bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundAlveolar 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.Methods2000 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.ResultsThe 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.ConclusionsOur 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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

AbstractBackgroundPoly (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.MethodsOlaparib 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.DiscussionWe 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 registrationClinicalTrials.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

Abstract

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

Abstract

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

AbstractBackgroundPeople 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+).MethodsA 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.DiscussionThis 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 registrationGerman Clinical Trial Registration:DRKS00014000. Registered on 09 April 2018.