bluuebunny/crossref_metadata_2025 huggingface dataset:
Proper evaluation of chemical cross-linking-based spatial restraints improves the precision of modeling homo-oligomeric protein complexes
Authors: Gaber Aljaž , Gunčar Gregor , Pavšič Miha
Published: September 2019

Background

The function of oligomeric proteins is inherently linked to their quaternary structure. In the absence of high-resolution data, low-resolution information in the form of spatial restraints can significantly contribute to the precision and accuracy of structural models obtained using computational approaches. To obtain such restraints, chemical cross-linking coupled with mass spectrometry (XL-MS) is commonly used. However, the use of XL-MS in the modeling of protein complexes comprised of identical subunits (homo-oligomers) is often hindered by the inherent ambiguity of intra- and inter-subunit connection assignment.

Results

We present a comprehensive evaluation of (1) different methods for inter-residue distance calculations, and (2) different approaches for the scoring of spatial restraints. Our results show that using Solvent Accessible Surface distances (SASDs) instead of Euclidean distances (EUCs) greatly reduces the assignation ambiguity and delivers better modeling precision. Furthermore, ambiguous connections should be considered as inter-subunit only when the intra-subunit alternative exceeds the distance threshold. Modeling performance can also be improved if symmetry, characteristic for most homo-oligomers, is explicitly defined in the scoring function.

Conclusions

Our findings provide guidelines for proper evaluation of chemical cross-linking-based spatial restraints in modeling homo-oligomeric protein complexes, which could facilitate structural characterization of this important group of proteins.
‘Candidatus Phytoplasma solani’ interferes with the distribution and uptake of iron in tomato
Authors: Buoso Sara , Pagliari Laura , Musetti Rita , Martini Marta , Marroni Fabio , Schmidt Wolfgang , Santi Simonetta
Published: September 2019

Background

‘Candidatus Phytoplasma solani’ is endemic in Europe and infects a wide range of weeds and cultivated plants. Phytoplasmas are prokaryotic plant pathogens that colonize the sieve elements of their host plant, causing severe alterations in phloem function and impairment of assimilate translocation. Typical symptoms of infected plants include yellowing of leaves or shoots, leaf curling, and general stunting, but the molecular mechanisms underlying most of the reported changes remain largely enigmatic. To infer a possible involvement of Fe in the host-phytoplasma interaction, we investigated the effects of ‘Candidatus Phytoplasma solani’ infection on tomato plants (Solanum lycopersicum cv. Micro-Tom) grown under different Fe regimes.

Results

Both phytoplasma infection and Fe starvation led to the development of chlorotic leaves and altered thylakoid organization. In infected plants, Fe accumulated in phloem tissue, altering the local distribution of Fe. In infected plants, Fe starvation had additive effects on chlorophyll content and leaf chlorosis, suggesting that the two conditions affected the phenotypic readout via separate routes. To gain insights into the transcriptional response to phytoplasma infection, or Fe deficiency, transcriptome profiling was performed on midrib-enriched leaves. RNA-seq analysis revealed that both stress conditions altered the expression of a large (> 800) subset of common genes involved in photosynthetic light reactions, porphyrin / chlorophyll metabolism, and in flowering control. In Fe-deficient plants, phytoplasma infection perturbed the Fe deficiency response in roots, possibly by interference with the synthesis or transport of a promotive signal transmitted from the leaves to the roots.

Conclusions

‘Candidatus Phytoplasma solani’ infection changes the Fe distribution in tomato leaves, affects the photosynthetic machinery and perturbs the orchestration of root-mediated transport processes by compromising shoot-to-root communication.
Construction of a high-resolution genetic map and identification of quantitative trait loci for salt tolerance in jute (Corchous spp.)
Authors: Yang Zemao , Yang Youxin , Dai Zhigang , Xie Dongwei , Tang Qing , Cheng Chaohua , Xu Ying , Liu Chan , Deng Canhui , Chen Jiquan , Su Jianguang
Published: September 2019

Background

Jute (Corchorus spp.) is the most important natural fiber crop after cotton in terms of cultivation area and production. Salt stress greatly restricts plant development and growth. A high-density genetic linkage map is the basis of quantitative trait locus (QTLs) mapping. Several high-density genetic maps and QTLs mapping related to salt tolerance have been developed through next-generation sequencing in many crop species. However, such studies are rare for jute. Only several low-density genetic maps have been constructed and no salt tolerance-related QTL has been mapped in jute to date.

Results

We developed a high-density genetic map with 4839 single nucleotide polymorphism markers spanning 1375.41 cM and an average distance of 0.28 cM between adjacent markers on seven linkage groups (LGs) using an F2 jute population, LGs ranged from LG2 with 299 markers spanning 113.66 cM to LG7 with 1542 markers spanning 350.18 cM. In addition, 99.57% of gaps between adjacent markers were less than 5 cM. Three obvious and 13 minor QTLs involved in salt tolerance were identified on four LGs explaining 0.58–19.61% of the phenotypic variance. The interval length of QTL mapping varied from 1.3 to 20.2 cM. The major QTL, qJST-1, was detected under two salt stress conditions that explained 11.81 and 19.61% of the phenotypic variation, respectively, and peaked at 19.3 cM on LG4.

Conclusions

We developed the first high-density and the most complete genetic map of jute to date using a genotyping-by-sequencing approach. The first QTL mapping related to salt tolerance was also carried out in jute. These results should provide useful resources for marker-assisted selection and transgenic breeding for salt tolerance at the germination stage in jute.
Capturing pharmacists’ impact in general practice: an e-Delphi study to attempt to reach consensus amongst experts about what activities to record
Authors: Karampatakis Georgios Dimitrios , Ryan Kath , Patel Nilesh , Stretch Graham
Published: September 2019

Background

In the UK, there is ongoing integration of pharmacists into general practice as a new healthcare service in primary care. Evaluation of the service involves national measures that require pharmacists to record their work, on the general practice clinical computer systems, using electronic activity codes. No national agreement, however, has been established on what activities to record. The purpose of this study was to attempt to reach consensus on what activities general practice-based pharmacists should record.

Methods

The e-Delphi method was chosen as it is an excellent technique for achieving consensus. The study began with an initial stage in which screening of a general practice clinical computer system and discussion groups with pharmacists from two ‘pharmacists in general practice’ sites identified 81 codes potentially relevant to general practice-based pharmacists’ work. Twenty-nine experts (pharmacists and pharmacy technicians from the two sites along with experts recruited through national committees) were then invited by e-mail to participate as a panel in three e-Delphi questionnaire rounds. In each round, panellists were asked to grade or rank codes and justify their choices. In every round, panellists were provided with anonymised feedback from the previous round which included their individual choices along with their co-panellists’ views. Final consensus (in Round 3) was defined as at least 80% agreement. Commentaries on the codes from all e-Delphi rounds were pooled together and analysed thematically.

Results

Twenty-one individual panellists took part in the study (there were 12 responses in Round 1, 18 in Round 2 and 16 in Round 3). Commentaries on the codes included three themes: challenges and facilitators; level of detail; and activities related to funding. Consensus was achieved for ten codes, eight of which related to activities (general and disease specific medication reviews, monitoring of high-risk drugs and medicines reconciliation) and two to patient outcomes (presence of side effects and satisfactory understanding of medication).

Conclusions

A formal consensus method revealed general practice-based pharmacists’ preferences for activity coding. Findings will inform policy so that any future shaping of activity coding for general practice-based pharmacists takes account of pharmacists’ actual needs and preferences.
Time to move? Factors associated with burden of care among informal caregivers of cognitively impaired older people facing housing decisions: secondary analysis of a cluster randomized trial
Authors: Boucher Alexandrine , Haesebaert Julie , Freitas Adriana , Adekpedjou Rhéda , Landry Marjolaine , Bourassa Henriette , Stacey Dawn , Croteau Jordie , Geneviève Painchaud-Guérard , Légaré France
Published: September 2019

Background

Making health-related decisions about loved ones with cognitive impairment may contribute to caregiver burden of care. We sought to explore factors associated with burden of care among informal caregivers who had made housing decisions on behalf of a cognitively impaired older person.

Methods

We conducted a secondary analysis within a cluster randomized trial (cRT) conducted in 16 publicly-funded home care service points across the Province of Quebec. The cRT assessed the impact of training home care teams in interprofessional shared decision making (IP-SDM). We assessed burden of care with the Zarit Burden Interview (ZBI) scale. We adapted Pallett’s framework to inform our data analysis. This framework posits that factors influencing burden of care among caregivers fall within four domains: (a) characteristics of the caregiver, (b) characteristics of the cognitively impaired older person, (c) characteristics of the relationship between the caregiver and the cognitively impaired older person, and (d) the caregiver’s perception of their social support resources. We computed the ZBI score and performed multilevel linear regression modelling.

Results

Among 296 caregivers included in the dataset, the mean ZBI score was 29.8 (SD = 17.5) out of 88. The typical participant was 62.6 years old (SD = 11.7), female(74.7%), and caring for a mother or father (61.2%). Using multivariate analysis, factors significantly associated with caregiver burden mapped onto: caregiver characteristics (caregivers with higher burden were female, experienced higher decision regret and decisional conflict, preferred that their loved one move into the caregiver’s home, into a private nursing home or a mixed private-public nursing home, and had made the decision more recently); relationship characteristics (spouses and children experienced higher burden); and caregiver’s perception of social support resources (caregivers who perceived that a joint decision making process had occurred had higher burden).

Conclusion

In line with the proposed framework used, we found that caregiver characteristics, relationship characteristics and caregiver’s perception of social support resources were associated with burden of care. Our results will help design interventions to prevent and/or reduce caregivers’ burden of care.

Trial registration

NCT02244359. Date of registration: September 18, 2014.
Blood pressure and hypertension prevalence among oldest-old in China for 16 year: based on CLHLS
Authors: Du Jiajun , Zhu Guoning , Yue Yanhong , Liu Miao , He Yao
Published: September 2019

Background

There were little national data on hypertension based on the oldest-old, and lack of information on chronological changes. This study aimed to describe trends of blood pressure (BP) levels and hypertension prevalence for the past 16 years among the oldest-old in China.

Methods

All the oldest-old who had participated in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) 1998 to 2014 with information about BP levels and hypertension were included in the analysis.

Results

There was fluctuation over the past 16 years for both SBP and DBP levels. The mean SBP level decreased from 148.4 ± 24.4 mmHg in 1998 to 130.8 ± 18.7 mmHg in 2005, and then increased to 139.7 ± 22.0 mmHg in 2014. The mean DBP level decreased from 84.3 ± 13.4 mmHg in 1998 to 78.9 ± 11.7 mmHg in 2008, and then increased to 79.7 ± 11.8 mmHg in 2014. The hypertension prevalence increased from 43.1 to 56.5% for the 16 years. The prevalence of isolated systolic hypertension was lowest in 2002–2005 (14.3%), and then increased to 30.7% in 2014. Multivariate logistic regression showed that older age, lower education and economic level, without health insurance were associated with higher hypertension prevalence.

Conclusions

There was a significant increase in hypertension prevalence among the Chinese oldest-old from 1998 to 2014. Greater efforts are needed for hypertension prevention among this specific population.
‘It’s what you do that makes a difference’ An interpretative phenomenological analysis of health care professionals and home care workers experiences of nutritional care for people living with dementia at home
Authors: Mole Louise , Kent Bridie , Hickson Mary , Abbott Rebecca
Published: September 2019

Background

People living with dementia at home are a group who are at increased risk of malnutrition. Health care professionals and home care workers, are ideally placed to support nutritional care in this vulnerable group. Yet, few, if any studies, have captured the experiences of these workers in respect of treating and managing nutritional issues. This interpretative phenomenological study aimed to explore the experiences and perceptions of the nutritional care of people living with dementia at home from the perspectives of health care professionals and home care workers.

Methods

Semi-structured interviews were conducted between December 2017 and March 2018, and supplemented with the use of a vignette outlining a scenario of a husband caring for his wife with dementia. Health care professionals and home care workers were purposively recruited from local care providers in the south west of England, who had experience of working with people with dementia. An Interpretative Phenomenological Analysis (IPA) approach was used throughout.

Results

Seven participants took part including two home care workers, a general practitioner, dietitian, occupational therapist, nurse and social worker. The time in their professions ranged from 3 to 15 years (mean = 8.9 years). Following analysis, four superordinate themes were identified: ‘responsibility to care’, ‘practice restrained by policy’, ‘in it together’, and ‘improving nutritional care’. This group of health care professionals and home care workers recognised the importance of improving nutritional care for people living with dementia at home, and felt a responsibility for it. However they felt that they were restricted by time and/or knowledge. The importance of supporting the family carer and working collaboratively was highlighted.

Conclusions

Health care professionals and home care workers require further training to better equip them to provide nutritional care for people living with dementia at home. Models of care may also need to be adapted to enable a more flexible and tailored approach to incorporate nutritional care. Future work in this area should focus on how health care professionals and home care workers can be better equipped to screen for malnutrition, and support changes to nutritional intake to mitigate malnutrition risk.
HLA-B*57:01 allele prevalence in treatment-Naïve HIV-infected patients from Colombia
Authors: Martínez Buitrago Ernesto , Oñate José Millán , García-Goez José Fernando , Álvarez Jorge , Lenis William , Sañudo Luz Marina , Rubiano Luisa Consuelo
Published: September 2019

Background

The HLA-B*57:01 allele is associated with a hypersensitivity reaction to abacavir. Due to the lack of knowledge of HLA-B*57:01 prevalence in Colombia, routine screening is not performed and is not recommended by the national guidelines. We aimed to determine the prevalence of HLA-B*57:01 in HIV population from Colombia.

Methods

This cross-sectional study included naïve HIV-infected adults from 13 cities of the country. The presence of HLA-B*57:01 was determined by using SSP-PCR in blood samples. Prevalence rates were stratified by sex, race, and region of origin.

Results

HLA-B*57:01 allele prevalence in Colombian HIV-infected individuals was 2.7%. When stratifying for the race, the prevalence was 4% for whites, 2.6% for other race (mainly mestizo), and 1.9% for Afro-Colombians. The prevalence varied from 0% up to 11.4% depending on the department of origin. The highest prevalence rates were found in Caldas (11.4%), Antioquia (5%), Risaralda (4.8%), and Valle del Cauca (4.3%). When distributed by country zones, the central, with a racial predominance of Caucasians and mestizos, was the highest (6.0%, 0R = 4.1, CI 1.2–12.8,p = 0,016).

Conclusions

The overall prevalence of HLA-B*57:01 in Colombia was lower than the reported rates for other Latin American countries such as Brazil, Costa Rica, and Argentina, but similar in comparison to Chile and Mexico. The diversity in the racial and ethnic heritage shown in our data supports the recommendation to implement routine screening for the HLA-B*57:01 allele before initiation of abacavir-containing antiretroviral therapy in the Colombian HIV management guidelines.
Echinococcus multilocularis inoculation induces NK cell functional decrease through high expression of NKG2A in C57BL/6 mice
Authors: Abulizi Abuduaini , Shao Yingmei , Aji Tuerganaili , Li Zhide , Zhang Chuanshan , Aini Abudusalamu , Wang Hui , Tuxun Tuerhongjiang , Li Liang , Zhang Ning , Lin Renyong , Wen Hao
Published: September 2019

Background

Alveolar echinococcosis (AE) is caused by the larval stage ofEchinococcus multilocularis(E. multilocularis), and considered as public health issue. Parasite-host immune interaction is pivotal during infection. As a subset of innate lymphoid cells, NK cells are known to play an important role during virus, bacteria, intra/extracellular parasitic infections and tumor progression. However, the possible role of NK cells inE. multilocularisinfection in both human and murine is little known. Herein, the functional alteration of hepatic NK cells and their related molecules inE. multilocularisinfected mice were studied.

Methods

2000 protoscoleces (PSCs) were injected to C57BL/6 mice via the portal vein to establish secondaryE. multilocularisinfection.NK cells population and their related molecules (CD69, Ly49D, Ly49G2, Ly49H, Ly49I, NKG2A, NKG2D, granzyme B, IFN-γ, TNF-α) were assessed by using fluorescence-activated cell sorter (FACS) techniques and qRT-PCR. NK cell depletion was performed for further understanding the possible function of NK cells during infection.

Results

The total frequencies of NK cells and NK-derived IFN-γ production were significantly reduced at designated time points (2, 4, 12 weeks). The liver resident (CD49a+DX5−) NK cells are decreased at 4 weeks after inoculation and which is significantly lower than in control mice. Moreover, in vivo antibody-mediated NK cell depletion increased parasitic load and decreased peri-parasitic fibrosis. Expression of the inhibitory receptor NKG2A was negatively related to NK- derived IFN-γ secretion.

Conclusions

Our study showed down regulates of NK cells and upper regulates of NKG2A expression on NK cells duringE. multilocularisinfection. Reduction of NK cell frequencies and increased NKG2A might result in low cytotoxic activity through decreased IFN-γ secretion inE. multilocularisinfection. This result might be helpful to restore NK cell related immunity againstE. multilocularisinfection to treat alveolar echinococcosis.
Estimating the impact of a novel drug regimen for treatment of tuberculosis: a modeling analysis of projected patient outcomes and epidemiological considerations
Authors: Kendall Emily A. , Malhotra Shelly , Cook-Scalise Sarah , Denkinger Claudia M. , Dowdy David W.
Published: September 2019

Background

Regimens that could treat both rifampin-resistant (RR) and rifampin-susceptible tuberculosis (TB) while shortening the treatment duration have reached late-stage clinical trials. Decisions about whether and how to implement such regimens will require an understanding of their likely clinical impact and how this impact depends on local epidemiology and implementation strategy.

Methods

A Markov state-transition model of 100,000 representative South African adults with TB was used to simulate implementation of the regimen BPaMZ (bedaquiline, pretomanid, moxifloxacin, and pyrazinamide), either for RR-TB only or universally for all patients. Patient outcomes, including cure rates, time with active TB, and time on treatment, were compared to outcomes under current care. Sensitivity analyses varied the drug-resistance epidemiology, rifampin susceptibility testing practices, and regimen efficacy.

Results

Using BPaMZ exclusively for RR-TB increased the proportion of all RR-TB that was cured by initial treatment from 60 ± 1% to 67 ± 1%. Expanding use of BPaMZ to all patients increased cure of RR-TB to 89 ± 1% and cure of all TB from 87.3 ± 0.1% to 89.5 ± 0.1%, while shortening treatment by 1.9 months/person. In sensitivity analyses, reducing the coverage of rifampin susceptibility testing resulted in lower projected proportions of patients cured under all regimen scenarios (current care, RR-only BPaMZ, and universal BPaMZ), compared to the proportions projected using South Africa’s high coverage; however, this reduced coverage resulted in greater expected incremental benefits of universal BPaMZ implementation, both when compared to RR-only BPaMZ implementation and when compared to to current care under the same low rifampin susceptibility testing coverage. In settings with higher RR-TB prevalence, the benefits of BPaMZ were magnified both for RR-specific and universal BPaMZ implementation.

Conclusions

Novel regimens such as BPaMZ could improve RR-TB outcomes and shorten treatment for all patients, particularly with universal use. Decision-makers weighing early options for implementing such regimens at scale will want to consider the expected impact on patient outcomes and on the burden of treatment in their local context.
Case report: extreme coronary calcifications and hypomagnesemia in a patient with a 17q12 deletion involving HNF1B
Authors: Li Howard J. , Groden Catherine , Hoenig Melanie P. , Ray Evan C. , Ferreira Carlos R. , Gahl Willam , Novacic Danica
Published: September 2019

Background

17q12 deletion syndrome encompasses a broad constellation of clinical phenotypes, including renal magnesium wasting, maturity-onset diabetes of the young (MODY), renal cysts, genitourinary malformations, and neuropsychiatric illness. Manifestations outside of the renal, endocrine, and nervous systems have not been well described.

Case presentation

We report a 62-year-old male referred to the Undiagnosed Diseases Program (UDP) at the National Institutes of Health (NIH) who presented with persistent hypermagnesiuric hypomagnesemia and was found to have a 17q12 deletion. The patient exhibited several known manifestations of the syndrome, including severe hypomagnesemia, renal cysts, diabetes and cognitive deficits. Coronary CT revealed extensive coronary calcifications, with a coronary artery calcification score of 12,427. Vascular calcifications have not been previously reported in this condition. We describe several physiologic mechanisms and a review of literature to support the expansion of the 17q12 deletion syndrome to include vascular calcification.

Conclusion

Extensive coronary and vascular calcifications may be an extension of the 17q12 deletion phenotype, particularly if hypomagnesemia and hyperparathyroidism are prevalent. In patients with 17q12 deletions involving HNF1B, hyperparathyroidism and hypomagnesemia may contribute to significant cardiovascular risk.
Adherence to guidelines and suboptimal practice in term breech delivery with perinatal death- a population-based case-control study in Norway
Authors: Bjellmo Solveig , Hjelle Sissel , Krebs Lone , Magnussen Elisabeth , Vik Torstein
Published: September 2019

Background

In a recent population-based study we reported excess risk of neonatal mortality associated with vaginal breech delivery. In this case-control study we examine whether deviations from Norwegian guidelines are more common in breech deliveries resulting in intrapartum or neonatal deaths than in breech deliveries where the offspring survives, and if these deaths are potentially avoidable.

Material and methods

Case-control study completed as a perinatal audit including term breech deliveries of singleton without congenital anomalies in Norway from 1999 to 2015. Deliveries where the child died intrapartum or in the neonatal period were case deliveries. For each case, two control deliveries who survived were identified. All the included deliveries were reviewed by four obstetricians independently assessing if the deaths in the case group might have been avoided and if the management of the deviations from Norwegian guidelines were more common in case than in control deliveries.

Results

Thirty-one case and 62 control deliveries were identified by the Medical Birth Registry of Norway. After exclusion of non-eligible deliveries, 22 case and 31 control deliveries were studied. Three case and two control deliveries were unplanned home deliveries, while all in-hospital deliveries were in line with national guidelines. Antenatal care and/or management of in-hospital deliveries was assessed as suboptimal in seven (37%) case and two (7%) control deliveries (p = 0.020). Three case deliveries were completed as planned caesarean delivery and 12 (75%) of the remaining 16 deaths were considered potentially avoidable had planned caesarean delivery been done. In seven of these 16 deliveries, death was associated with cord prolapse or difficult delivery of the head.

Conclusion

All in-hospital breech deliveries were in line with Norwegian guidelines. Seven of twelve potentially avoidable deaths were associated with birth complications related to breech presentation. However, suboptimal care was more common in case than control deliveries. Further improvement of intrapartum care may be obtained through continuous rigorous training and feedback from repeated perinatal audits.
What factors influence midwives to provide obstetric high dependency care on the delivery suite or request care be escalated away from the obstetric unit? Findings of a focus group study
Authors: James Alison , Cooper Simon , Stenhouse Elizabeth , Endacott Ruth
Published: September 2019

Background

In the United Kingdom, midwives will engage in discussions with the multidisciplinary team as to whether they can provide Obstetric High Dependency Care (OHDC) on the Delivery Suite or whether a woman’s care should be escalated to the critical care team. This study aimed to explore the question: What factors influence midwives to provide OHDC or request care be escalated away from the obstetric unit in hospitals remote from tertiary referral centres?

Methods

Focus groups were undertaken with midwives (n = 34) across three obstetric units in England, with annual birth rates ranging from 1500 to 5000 per annum, in District General Hospitals. Three scenarios in the form of video vignettes of handover were used as triggers for the focus groups. Scenario 1; severe pre-eclampsia, physiologically unstable 2; major postpartum haemorrhage requiring invasive monitoring 3; recent admission of woman with chest pain receiving facial oxygen and requiring continuous electrocardiogram (ECG) monitoring. Two focus groups were conducted in each of the obstetric units with experienced midwives. Data were analysed using a qualitative framework approach.

Results

Factors influencing midwives’ care escalation decisions included the care environment, a woman’s diagnosis and fetal or neonatal factors. The overall plan of care including the need for ECG and invasive monitoring were also influential factors. Midwives in the smallest obstetric unit did not have access to the facilities for OHDC provision. Midwives in the larger obstetric units provided OHDC but identified varying degrees of skill and sometimes used ‘workarounds’ to facilitate care provision. Midwifery staffing levels, skill mix and workload were also influential. Some differences of opinion were evident between midwives working in the same obstetric units as to whether OHDC could be provided and the support they would enlist to help them provide it. Reliance on clinical guidelines appeared variable.

Conclusions

Findings indicate that there may be inequitable OHDC provision at a local level. Organisationally robust systems are required to promote safe, equitable OHDC care including skills development for midwives and precise escalation guidelines to minimise workarounds. Training for midwives must include strategies that prevent skills fade.
Clinical outcomes of muscle invasive bladder Cancer according to the BASQ classification
Authors: Yuk Hyeong Dong , Jeong Chang Wook , Kwak Cheol , Kim Hyeon Hoe , Moon Kyung Chul , Ku Ja Hyeon
Published: September 2019

Background

We evaluated the clinical efficacy and prognosis of muscle-invasive bladder cancer according to the basal/squamous-like (BASQ) classification system based on immunohistochemical staining [CK5/6(+), CK14(+), GATA3(−), and FOXA1(−)].

Methods

One hundred patients diagnosed with muscle-invasive bladder cancer (cT2-4 N0-3 M0) were included in the study. All patients underwent radical cystectomy after transurethral removal of bladder tumor. Immunostaining was performed for CK5/6, CK14, FOXA1, and GATA3 antibodies on tissue microarray slides, and expression patterns were quantitatively analyzed using a scanning program.

Results

The median follow-up time was 77.4 (interquartile range: 39–120.9) months. The mean age of the patients was 65.1 ± 11.2 years. FOXA1 or CK14 expression greater than 1% was respectively positively and negatively correlated with overall survival (OS; p = 0.011 and p = 0.042, respectively), cancer-specific survival (CSS; p = 0.050 for both), and recurrence-free survival (RFS; p = 0.018 and p = 0.040, respectively). For CK5/6+ and GATA3- or FOXA1- expression, 10% CK5/6+ cells were negatively correlated with OS (p = 0.032 and p = 0.039, respectively) and with RFS in combination with FOXA1- only (p = 0.050).

Conclusions

In this study, CK14 expression was associated with a poor prognosis. The new classification system of bladder cancer based on molecular characteristics is expected to helpful tool for the establishment of personalized treatment strategies and associated prediction of therapeutic responses.
Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib
Authors: de Haan R. , van Werkhoven E. , van den Heuvel M.M. , Peulen H. M. U. , Sonke G. S. , Elkhuizen P. , van den Brekel M. W. M. , Tesselaar M. E. T. , Vens C. , Schellens J. H. M. , van Triest B. , Verheij M.
Published: September 2019

Background

Poly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited.

Methods

Olaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for pharmacokinetic and pharmacodynamic analyses.

Discussion

We designed three parallel phase 1 trials to assess the safety and tolerability of the PARP inhibitor olaparib in combination with radical (chemo-)radiotherapy treatment regimens. PARP inhibitors have the potential to improve outcomes in patients treated with radical (chemo-)radiotherapy, by achieving higher locoregional control rates and/or less treatment associated toxicity.

Trial registration

ClinicalTrials.govIdentifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).
LETM1 is a potential biomarker of prognosis in lung non-small cell carcinoma
Authors: Piao Longzhen , Yang Zhaoting , Feng Ying , Zhang Chengye , Cui Chunai , Xuan Yanhua
Published: September 2019

Background

Although the leucine zipper-EF-hand-containing transmembrane protein 1 (LETM1) is one of the mitochondrial inner membrane proteins that is involved in cancer prognosis in various tumors, LETM1 as a biomarker for prognostic evaluation of non-small cell lung carcinoma (NSCLC) has not been well studied.

Methods

To address this issue, we used 75 cases NSCLC, 20 cases adjacent normal lung tissues and NSCLC cell lines. We performed immunohistochemistry staining and western blot analysis as well as immunofluorescence imaging.

Results

Our studies show that expression of LETM1 is significantly correlated with the lymph node metastasis (p = 0.003) and the clinical stage (p = 0.005) of NSCLC. The Kaplan-Meier survival analysis revealed that NSCLC patients with positive expression of LETM1 exhibits a shorter overall survival (OS) rate (p = 0.005). The univariate and multivariate Cox regression analysis indicated that LETM1 is a independent poor prognostic marker of NSCLC. In addition, the LETM1 expression is correlated with cancer stemness-related gene LGR5 (p < 0.001) and HIF1α expression (p < 0.001), but not with others. Moreover, LETM1 expression was associated with the expression of cyclin D1 (p = 0.003), p27 (p = 0.001), pPI3K(p85) (p = 0.025), and pAkt-Thr308 (p = 0.004). Further, our studies show in LETM1-positive NSCLC tissues the microvessel density was significantly higher than in the negative ones (p = 0.024).

Conclusion

These results indicate that LETM1 is a potential prognostic biomarker of NSCLC.
CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing
Authors: Andersch Lena , Radke Josefine , Klaus Anika , Schwiebert Silke , Winkler Annika , Schumann Elisa , Grunewald Laura , Zirngibl Felix , Flemmig Carina , Jensen Michael C. , Rossig Claudia , Joussen Antonia , Henssen Anton , Eggert Angelika , Schulte Johannes H. , Künkele Annette
Published: September 2019

Background

Chimeric antigen receptor (CAR)-based T cell therapy is in early clinical trials to target the neuroectodermal tumor, neuroblastoma. No preclinical or clinical efficacy data are available for retinoblastoma to date. Whereas unilateral intraocular retinoblastoma is cured by enucleation of the eye, infiltration of the optic nerve indicates potential diffuse scattering and tumor spread leading to a major therapeutic challenge. CAR-T cell therapy could improve the currently limited therapeutic strategies for metastasized retinoblastoma by simultaneously killing both primary tumor and metastasizing malignant cells and by reducing chemotherapy-related late effects.

Methods

CD171 and GD2 expression was flow cytometrically analyzed in 11 retinoblastoma cell lines. CD171 expression and T cell infiltration (CD3+) was immunohistochemically assessed in retrospectively collected primary retinoblastomas. The efficacy of CAR-T cells targeting the CD171 and GD2 tumor-associated antigens was preclinically tested against three antigen-expressing retinoblastoma cell lines. CAR-T cell activation and exhaustion were assessed by cytokine release assays and flow cytometric detection of cell surface markers, and killing ability was assessed in cytotoxic assays. CAR constructs harboring different extracellular spacer lengths (short/long) and intracellular co-stimulatory domains (CD28/4-1BB) were compared to select the most potent constructs.

Results

All retinoblastoma cell lines investigated expressed CD171 and GD2. CD171 was expressed in 15/30 primary retinoblastomas. Retinoblastoma cell encounter strongly activated both CD171-specific and GD2-specific CAR-T cells. Targeting either CD171 or GD2 effectively killed all retinoblastoma cell lines examined. Similar activation and killing ability for either target was achieved by all CAR constructs irrespective of the length of the extracellular spacers and the co-stimulatory domain. Cell lines differentially lost tumor antigen expression upon CAR-T cell encounter, with CD171 being completely lost by all tested cell lines and GD2 further down-regulated in cell lines expressing low GD2 levels before CAR-T cell challenge. Alternating the CAR-T cell target in sequential challenges enhanced retinoblastoma cell killing.

Conclusion

Both CD171 and GD2 are effective targets on human retinoblastoma cell lines, and CAR-T cell therapy is highly effective against retinoblastoma in vitro. Targeting of two different antigens by sequential CAR-T cell applications enhanced tumor cell killing and preempted tumor antigen loss in preclinical testing.
Clinical and cost-effectiveness of guided internet-based interventions in the indicated prevention of depression in green professions (PROD-A): study protocol of a 36-month follow-up pragmatic randomized controlled trial
Authors: Braun Lina , Titzler Ingrid , Ebert David Daniel , Buntrock Claudia , Terhorst Yannik , Freund Johanna , Thielecke Janika , Baumeister Harald
Published: September 2019

Background

People in green professions are exposed to a variety of risk factors, which could possibly enhance the development of depression. Amongst possible prevention approaches, internet- and mobile-based interventions (IMIs) have been shown to be effective and scalable. However, little is known about the effectiveness in green professions. The aim of the present study is to examine the (cost-)effectiveness of a tailored IMI program for reducing depressive symptoms and preventing the onset of clinical depression compared to enhanced treatment as usual (TAU+).

Methods

A pragmatic randomized controlled trial (RCT) will be conducted to evaluate a tailored and therapeutically guided preventive IMI program in comparison to TAU+ with follow-ups at post-treatment (9 weeks), 6-, 12-, 24-, and 36-months. Entrepreneurs in green professions, collaborating spouses, family members and pensioners (N = 360) with sufficient insurance status and at least subthreshold depression (PHQ-9 ≥ 5) are eligible for inclusion. Primary outcome is depressive symptom severity (QIDS-SR16). Secondary outcomes include incidence of depression (QIDS-SR16), quality of life (AQoL-8D) and negative treatment effects (INEP). A health-economic evaluation will be conducted from a societal perspective. The IMI program is provided by psychologists of an external service company and consists of six guided IMIs (6–8 modules, duration: 6–8 weeks) targeting different symptoms (depressive mood, depressive mood with comorbid diabetes, perceived stress, insomnia, panic and agoraphobic symptoms or harmful alcohol use). Intervention choice depends on a screening of participants’ symptoms and individual preferences. The intervention phase is followed by a 12-months consolidating phase with monthly contact to the e-coach.

Discussion

This is the first pragmatic RCT investigating long-term effectiveness of a tailored guided IMI program for depression prevention in green professions. The present trial builds on a large-scale strategy for depression prevention in green professions. The intended implementation of the IMI program with a nationwide rollout has the potential to reduce overall depression burden and associated health care costs in case of given effectiveness.

Trial registration

German Clinical Trial Registration:DRKS00014000. Registered on 09 April 2018.
Physical activity and emotional intelligence among undergraduate students: a correlational study
Authors: Acebes-Sánchez Jorge , Diez-Vega Ignacio , Esteban-Gonzalo Sara , Rodriguez-Romo Gabriel
Published: September 2019

Background

Physical activity (PA) can be a mechanism that develops emotions. Emotional intelligence (EI) is related to significant public health and psychological benefits. However, there is little information about the relationships between PA and EI dimensions: emotional attention, clarity, and repair. This study examined the possible relationships between these variables in undergraduate students from Madrid. As a secondary aim, sex differences in PA domains and EI dimensions were examined.

Methods

A total of 2960 (21.34 ± 4.34 years) undergraduate students from Madrid (Spain) fulfilled the Trait Meta-Mood Scale (TMMS-24) and Global Physical Activity Questionnaire (GPAQ). We used a MANOVA to compare EI and PA levels according to sex. Different linear regressions were conducted to calculate the PA and age prediction power based on EI.

Results

We found a significant association between EI dimensions and PA levels, although these relationships were small. Fully adjusted linear regression showed that sex and leisure-time PA (LTPA) were associated of emotional attention (r2c = .025). Sex, age, and LTPA were associated of emotional repair (r2c = .024). There were statistically significant differences in EI by sex (p ≤ .001; η2p =.039), with higher scores in emotional attention for women (p ≤ .001) and emotional clarity (p ≤ .001) and repair (p ≤ .001) for men. PA levels differed according to sex (p ≤ .001; η2p =.038). Men show higher scores in LTPA levels (p = .002) and occupational PA (p ≤ .001).

Conclusions

Undergraduate students with higher levels of LTPA showed a better score on EI, specifically in emotional attention and emotional repair. However, these associations and the predictive power of LTPA regarding emotional attention and emotional repair were weak. Men engaged in more LTPA and occupational PA and had higher emotional clarity and emotional repair than women. However, women had higher emotional attention.
A survey of the prevalence of modifiable health risk behaviours among carers of people with a mental illness
Authors: Bailey Jacqueline M. , Regan Tim W. , Bartlem Kate M. , Wiggers John H. , Wye Paula M. , Bowman Jenny A.
Published: September 2019

Background

Family carers provide significant support to people with a mental illness; yet may experience poor mental and physical health themselves. Among limited research addressing the physical health of carers, studies of carers of people with dementia and young people with psychosis suggest increased risk of chronic diseases in conjunction with higher levels of potentially modifiable lifestyle risk behaviours. This exploratory study, conducted with carers of people with various mental illnesses, aimed to determine: carer prevalence of health risk behaviours (inadequate fruit and vegetable consumption, inadequate physical activity, harmful alcohol consumption, and tobacco smoking); interest in changing ‘at risk’ behaviours; and potential associations of socio-demographic characteristics with risk status and interest in change.

Methods

A cross-sectional survey was conducted among family carers of people with a mental illness (N = 144) residing in New South Wales, Australia. Analyses explored risk behaviour prevalence and interest in change, and associations with socio-demographic variables.

Results

Inadequate fruit and vegetable consumption was most prevalent (74.8%), followed by engaging in inadequate amounts of physical activity (57.6%); harmful alcohol consumption (36.3%) and smoking (11.8%). The majority of carers were interested in improving ‘at risk’ behaviours (56.3–89.2%), with the exception of alcohol consumption (41.5%). Previously or never married participants were more likely to consume inadequate amounts of fruits and/or vegetables compared to those married or cohabiting (Odds Ratio [OR]: 4.1, 95% Confidence Interval [CI]: 1.3–12.9, p = .02). Carers in the workforce were more likely to be engaging in inadequate physical activity (OR: 2.6, 95% CI: 1.2–5.7, p =  .02); and male participants were more likely to engage in harmful alcohol consumption (OR: 2.9, 95% CI: 1.1–7.9, p = .03). Working carers were approximately five times more likely to report interest in improving their alcohol consumption (OR: 5.1, 95% CI: 1.3–20.5, p = .02) compared to those not currently in the workforce.

Conclusions

Results suggest high engagement in health risk behaviours among carers of people with a mental illness, particularly with regards to harmful alcohol consumption. Findings suggest a need to develop and implement chronic disease prevention strategies. Further research with larger representative samples is needed to confirm findings.