK2 hyperphosphorylation occurs in various EGFR-TKI-resistant NSCLCs. Combination of PTK2 inhibitor and EGFR-TKI (defactinib and osimertinib) recovered EGFR-TKI sensitivity in the EGFR-TKI-resistant NSCLC. Our study result suggests that this combination therapy may be a viable option to overcome EGFR-TKI resistance in NSCLC.
Absence of knockdown mutations in pyrethroid and DDT resistant populations of the main malaria vectors in Colombia
Authors: Orjuela Lorena I. , Álvarez-Diaz Diego A. , Morales Juliana A. , Grisales Nelson , Ahumada Martha L. , Venegas H Juan , Quiñones Martha L. , Yasnot María F.
Published: December 2019

Background

Knockdown resistance (kdr) is a well-characterized target-site insecticide resistance mechanism that is associated with DDT and pyrethroid resistance. Even though insecticide resistance to pyrethroids and DDT have been reported in Anopheles albimanus, Anopheles benarrochi sensu lato (s.l.), Anopheles darlingi, Anopheles nuneztovari s.l., and Anopheles pseudopunctipennis s.l. malaria vectors in Latin America, there is a knowledge gap on the role that kdr resistance mechanisms play in this resistance. The aim of this study was to establish the role that kdr mechanisms play in pyrethroid and DDT resistance in the main malaria vectors in Colombia, in addition to previously reported metabolic resistance mechanisms, such as mixed function oxidases (MFO) and nonspecific esterases (NSE) enzyme families.

Methods

Surviving (n = 62) and dead (n = 67) An. nuneztovari s.l., An. darlingi and An. albimanus mosquitoes exposed to diagnostic concentrations of DDT and pyrethroid insecticides were used to amplify and sequence a ~ 225 bp fragment of the voltage-gated sodium channels (VGSC) gene. This fragment spanning codons 1010, 1013 and 1014 at the S6 segment of domain II to identify point mutations, which have been associated with insecticide resistance in different species of Anopheles malaria vectors.

Results

No kdr mutations were detected in the coding sequence of this fragment in 129 samples, 62 surviving mosquitoes and 67 dead mosquitoes, of An. darlingi, An. nuneztovari s.l. and An. albimanus.

Conclusion

Mutations in the VGSC gene, most frequently reported in other species of the genus Anopheles resistant to pyrethroid and DDT, are not associated with the low-intensity resistance detected to these insecticides in some populations of the main malaria vectors in Colombia. These results suggest that metabolic resistance mechanisms previously reported in these populations might be responsible for the resistance observed.
Treatment experience of delayed massive gastrointestinal bleeding caused by intra-abdominal arteriointestinal fistula in gastric cancer patients after radical gastrectomy
Authors: Chen Liang , Ming Xuezhi , Gu Rongmin , Wen Xu , Li Gang , Zhou Bin , Wei Wei , Chen Huanqiu
Published: December 2019

Background

Gastric cancer (GC) remains one of the leading causes of cancer-related death. Arteriointestinal fistula is a very rare but lethal postoperative complication in GC patients after gastrectomy. However, very few reports associated with arteriointestinal fistula have been published, and there is no matured diagnosis and treatment consensus for arteriointestinal fistula. Herein, we will investigate the etiology, clinical feature, diagnostic method, treatment, and prognosis by summarizing two patients we treated and consulting related cases reported in recent years.

Case presentation

A 61-year-old male and 75-year-old female with advanced gastric cancer of gastric antrum underwent radical distal gastrectomy and D2 regional lymphadenectomy. Residual gastrojejunostomies by the Roux-en-Y method were performed. The two patients recovered well after gastrectomy, and they received postoperative adjuvant chemotherapy. However, both of them suffered sudden hematemesis and melena about 2 months after surgery, resulting in unstable vital signs. Emergency exploratory laparotomy and interventional embolotherapy by digital subtraction angiography were immediately respectively performed. During this process, arteriointestinal fistulas were found in both of them. Pseudoaneurysms of gastroduodenal artery and common hepatic artery were respectively ruptured and bleeding into the duodenum. Finally, the male patient recovered, while the female patient died because of rebleeding and hemorrhagic shock.

Conclusions

Arteriointestinal fistula, with low morbidity but high mortality, is an acute and fatal postoperative complication for GC patients after radical gastrectomy. DSA is the preferred method to diagnose arteriointestinal fistula. Embolotherapy by DSA should be performed immediately once arteriointestinal fistula is confirmed. Emergency laparotomy is another selection if the embolotherapy failed. We should pay more attention to perioperative preventive measures for formation of pseudoaneurysm, which is the leading cause of arteriointestinal fistula.
Pre- and in-service training of health care workers on immunization data management in LMICs: a scoping review
Authors: Nicol Edward , Turawa Eunice , Bonsu George
Published: December 2019

Background

Healthcare providers (HCPs) are recognized as one of the cornerstones and drivers of health interventions. Roles such as documentation of patient care, data management, analysing, interpreting and appropriate use of data are key to ending vaccine-preventable diseases (VPDs). However, there is a great deal of uncertainty and concerns about HCPs’ skills and competencies regarding immunization data handling and the importance of data use for improving service delivery in low- and middle-income countries (LMICs). Questions about the suitability and relevance of the contents of training curriculum, appropriateness of platforms through which training is delivered and the impact of such training on immunization data handling competencies and service delivery remain a source of concern. This review identified and assessed published studies that report on pre- and in-service training with a focus on HCPs’ competencies and skills to manage immunization data in LMICs.

Methods

An electronic search of six online databases was performed, in addition to websites of the WHO, Global Alliance for Vaccines and Immunization (GAVI), Oxfam International, Save the Children, Community Health Workers Central (CHW Central), UNAIDS and UNICEF. Using appropriate keywords, MeSH terms and selection procedure, 12 articles published between January 1980 and May 2019 on pre- and in-service training of HCPs, interventions geared towards standardized data collection procedures, data documentation and management of immunization data in LMICs, including curriculum reviews, were considered for analysis.

Results

Of the 2705 identified references, only 12 studies met the inclusion criteria. The review provides evidence that shows that combined and multifaceted training interventions could help improve HCPs’ knowledge, skills and competency on immunization data management. It further suggests that offering the right training to HCPs and sustaining standard immunization data management is hampered in LMICs by limited or/lack of training resources.

Conclusion

Pre-service training is fundamental in the skills’ acquisition of HCPs; however, they require additional in-service training and supportive supervision to function effectively in managing immunization data tasks. Continuous capacity development in immunization data-management competencies such as data collection, analysis, interpretation, synthesis and data use should be strengthened at all levels of the health system. Furthermore, there is a need for periodic review of the immunization-training curriculum in health training institutions, capacity development and retraining tutors on the current trends in immunization data management.
Adoption, implementation and sustainability of school-based physical activity and sedentary behaviour interventions in real-world settings: a systematic review
Authors: Cassar Samuel , Salmon Jo , Timperio Anna , Naylor Patti-Jean , van Nassau Femke , Contardo Ayala Ana María , Koorts Harriet
Published: December 2019

Background

Globally, many children fail to meet the World Health Organization’s physical activity and sedentary behaviour guidelines. Schools are an ideal setting to intervene, yet despite many interventions in this setting, success when delivered under real-world conditions or at scale is limited. This systematic review aims to i) identify which implementation models are used in school-based physical activity effectiveness, dissemination, and/or implementation trials, and ii) identify factors associated with the adoption, implementation and sustainability of school-based physical activity interventions in real-world settings.

Methods

The review followed PRISMA guidelines and included a systematic search of seven databases from January 1st, 2000 to July 31st, 2018: MEDLINE, EMBASE, CINAHL, SPORTDiscus, PsycINFO, CENTRAL, and ERIC. A forward citation search of included studies using Google Scholar was performed on the 21st of January 2019 including articles published until the end of 2018. Study inclusion criteria: (i) a primary outcome to increase physical activity and/or decrease sedentary behaviour among school-aged children and/or adolescents; (ii) intervention delivery within school settings, (iii) use of implementation models to plan or interpret study results; and (iv) interventions delivered under real-world conditions. Exclusion criteria: (i) efficacy trials; (ii) studies applying or testing school-based physical activity policies, and; (iii) studies targeting special schools or pre-school and/or kindergarten aged children.

Results

27 papers comprising 17 unique interventions were included. Fourteen implementation models (e.g., RE-AIM, Rogers’ Diffusion of Innovations, Precede Proceed model), were applied across 27 papers. Implementation models were mostly used to interpret results (n = 9), for planning evaluation and interpreting results (n = 8), for planning evaluation (n = 6), for intervention design (n = 4), or for a combination of designing the intervention and interpreting results (n = 3). We identified 269 factors related to barriers (n = 93) and facilitators (n = 176) for the adoption (n = 7 studies), implementation (n = 14 studies) and sustainability (n = 7 studies) of interventions.

Conclusions

Implementation model use was predominately centered on the interpretation of results and analyses, with few examples of use across all study phases as a planning tool and to understand results. This lack of implementation models applied may explain the limited success of interventions when delivered under real-world conditions or at scale.

Trial registration

PROSPERO (CRD42018099836).
Anti-MOG autoantibodies pathogenicity in children and macaques demyelinating diseases
Authors: Serguera Che , Stimmer Lev , Fovet Claire-Maelle , Horellou Philippe , Contreras Vanessa , Tchitchek Nicolas , Massonneau Julie , Leroy Carole , Perrin Audrey , Flament Julien , Hantraye Philippe , Demilly Joanna , Marignier Romain , Chrétien Pascale , Hart Bert‘t , Boutonnat Jean , Adam Clovis , Le-Grand Roger , Deiva Kumaran
Published: December 2019

Background

Autoantibodies against myelin oligodendrocyte glycoprotein (anti-MOG-Abs) occur in a majority of children with acquired demyelinating syndromes (ADS) and physiopathology is still under investigation. As cynomolgus macaques immunized with rhMOG, all develop an experimental autoimmune encephalomyelitis (EAE), we assessed relatedness between anti-MOG-Abs associated diseases in both species.

Methods

The study includes 27 children followed for ADS and nine macaques with rhMOG-induced EAE. MRI lesions, cytokines in blood, and CSF at onset of ADS or EAE, as well as histopathological features of brain lesions were compared.

Results

Twelve children with anti-MOG-Abs ADS (ADS MOG+) and nine macaques with EAE, presented increased IL-6 and G-CSF in the CSF, whereas no such signature was found in 15 ADS MOG−. Furthermore, IgG and C1q were associated to myelin and phagocytic cells in brains with EAE (n = 8) and in biopsies of ADS MOG+ (n = 2) but not ADS MOG− children (n = 1). Macaque brains also revealed prephagocytic lesions with IgG and C1q depositions but no leukocyte infiltration.

Conclusions

Children with ADS MOG+ and macaques with EAE induced with rhMOG, present a similar cytokine signature in the CSF and a comparable aspect of brain lesions indicating analogous pathophysiological processes. In EAE, prephagocytic lesions points at IgG as an initial effector of myelin attack. These results support the pertinence of modeling ADS MOG+ in non-human primates to apprehend the natural development of anti-MOG-associated disease, find markers of evolution, and above all explore the efficacy of targeted therapies to test primate-restricted molecules.
Endocrine and metabolic disorders in patients with Gaucher disease type 1: a review
Authors: Kałużna Małgorzata , Trzeciak Isabella , Ziemnicka Katarzyna , Machaczka Maciej , Ruchała Marek
Published: December 2019

Background

Gaucher disease (GD) is one of the most prevalent lysosomal storage diseases and is associated with hormonal and metabolic abnormalities, including nutritional status disorders, hypermetabolic state with high resting energy expenditures, peripheral insulin resistance, hypoadiponectinaemia, leptin and ghrelin impairments, hypolipidaemia, linear growth deceleration and growth hormone deficiency, delayed puberty, hypocalcaemia and vitamin D deficiency. Specific treatments for GD such as enzyme replacement therapy and substrate reduction therapy display significant effects on the metabolic profile of GD patients.

Main body of the abstract

Hormonal and metabolic disturbances observed in both adult and paediatric patients with Gaucher disease type 1 (GD1) are discussed in this review. The PubMed database was used to identify articles on endocrine and metabolic disorders in GD1. GD1 appears to facilitate the development of disorders of nutrition, glucose metabolism and vitamin D insufficiency. Metabolic and hormonal diseases may have a significant impact on the course of the underlying disease and patient quality of life.

Conclusions

Conditions relating to hormones and metabolism can be wide-ranging in GD1. Obtained findings were intrinsic to GD either as a deleterious process or a compensatory response and some changes detected may represent co-morbidities. Actively seeking and diagnosing endocrine and metabolic disorders are strongly recommended in GD1 patients to optimize healthcare.
Poor child complementary Feeding Practices in northwest Ethiopia: Finding from the Baseline Survey of Nutrition Project, 2016
Authors: Abebe Zegeye , Tariku Amare , Bikes Gashaw Andargie , Wassie Molla Mesele , Gonete Kedir Abdela , Awoke Tadesse , Gebeye Ejigu , Gete Azeb Atnafu , Yesuf Melkie Edris , Kebede Yigzaw , Alemu Kassahun , Addis Abebaw , Muhammad Esmael Ali , Abebe Solomon Mekonnen , Kasahun belew Aysheshim , Hunegnaw Melkamu Tamir , Fentie Melkitu , Kebede Adane , Muchie Kindie Fentahun
Published: December 2019

Background

Improving infant and young child feeding practices is critical to improved nutrition, health, and development of children. Ethiopia adopted the WHO recommendations of child feeding practices and developed the national guideline. In spite of this fact, only few children start and received appropriate complementary feeding based on the recommendation. Therefore, the study aimed to determine dietary diversity score and its associated factors among under five children at Dabat Health and Demographic Surveillance System site (HDSS), northwest Ethiopia.

Methods

A cross-sectional community based study was carried out from February to June 2016. All children aged 6–59 months old who lived in HDSS site were included in the survey. Odds ratio (OR) with the corresponding 95% confidence interval (CI) was calculated to show the strength of association. Finally, variables with a P-value of < 0.05 were considered statistically significant..

Results

In this study, a total of 3433 children were included. About 34.87% (95%CI: 33.27, 36.49%) of the children received adequately diversified diet. The odds of receiving adequately diversified diet was higher among children whose mother had secondary and above education (AOR = 6.51; 95%CI: 4.95, 8.56), had antenatal care (AOR = 1.90; 95%CI: 1.60, 2.26) and postnatal care visits (AOR = 1.31; 95%CI: 1.00, 1, 72), and children who feed with their family (AOR = 1.39; 95%CI: 1.17, 1.65). However, a lower dietary diversity score was observed among younger children; 6–11 months old (AOR = 0.59; 95%CI: 0.41, 0.85), and children from food insecure household (AOR = 0.76; 95%CI: 0.63, 0.92).

Conclusions

Diversified diet feeding practice is low in Dabat HDSS site. Age of the child, maternal education, antenatal and postnatal care visits, and household food insecurity were significantly associated with dietary diversity of children. Hence, ensuring household food security and enhancing the coverage of maternal health care utilization are recommended to increase dietary diversity of children.
Improving risk perception and uptake of pre-exposure prophylaxis (PrEP) through interactive feedback-based counselling with and without community engagement in young women in Manicaland, East Zimbabwe: study protocol for a pilot randomized trial
Authors: Thomas Ranjeeta , Skovdal Morten , Galizzi Matteo M. , Schaefer Robin , Moorhouse Louisa , Nyamukapa Constance , Maswera Rufurwokuda , Mandizvidza Phyllis , Hallett Timothy B. , Gregson Simon
Published: December 2019

Background

HIV incidence in adolescent girls and young women remains high in sub-Saharan Africa. Progress towards uptake of HIV prevention methods remains low. Studies of oral pre-exposure prophylaxis (PrEP) have shown that uptake and adherence may be low due to low-risk perception and ambivalence around using antiretrovirals for prevention. No evidence exists on whether an interactive intervention aimed at adjusting risk perception and addressing the uncertainty around PrEP will improve uptake. This pilot research trial aims to provide an initial evaluation of the impact of an interactive digital tablet-based counselling session, correcting risk perception, and addressing ambiguity around availability, usability, and effectiveness of PrEP.

Methods/Design

This is a matched-cluster randomized controlled trial which will compare an interactive tablet-based education intervention against a control with no intervention. The study will be implemented in eight sites. In each site, two matched clusters of villages will be created. One cluster will be randomly allocated to intervention. In two sites, a community engagement intervention will also be implemented to address social obstacles and to increase support from peers, families, and social structures. A total of 1200 HIV-negative young women aged 18–24 years, not on PrEP at baseline, will be eligible. Baseline measures of endpoints will be gathered in surveys. Follow-up assessment at six months will include biomarkers of PrEP uptake and surveys.

Discussion

This will be the first randomized controlled trial to determine whether interactive feedback counselling leads to uptake of HIV prevention methods such as PrEP and reduces risky sexual behavior. If successful, policymakers could consider such an intervention in school-based education campaigns or as post-HIV-testing counselling for young people.

Trial registration

Clinicaltrials.gov,NCT03565575. Registered on 21 June 2018.
ALW peptide ameliorates lupus nephritis in MRL/lpr mice
Authors: Wang Huixia , Lu Mei , Zhai Siyue , Wu Kunyi , Peng Lingling , Yang Jie , Xia Yumin
Published: December 2019

Background

Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus. Anti-double-stranded (ds) DNA immunoglobulin G (IgG) plays a pivotal role in the pathogenesis of LN. Currently, there are various therapies for patients with LN; however, most of them are associated with considerable side effects. We confirmed previously that ALW (ALWPPNLHAWVP), a 12-amino acid peptide, inhibited the binding of polyclonal anti-dsDNA antibodies to mesangial cells and isolated glomeruli in vitro. In this study, we further investigate whether the administration of ALW peptide decreases renal IgG deposition and relevant damage in MRL/lpr lupus-prone mice.

Methods

Forty female MRL/lpr mice were randomly divided into four groups. The mice were intravenously injected with D-form ALW peptide (ALW group), scrambled peptide (PLP group), and normal saline (NaCl group) or were not treated (blank group). The IgG deposition, the histopathologic changes, and the expressions of profibrotic factors were analyzed in the kidney of MRL/lpr mice.

Results

Compared with the other groups, glomerular deposition of IgG, IgG2a, IgG2b, and IgG3 was decreased in the ALW group. Moreover, ALW administration attenuated renal histopathologic changes in MRL/lpr mice, including mesangial proliferation and infiltration of inflammatory cells. Furthermore, the expressions of profibrotic cytokines, such as transforming growth factor-beta1 (TGF-β1) and platelet-derived growth factor B (PDGF-B), decreased in the serum and kidney tissue of ALW-treated mice.

Conclusions

Our study demonstrated that ALW peptide ameliorates the murine model of LN, possibly through inhibiting renal IgG deposition and relevant tissue inflammation and fibrosis.
Effects of upadacitinib on patient-reported outcomes: results from SELECT-BEYOND, a phase 3 randomized trial in patients with rheumatoid arthritis and inadequate responses to biologic disease-modifying antirheumatic drugs
Authors: Strand Vibeke , Schiff Michael , Tundia Namita , Friedman Alan , Meerwein Sebastian , Pangan Aileen , Ganguli Arijit , Fuldeore Mahesh , Song Yan , Pope Janet
Published: December 2019

Background

Patient-reported outcomes (PROs) are important when evaluating treatment benefits in rheumatoid arthritis (RA). We compared upadacitinib, an oral, selective JAK-1 inhibitor, with placebo to assess clinically meaningful improvements in PROs in patients with RA who have had inadequate responses to biologic disease-modifying antirheumatic drugs (bDMARD-IR).

Methods

PRO responses between upadacitinib 15 mg or 30 mg and placebo were evaluated at week 12 from the SELECT-BEYOND trial. Improvement was determined by measuring Patient Global Assessment of Disease Activity (PtGA), pain, Health Assessment Questionnaire Disability Index (HAQ-DI), Short Form-36 Health Survey (SF-36), duration and severity of morning (AM) stiffness, and Insomnia Severity Index (ISI). Least squares mean changes and percentage of patients reporting improvements ≥ minimum clinically important differences (MCID) and scores greater than or equal to normative values were determined. The number needed to treat (NNT) to achieve clinically meaningful improvements was calculated.

Results

In 498 patients, both upadacitinib doses resulted in statistically significant changes from baseline versus placebo in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 7 of 8 SF-36 domains (15 mg), 6 of 8 SF-36 domains (30 mg), and AM stiffness duration and severity. Compared with placebo, more upadacitinib-treated patients reported improvements ≥ MCID in PtGA, pain, HAQ-DI, SF-36 PCS, 7 of 8 SF-36 domains (15 mg), 5 of 8 SF-36 domains (30 mg), AM stiffness duration and severity, and ISI (30 mg) and scores ≥ normative values in HAQ-DI and SF-36 domains. Across most PROs, NNTs to achieve MCID with upadacitinib ranged from 4 to 7 patients.

Conclusions

In bDMARD-IR RA patients, upadacitinib (15 mg or 30 mg) improved multiple aspects of quality of life, and more patients reached clinically meaningful improvements approaching normative values compared with placebo.

Trial registration

The trial is registered with ClinicalTrials.gov (NCT02706847), registered 6 March 2016.
Sonographic features of carotid artery dissection due to extension of aortic dissection: a case report
Authors: Boßelmann Christian , Poli Sven
Published: December 2019

Background

Carotid artery dissection due to extension of aortic dissection (CAEAD) is a severe complication of acute aortic dissection. The risk of ischemic stroke is increased. Early sonographic detection and repeat evaluation are necessary to guide clinical management.

Case presentation

A 58-year-old male patient presents with sudden, tearing retrosternal pain. Point-of-care carotid ultrasound is used to establish the diagnosis of CAEAD. We describe a number of sonographic features and compare ultrasound to other imaging modalities.

Conclusions

Bedside carotid ultrasound enables rapid, sensitive and safe hemodynamic assessment, especially in critically ill patients.
Physiological serum total bilirubin concentrations were inversely associated with diabetic peripheral neuropathy in Chinese patients with type 2 diabetes: a cross-sectional study
Authors: Yan Pijun , Zhang Zhihong , Miao Ying , Xu Yong , Zhu Jianhua , Wan Qin
Published: December 2019

Background

Although bilirubin has been generally regarded as a waste with potential neurotoxicity at high levels, a few clinical studies suggest a potential protective role of physiological serum total bilirubin (TBIL) concentrations in diabetic peripheral neuropathy (DPN). However, the pathological mechanisms underlying the relationship remain poorly understood. The objective of this study was to explore the relationship between serum TBIL and DPN, and clinical and laboratory parameters.

Methods

Serum TBIL was measured in 1342 patients with type 2 diabetes mellitus (T2DM). The relationship between TBIL and DPN and other parameters was analyzed.

Results

Serum TBIL levels were significantly lower in T2DM patients with DPN, and were independently and negatively associated with vibration perception thresholds (VPT) (P < 0.01 or P < 0.05). Moreover, serum TBIL was negatively associated with neutrophil and white blood cell counts, fibrinogen, and the prevalence of hypertension, diabetic foot ulceration, peripheral arterial disease, diabetic nephropathy and diabetic retinopathy (P < 0.01 or P < 0.05). Additionally, serum TBIL was an independent decisive factor for the presence of DPN after multivariate adjustment. Compared to the highest quartile of TBIL, the lower quartiles were associated with a significantly increased risk of DPN (P < 0.01). Last but most importantly, the analysis of receiver operating characteristic curves revealed that the best cutoff value for serum TBIL to predict DPN was 10.75 μmol/L (sensitivity 54.6% and specificity 62.9%).

Conclusions

These findings suggest that lower physiological serum TBIL may be associated with the presence of DPN due to its decreased anti-inflammatory and vascular protective effects.
Body mass index is associated with epigenetic age acceleration in the visceral adipose tissue of subjects with severe obesity
Authors: de Toro-Martín Juan , Guénard Frédéric , Tchernof André , Hould Frédéric-Simon , Lebel Stéfane , Julien François , Marceau Simon , Vohl Marie-Claude
Published: December 2019

Background

There is solid evidence that obesity induces the acceleration of liver epigenetic aging. However, unlike easily accessible blood or subcutaneous adipose tissue, little is known about the impact of obesity on epigenetic aging of metabolically active visceral adipose tissue (VAT). Herein, we aimed to test whether obesity accelerates VAT epigenetic aging in subjects with severe obesity.

Results

A significant and positive correlation between chronological age and epigenetic age, estimated with a reduced version of the Horvath’s epigenetic clock, was found in both blood (r = 0.78, p = 9.4 × 10−12) and VAT (r = 0.80, p = 1.1 × 10−12). Epigenetic age acceleration, defined as the residual resulting from regressing epigenetic age on chronological age, was significantly correlated with body mass index (BMI) in VAT (r = 0.29, p = 0.037). Multivariate linear regression analysis showed that, after adjusting for chronological age, sex and metabolic syndrome status, BMI remained significantly associated with epigenetic age acceleration in VAT (beta = 0.15, p = 0.035), equivalent to 2.3 years for each 10 BMI units. Binomial logistic regression showed that BMI-adjusted epigenetic age acceleration in VAT was significantly associated with a higher loss of excess body weight following biliopancreatic diversion with duodenal switch surgery (odds ratio = 1.21; 95% CI = 1.04–1.48; p = 0.03).

Conclusions

Epigenetic age acceleration increases with BMI in VAT, but not in blood, as previously reported in liver. These results suggest that obesity is associated with epigenetic age acceleration of metabolically active tissues. Further studies that deepen the physiological relevance of VAT epigenetic aging will help to better understand the onset of metabolic syndrome and weight loss dynamics following bariatric surgery.
The timeline of epigenetic drug discovery: from reality to dreams
Authors: Ganesan A. , Arimondo Paola B. , Rots Marianne G. , Jeronimo Carmen , Berdasco María
Published: December 2019

The flexibility of the epigenome has generated an enticing argument to explore its reversion through pharmacological treatments as a strategy to ameliorate disease phenotypes. All three families of epigenetic proteins—readers, writers, and erasers—are druggable targets that can be addressed through small-molecule inhibitors. At present, a few drugs targeting epigenetic enzymes as well as analogues of epigenetic modifications have been introduced into the clinic use (e.g. to treat haematological malignancies), and a wide range of epigenetic-based drugs are undergoing clinical trials. Here, we describe the timeline of epigenetic drug discovery and development beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetic drug discovery using validated targets. Finally, we will highlight some of the major aspects that need further research and discuss the challenges that need to be overcome to implement epigenetic drug discovery into clinical management of human disorders. To turn into reality, researchers from various disciplines (chemists, biologists, clinicians) need to work together to optimise the drug engineering, read-out assays, and clinical trial design.
Early detection of the major male cancer types in blood-based liquid biopsies using a DNA methylation panel
Authors: Constâncio Vera , Nunes Sandra P. , Moreira-Barbosa Catarina , Freitas Rui , Oliveira Jorge , Pousa Inês , Oliveira Júlio , Soares Marta , Dias Carlos Gonçalves , Dias Teresa , Antunes Luís , Henrique Rui , Jerónimo Carmen
Published: December 2019

Background

Lung (LC), prostate (PCa) and colorectal (CRC) cancers are the most incident in males worldwide. Despite recent advances, optimal population-based cancer screening methods remain an unmet need. Due to its early onset, cancer specificity and accessibility in body fluids, aberrant DNA promoter methylation might be a valuable minimally invasive tool for early cancer detection. Herein, we aimed to develop a minimally invasive methylation-based test for simultaneous early detection of LC, PCa and CRC in males, using liquid biopsies.

Results

Circulating cell-free DNA was extracted from 102 LC, 121 PCa and 100 CRC patients and 136 asymptomatic donors’ plasma samples. Sodium-bisulfite modification and whole-genome amplification was performed. Promoter methylation levels ofAPCme, FOXA1me, GSTP1me, HOXD3me,RARβ2me, RASSF1Ame, SEPT9meandSOX17mewere assessed by multiplex quantitative methylation-specific PCR.

SEPT9meandSOX17mewere the only biomarkers shared by all three cancer types, although they detected CRC with limited sensitivity. A “PanCancer” panel (FOXA1me, RARβ2meandRASSF1Ame) detected LC and PCa with 64% sensitivity and 70% specificity, complemented with “CancerType” panel (GSTP1meandSOX17me) which discriminated between LC and PCa with 93% specificity, but with modest sensitivity. Moreover, aHOXD3meandRASSF1Amepanel discriminated small cell lung carcinoma from non-small cell lung carcinoma with 75% sensitivity, 88% specificity, 6.5 LR+ and 0.28 LR–. AnAPCmeandRASSF1Amepanel independently predicted disease-specific mortality in LC patients.

Conclusions

We concluded that a DNA methylation-based test in liquid biopsies might enable minimally invasive screening of LC and PCa, improving patient compliance and reducing healthcare costs. Moreover, it might assist in LC subtyping and prognostication.
Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study
Authors:   The AB255 Study Group, Pérez-Grijalba Virginia , Arbizu Javier , Romero Judith , Prieto Elena , Pesini Pedro , Sarasa Leticia , Guillen Fernando , Monleón Inmaculada , San-José Itziar , Martínez-Lage Pablo , Munuera Josep , Hernández Isabel , Buendía Mar , Sotolongo-Grau Oscar , Alegret Montserrat , Ruiz Agustín , Tárraga Lluis , Boada Mercè , Sarasa Manuel
Published: December 2019

Background

To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer’s disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers.

Methods

We included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification.

Results

Eighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779–0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden’s cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913–0.100).

Conclusions

Plasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer’s disease.
Characterization of the selective in vitro and in vivo binding properties of crenezumab to oligomeric Aβ
Authors: Meilandt William J. , Maloney Janice A. , Imperio Jose , Lalehzadeh Guita , Earr Tim , Crowell Susan , Bainbridge Travis W. , Lu Yanmei , Ernst James A. , Fuji Reina N. , Atwal Jasvinder K.
Published: December 2019

Background

Accumulation of amyloid β (Aβ) in the brain is proposed as a cause of Alzheimer’s disease (AD), with Aβ oligomers hypothesized to be the primary mediators of neurotoxicity. Crenezumab is a humanized immunoglobulin G4 monoclonal antibody that has been shown to bind to synthetic monomeric and aggregated Aβ in vitro; however, less is known about the binding characteristic in vivo. In this study, we evaluated the binding patterns of crenezumab to synthetic and native forms of Aβ both in vitro and in vivo.

Methods

Crenezumab was used to immunoprecipitate Aβ from synthetic Aβ preparations or brain homogenates from a PS2APP mouse model of AD to determine the forms of Aβ that crenezumab interacts with. Following systemic dosing in PS2APP or nontransgenic control mice, immunohistochemistry was used to localize crenezumab and assess its relative distribution in the brain, compared with amyloid plaques and markers of neuritic dystrophies (BACE1; LAMP1). Pharmacodynamic correlations were performed to investigate the relationship between peripheral and central target engagement.

Results

In vitro, crenezumab immunoprecipitated Aβ oligomers from both synthetic Aβ preparations and endogenous brain homogenates from PS2APP mice. In vivo studies in the PS2APP mouse showed that crenezumab localizes to regions surrounding the periphery of amyloid plaques in addition to the hippocampal mossy fibers. These regions around the plaques are reported to be enriched in oligomeric Aβ, actively incorporate soluble Aβ, and contribute to Aβ-induced neurotoxicity and axonal dystrophy. In addition, crenezumab did not appear to bind to the dense core region of plaques or vascular amyloid.

Conclusions

Crenezumab binds to multiple forms of amyloid β (Aβ), particularly oligomeric forms, and localizes to brain areas rich in Aβ oligomers, including the halo around plaques and hippocampal mossy fibers, but not to vascular Aβ. These insights highlight a unique mechanism of action for crenezumab of engaging Aβ oligomers.
An additional challenge for head and neck radiologists: anatomic variants posing a surgical risk – a pictorial review
Authors: Farina Davide , Lombardi Davide , Bertuletti Martina , Palumbo Giovanni , Zorza Ivan , Ravanelli Marco
Published: December 2019

Anatomic variants in the head and neck are quite numerous and occur frequently: a minority of them increase the risk of complications during surgical procedures and may be visualized on cross-sectional images. As some of these complications are potentially fatal, awareness (and accurate reporting) of such variants is a basic responsibility of radiologists, particularly when surgery in the pertinent anatomic area is under consideration.
Successful resuscitation from prolonged hypothermic cardiac arrest without extracorporeal life support: a case report
Authors: Kuhnke Melanie , Albrecht Roland , Schefold Joerg C. , Paal Peter
Published: December 2019

Background

We report a case of successful prolonged cardiopulmonary resuscitation (5 hours and 44 minutes) following severe accidental hypothermia with cardiac arrest treated without rewarming on extracorporeal life support.

Case presentation

A 52-year-old Italian mountaineer, was trapped in a crevasse and rescued approximately 7 hours later by a professional rescue team. After extrication, he suffered a witnessed cardiac arrest with ventricular fibrillation. Immediate defibrillation and cardiopulmonary resuscitation were started. His core temperature was 26.0 °C. Due to weather conditions, air transport to an extracorporeal life support center was not possible. Thus, he was rewarmed with conventional rewarming methods in a rural hospital. Auto-defibrillation occurred at a core temperature of 29.8 °C after 5 hours and 44 minutes of continued cardiopulmonary resuscitation. With a core temperature of 33.4 °C, he was finally admitted to a level 1 trauma center and extracorporeal life support was no longer required. Seven weeks following the accident, he was discharged home with complete neurological recovery.

Conclusions

Successful rewarming from severe hypothermia without extracorporeal life support use as performed in this case suggests that patients with primary hypothermic cardiac arrest have a chance of a favorable neurological outcome even after several hours of cardiac arrest when cardiopulmonary resuscitation and conventional rewarming are performed continuously. This may be especially relevant in remote areas, where extracorporeal life support rewarming is not available.
Synergistic modulation of signaling pathways to expand and maintain the bipotency of human hepatoblasts
Authors: Pan Tingcai , Chen Yan , Zhuang Yuanqi , Yang Fan , Xu Yingying , Tao Jiawang , You Kai , Wang Ning , Wu Yuhang , Lin Xianhua , Wu Feima , Liu Yanli , Li Yingrui , Wang Guodong , Li Yin-xiong
Published: December 2019

Background

The limited proliferative ability of hepatocytes is a major limitation to meet their demand for cell-based therapy, bio-artificial liver device, and drug tests. One strategy is to amplify cells at the hepatoblast (HB) stage. However, expansion of HBs with their bipotency preserved is challenging. Most HB expansion methods hardly maintain the bipotency and also lack functional confirmation.

Methods

On the basis of analyzing and manipulating related signaling pathways during HB (derived from human induced pluripotent stem cells, iPSCs) differentiation and proliferation, we established a specific chemically defined cocktails to synergistically regulate the related signaling pathways that optimize the balance of HB proliferation ability and stemness maintenance, to expand the HBs and investigate their capacity for injured liver repopulation in immune-deficient mice.

Results

We found that the proliferative ability progressively declines during HB differentiation process. Small molecule activation of Wnt or inhibition of TGF-β pathways promoted HB proliferation but diminished their bipotency, whereas activation of hedgehog (HH) signaling stimulated proliferation and sustained HB phenotypes. A cocktail synergistically regulating the BMP/WNT/TGF-β/HH pathways created a fine balance for expansion and maintenance of the bipotency of HBs. After purification, colony formation, and expansion for 20 passages, HBs retained their RNA profile integrity, normal karyotype, and ability to differentiate into mature hepatocytes and cholangiocytes. Moreover, upon transplantation into liver injured mice, the expanded HBs could engraft and differentiate into mature human hepatocytes and repopulate liver tissue with restoring hepatocyte mass.

Conclusion

Our data contribute to the understanding of some signaling pathways for human HB proliferation in vitro. Simultaneous BMP/HGF induction, activation of Wnt and HH, and inhibition of TGF-β pathways created a reliable method for long-term stable large-scale expansion of HBs to obtain mature hepatocytes that may have substantial clinical applications.

Graphical abstract
Compliance, adherence and effectiveness of a community-based pre-operative exercise programme: a pilot study
Authors: Loughney Lisa , Cahill Ronan , O’Malley Kiaran , McCaffrey Noel , Furlong Brona
Published: December 2019

Background

Pre-operative exercise training improves HR components of fitness and HRQoL following hospital-based programmes.

Objective

To assess compliance and adherence of a pragmatic community-based preoperative exercise programme and its effect on health-related (HR) components of fitness and health-related quality of life (HRQoL).

Methods

Thirty-two surgical oncological participants (15 prostate cancer and 17 colorectal cancer (CRC)) were recruited and assessed to measure HR components of fitness (strength and functional exercise capacity) and HRQoL. An exercise programme was prescribed in the time available prior to surgery with repeat assessments pre-operatively.

Results

Twenty-four participants (14 prostate cancer and 10 CRC) completed the full study (75% compliance). Exercise training was delivered over a median interquartile range (IQR) of 4 (3-4) weeks and 2 (1–3) weeks for the prostate cancer and CRC participants, with > 80% adherence. From baseline to post-exercise intervention, there were significant improvements in lower body strength in the prostate cancer group (p= 0.045), the CRC group (p= 0.001), and in both groups overall (p= .001). Additionally, there were statistically significant improvements in HRQoL: global health status for CRC group (p= 0.025) and for both groups overall (p= 0.023); emotional health subscale for the prostate cancer group (p= 0.048) and for both groups overall (p= 0.027); nausea/vomiting/pain subscale for the CRC group (p= 0.005) and for both groups overall (p= 0.030); and for health scale status for the prostate cancer group (p= 0.019) and for both groups overall (p= 0.006).

Conclusion

This community-based pre-operative exercise programme showed acceptable compliance and adherence rates, and significantly increased upper and lower body strength and HRQoL. Pre-operative exercise training should be considered as early as possible in the surgical-oncology pathway and respected within patient scheduling.
Mechanical Behavior of Recycled Fine Aggregate Concrete with High Slump Property in Normal- and High-Strength
Authors: Ju Minkwan , Park Kyoungsoo , Park Won-Jun
Published: December 2019

This study investigated the mechanical behavior of normal strength (NS) and high strength (HS) concrete containing recycled fine aggregates (RFAs). A high slump mixing design was employed, which may be potentially used as filled structural concrete. The compressive strength, tensile strength, and elastic modulus were measured according to the RFA replacement ratio and curing time. In addition, the shrinkage strain was measured in a temperature and humidity chamber over 260 days. The compressive strength and elastic modulus of RFA concrete were approximately 70–90% of those of virgin concrete. The decreases in the compressive strength and elastic modulus for NS concrete were larger than those for HS concrete. This could be explained by the difference in failure mechanism between NS and HS concrete. The average ratio of the compressive strength at 190 days to that at 28 days was 1.15–1.3, and the ratio of the tensile strength at 190 days to that at 28 days was 1.15–1.25. These demonstrate good strength development. The ratios between the elastic modulus and compressive strength for RFA concrete were dissimilar to those for virgin concrete but similar to those for recycled coarse aggregate concrete. ACI
318-14 (Building code requirements for structural concrete and commentary, 2014) and Model Code (Fib
model code for concrete structures, 2010) overestimated the elastic modulus of RFA concrete. Therefore, this study suggested an empirical expression to approximate the elastic modulus of RFA concrete. The increase in shrinkage owing to the use of RFA was at most 5–6% of the ultimate compressive strain of concrete.