bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional specialization of retinal Müller cell endfeet depends on an interplay between two syntrophin isoforms
Authors: Katoozi Shirin , Rao Shreyas B. , Skauli Nadia , Froehner Stanley C. , Ottersen Ole Petter , Adams Marvin E. , Amiry-Moghaddam Mahmood
Published: March 2020

Retinal Müller cells are highly polarized macroglial cells with accumulation of the aquaporin-4 (AQP4) water channel and the inwardly rectifying potassium channel Kir4.1 at specialized endfoot membrane domains abutting microvessels and corpus vitreum. Proper water and potassium homeostasis in retina depends on these membrane specializations. Here we show that targeted deletion of β1-syntrophin leads to a partial loss of AQP4 from perivascular Müller cell endfeet and that a concomitant deletion of both α1- and β1-syntrophin causes a near complete loss of AQP4 from both perivascular and subvitreal endfoot membranes. α1-syntrophin is normally very weakly expressed in Müller cell endfeet but β1-syntrophin knockout mice display an increased amount of α1-syntrophin at these sites. We suggest that upregulation of perivascular α1-syntrophin restricts the effect of β1-syntrophin deletion. The present findings indicate that β1-syntrophin plays an important role in maintaining the functional polarity of Müller cells and that α1-syntrophin can partially substitute for β1-syntrophin in AQP4 anchoring. Functional polarization of Müller cells thus depends on an interplay between two syntrophin isoforms.
Haploidentical versus HLA-matched sibling transplantation for refractory acute leukemia undergoing sequential intensified conditioning followed by DLI: an analysis from two prospective data
Authors: Yu Sijian , Huang Fen , Fan Zhiping , Xuan Li , Nie Danian , Xu Yajing , Yang Ting , Wang Shunqing , Jiang Zujun , Xu Na , Lin Ren , Ye Jieyu , Lin Dongjun , Sun Jing , Huang Xiaojun , Wang Yu , Liu Qifa
Published: March 2020

Background

Compared with HLA-matched sibling donor (MSD) transplant, the outcomes of haploidentical donor (HID) transplant for refractory acute leukemia need to be further explored. In this study, we compared the outcomes of HID with MSD for refractory acute leukemia.

Patients and methods

This study population came from two prospective multicenter trials (NCT01883180, NCT02673008). Two hundred and seventy-eight patients with refractory acute leukemia were enrolled in this study, including 119 in HID group and 132 in MSD group. Sequential intensified conditioning was employed in all patients, and donor lymphocyte infusion (DLI) was administered in patients in the absence of active GVHD and according to minimal residual disease (MRD) from day + 60 post-transplantation for preventing relapse.

Results

The complete remission of leukemia by day + 30 post-transplant were 94% and 93%, respectively, in HID and MSD groups (p = .802). The 1-year incidence of grades II–IV acute GVHD was 62% and 54% (p = .025), and 3-year incidence of chronic GVHD was 55% and 55% (p = .789), respectively, in two groups. HID transplant had lower incidence of first episode of MRD positivity and relapse than MSD transplant (28% vs 45%, p = .006; 26% vs 38%, p = .034). There was higher infection-related mortality in HID than MSD (8% vs 2%, p = .049) within the first 100 days’ post-transplant. The 5-year overall survival was 46% and 42% (p = .832), respectively; the 5-year disease-free survival was 43% and 39% (p = .665), in HID and MSD groups, respectively.

Conclusions

HID transplant has lower relapse, but higher infection-related mortality and similar survival rates in refractory acute leukemia by the strategy of sequential intensified conditioning followed by DLI compared with MSD transplant.
Intrinsic foot joints adapt a stabilized‐resistive configuration during the stance phase
Authors: Deleu Paul‐André , Chèze Laurence , Dumas Raphaël , Besse Jean‐Luc , Leemrijse Thibaut , Devos Bevernage Bernhard , Birch Ivan , Naaim Alexandre
Published: March 2020

Background

This study evaluated the 3D angle between the joint moment and the joint angular velocity vectors at the intrinsic foot joints, and investigated if these joints are predominantly driven or stabilized during gait.

Methods

The participants were 20 asymptomatic subjects. A four‐segment kinetic foot model was used to calculate and estimate intrinsic foot joint moments, powers and angular velocities during gait. 3D angles between the joint moment and the joint angular velocity vectors were calculated for the intrinsic foot joints defined as follows: ankle joint motion described between the foot and the shank for the one‐segment foot model (hereafter referred as Ankle), and between the calcaneus and the shank for the multi‐segment foot model (hereafter referred as Shank‐Calcaneus); joint motion described between calcaneus and midfoot segments (hereafter referred as Chopart joint); joint motion described between midfoot and metatarsus segments (hereafter referred as Lisfranc joint); joint motion described between first phalanx and first metatarsal (hereafter referred as First Metatarso‐Phalangeal joint). When the vectors were approximately aligned, the moment was considered to result in propulsion (3D angle <60o) or resistance (3D angle >120o) at the joint. When the vectors are approximately orthogonal (3D angle close to 90°), the moment was considered to stabilize the joint.

Results

The results showed that the four intrinsic joints of the foot are never fully propelling, resisting or being stabilized, but are instead subject to a combination of stabilization with propulsion or resistance during the majority of the stance phase of gait. However, the results also show that during pre‐swing all four the joints are subject to moments that result purely in propulsion. At heel off, the propulsive configuration appears for the Lisfranc joint first at terminal stance, then for the other foot joints at pre‐swing in the following order: Ankle, Chopart joint and First Metatarso‐Phalangeal joint.

Conclusions

Intrinsic foot joints adopt a stabilized‐resistive configuration during the majority of the stance phase, with the exception of pre‐swing during which all joints were found to adopt a propulsive configuration. The notion of stabilization, resistance and propulsion should be further investigated in subjects with foot and ankle disorders.
Trauma research in the Nordic countries, 1995–2018 – a systematic review
Authors: Jeppesen Elisabeth , Iversen Valdemar Vea , Hansen Ingrid Schrøder , Reierth Eirik , Wisborg Torben
Published: March 2020

Background

Trauma is a major cause of mortality and reduced quality of life. Most trauma-related research originates from trauma centres, and there are limited available data regarding the treatment of trauma patients throughout the Nordic countries. These countries differ from economically similar countries due to their cold climate, mix of rural and urban areas, and the long distances separating many residents from a trauma centre. Research funders and the general public expect trauma research to focus on all links in the treatment chain. Here we conducted a systematic review to assess the amount of trauma-related research from the Nordic countries between January 1995 and April 2018, and the distribution of this research among different countries and different parts of the trauma treatment chain.

Methods

A systematic literature search was conducted in Medline, Embase, the Cochrane Library, Web of Science, and Scopus. We included studies concerning the trauma population from Nordic countries, and published between January 1995 and April 2018. Two independent reviewers screened titles and abstracts, and performed data extraction from full-text articles.

Results

The literature search yielded 5117 titles and abstracts, of which 844 full-text articles were included in our analysis. During this period, the annual number of publications increased. Publications were equally distributed among Norway, Sweden, and Denmark in terms of numbers; however, Norway had more publications relative to inhabitants. There were fewer overall publications from Finland and Iceland. We identified mostly cohort studies and very few randomized controlled trials. Studies focused on the level of care were predominantly epidemiological studies. Research at the pre-hospital level was three-fold more frequent than research on other elements of the trauma treatment chain.

Conclusion

The rate of publications in the field of trauma care in the Nordic countries has increased over recent years. However, several parts of the trauma treatment chain are still unexplored and most of the available studies are observational studies with low research evidence.
Demographic, socioeconomic and disease knowledge factors, but not population mobility, associated with lymphatic filariasis infection in adult workers in American Samoa in 2014
Authors: Graves Patricia M. , Sheridan Sarah , Fuimaono Saipale , Lau Colleen L.
Published: March 2020

Background

Prevalence of lymphatic filariasis (LF) antigen in American Samoa was 16.5% in 1999. Seven rounds of mass drug administration (MDA) programmes between 2000 and 2006 reduced antigen prevalence to 2.3%. The most efficient methods of surveillance after MDA are not clear, but testing specific at-risk groups such as adults may provide earlier warning of resurgence. The role of migration from LF endemic countries in maintaining transmission also needs investigation. Few studies have investigated knowledge about LF and how that relates to infection risk. This study aims to investigate associations between socio-demographics, population mobility, disease knowledge and LF infection risk.

Methods

In 2014, we surveyed 670 adults aged 16–68 years (62% female) at two worksites in American Samoa. Sera were tested for LF antigen and antibodies (Bm14 and Wb123) by rapid test and/or ELISA. Multivariate logistic regression was used to assess association between seromarkers and demographic factors, household socioeconomic status (SES), residence, travel history, and knowledge of LF.

Results

Overall, 1.8% of participants were positive for antigen, 11.8% for Bm14, 11.3% for Wb123 and 17.3% for at least one antibody. Recent travel outside American Samoa was not associated with positivity for any seromarker. Men had higher seroprevalence than women for all outcomes (any antibody: adjusted odds ratio (aOR) = 3.49 (95% CI: 2.21–5.49). Those aged over 35 years (compared to 15–24 years) had higher prevalence of Bm14 antibody (aOR = 3.75, 3.76 and 4.17 for ages 35–44, 45–54 and ≥ 55 years, respectively, P < 0.05). Lower SES was associated with seropositivity (antigen: aOR = 2.89, 95% CI: 1.09–7.69; either antibody: aOR = 1.51, 95% CI: 1.12–2.05). Those who knew that mosquitoes transmitted LF had lower Wb123 antibody prevalence (aOR = 0.55, 95% CI: 0.32–0.95).

Conclusions

Opportunistic sampling of adults at worksites provided an efficient and representative way to assess prevalence and risk factors for LF in American Samoa and in hindsight, foreshadowed the resurgence of transmission. Risk of LF infection, detected by one or more serological markers, was not related to recent travel history, but was strongly associated with male gender, older age, lower SES, and lack of knowledge about mosquito transmission. These results could guide future efforts to increase MDA participation.
Pleiotropic effect of the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout
Authors: Wrigley Rebekah , Phipps-Green Amanda J. , Topless Ruth K. , Major Tanya J. , Cadzow Murray , Riches Philip , Tausche Anne-Kathrin , Janssen Matthijs , Joosten Leo A. B. , Jansen Tim L. , So Alexander , Harré Hindmarsh Jennie , Stamp Lisa K. , Dalbeth Nicola , Merriman Tony R.
Published: March 2020

Background

The ABCG2 Q141K (rs2231142) and rs10011796 variants associate with hyperuricaemia (HU). The effect size of ABCG2 rs2231142 on urate is ~ 60% that of SLC2A9, yet the effect size on gout is greater. We tested the hypothesis that ABCG2 plays a role in the progression from HU to gout by testing for association of ABCG2 rs2231142 and rs10011796 with gout using HU controls.

Methods

We analysed 1699 European gout cases and 14,350 normouricemic (NU) and HU controls, and 912 New Zealand (NZ) Polynesian (divided into Eastern and Western Polynesian) gout cases and 696 controls. Association testing was performed using logistic and linear regression with multivariate adjusting for confounding variables.

Results

In Europeans and Polynesians, the ABCG2 141K (T) allele was associated with gout using HU controls (OR = 1.85, P = 3.8E− 21 and ORmeta = 1.85, P = 1.3E− 03, respectively). There was evidence for an effect of 141K in determining HU in European (OR = 1.56, P = 1.7E− 18) but not in Polynesian (ORmeta = 1.49, P = 0.057). For SLC2A9 rs11942223, the T allele associated with gout in the presence of HU in European (OR = 1.37, P = 4.7E− 06), however significantly weaker than ABCG2 rs2231142 141K (PHet = 0.0023). In Western Polynesian and European, there was epistatic interaction between ABCG2 rs2231142 and rs10011796. Combining the presence of the 141K allele with the rs10011796 CC-genotype increased gout risk, in the presence of HU, 21.5-fold in Western Polynesian (P = 0.009) and 2.6-fold in European (P = 9.9E− 06). The 141K allele of ABCG2 associated with increased gout flare frequency in Polynesian (Pmeta = 2.5E− 03).

Conclusion

These data are consistent with a role for ABCG2 141K in gout in the presence of established HU.
A computerized version of the Short Form of the Face-Name Associative Memory Exam (FACEmemory®) for the early detection of Alzheimer’s disease
Authors: Alegret Montserrat , Muñoz Nathalia , Roberto Natalia , Rentz Dorene M. , Valero Sergi , Gil Silvia , Marquié Marta , Hernández Isabel , Riveros Catalina , Sanabria Angela , Perez-Cordon Alba , Espinosa Ana , Ortega Gemma , Mauleón Ana , Abdelnour Carla , Rosende-Roca Maitee , Papp Kathryn V. , Orellana Adela , Benaque Alba , Tarraga Lluís , Ruiz Agustín , Boada Mercè
Published: March 2020

Background

Computerized neuropsychological tests for early detection of Alzheimer’s disease (AD) have attracted increasing interest. Memory for faces and proper names is a complex task because its association is arbitrary. It implicates associative occipito-temporal cerebral regions, which are disrupted in AD. The short form of the Face-Name Associative Memory Exam (FNAME-12), developed to detect preclinical and prodromal AD, asks individuals to learn the names and occupations associated with 12 faces. The current work advances this field by using voice recognition and touchscreen response format. The purpose of this study is to create the first self-administered episodic memory test, FACEmemory®, by adapting the FNAME-12 for tablet use with voice recognition, touchscreen answers, and automatic scoring. The test was minimally supervised by a psychologist to avoid technological problems during execution and scored manually to assess the reliability of the automatic scoring. The aims of the present study were (1) to determine whether FACEmemory® is a sensitive tool for the detection of cognitive impairment, (2) to examine whether performances on FACEmemory® are correlated with those on the S-FNAME (paper-and-pencil version with 16 images), and (3) to determine whether performances on FACEmemory® are related to AD biomarkers in the cerebrospinal fluid (CSF) (Aβ42, p-tau, and Aβ42/p-tau ratio).

Methods

FACEmemory® was completed by 154 cognitively healthy (CH) individuals and 122 subjects with mild cognitive impairment, of whom 61 were non-amnestic (naMCI) and 61 amnestic (aMCI). A subsample of 65 individuals completed the S-FNAME, and 65 subjects received lumbar punctures.

Results

Performance on FACEmemory® was progressively worse from CH to the naMCI and aMCI groups. A cutoff of 31.5 in total FACEmemory® obtained 80.5% and 80.3% sensitivity and specificity values, respectively, for discriminating between CH and aMCI. Automatically corrected FACEmemory® scores were highly correlated with the manually corrected ones. FACEmemory® scores and AD CSF biomarker levels were significantly correlated as well, mainly in the aMCI group.

Conclusions

FACEmemory® may be a promising memory prescreening tool for detecting subtle memory deficits related to AD. Our findings suggest FACEmemory® performance provides a useful gradation of impairment from normal aging to aMCI, and it is related to CSF AD biomarkers.
Correction to: Production of high-value bioproducts enriched with γ-linolenic acid and β-carotene by filamentous fungi Umbelopsis isabellina using solid-state fermentations
Authors: Slaný Ondrej , Klempová Tatiana , Marcinčák Slavomír , Čertík Milan
Published: March 2020

Following publication of the original article (Tao et al. 2020), the authors reported a missing funding source in the ‘Acknowledgements’ section.
Thoracic abnormal air collections in patients in the intensive care unit: radiograph findings correlated with CT
Authors: Sakai Masafumi , Hiyama Takashi , Kuno Hirofumi , Mori Kensaku , Saida Tsukasa , Ishiguro Toshitaka , Takahashi Hiroaki , Koyama Ken , Minami Manabu
Published: March 2020

An abnormal collection of air in the thorax is one of the most common life-threatening events that occurs in the intensive care unit. Patient management differs depending on the location of the air collection; therefore, detecting abnormal air collection and identifying its exact location on supine chest radiographs is essential for early treatment and positive patient outcomes. Thoracic abnormal air collects in multiple thoracic spaces, including the pleural cavity, chest wall, mediastinum, pericardium, and lung. Pneumothorax in the supine position shows different radiographic findings depending on the location. Many conditions, such as skin folds, interlobar fissure, bullae in the apices, and air collection in the intrathoracic extrapleural space, mimic pneumothorax on radiographs. Additionally, pneumopericardium may resemble pneumomediastinum and needs to be differentiated. Further, some conditions such as inferior pulmonary ligament air collection versus a pneumatocele or pneumothorax in the posteromedial space require a differential diagnosis based on radiographs. Computed tomography (CT) is required to localize the air and delineate potential etiologies when a diagnosis by radiography is difficult. The purposes of this article are to review the anatomy of the potential spaces in the chest where abnormal air can collect, explain characteristic radiographic findings of the abnormal air collection in supine patients with illustrations and correlated CT images, and describe the distinguishing features of conditions that require a differential diagnosis. Since management differs based on the location of the air collection, radiologists should try to accurately detect and identify the location of air collection on supine radiographs.
The replisome guides nucleosome assembly during DNA replication
Authors: Zhang Wenshuo , Feng Jianxun , Li Qing
Published: March 2020

Nucleosome assembly during DNA replication is tightly coupled to ongoing DNA synthesis. This process, termed DNA replication-coupled (RC) nucleosome assembly, is essential for chromatin replication and has a great impact on both genome stability maintenance and epigenetic inheritance. This review discusses a set of recent findings regarding the role of replisome components contributing to RC nucleosome assembly. Starting with a brief introduction to the factors involved in nucleosome assembly and some aspects of the architecture of the eukaryotic replisome, we discuss studies from yeast to mammalian cells and the interactions of replisome components with histones and histone chaperones. We describe the proposed functions of replisome components during RC nucleosome assembly and discuss their impacts on histone segregation and implications for epigenetic inheritance.
Semi-structured data protection scheme based on robust watermarking
Authors: He Jiahuan , Ying Qichao , Qian Zhenxing , Feng Guorui , Zhang Xinpeng
Published: March 2020

Semi-structured data is a widely used text format for data interchange and storage. This paper proposes a robust watermarking scheme of data protection for semi-structured data, which uses JSON format as an example for illustration. We first parse JSON file into a data structure of distinct pairs. Afterwards, we generate a transfer matrix to get the intermediate sequences, which are then encoded using error-correction codes and embedded into the pairs. A private key is shared by the data hider and the recipient to resist collusion attacks. On the recipient’s side, data extraction can be successfully carried out even the received stego data are tampered. The imperceptibility is realized by embedding data into the less significant digits of numeric data in the cover file. The proposed scheme can be extended on several other formats. The experimental results show that the proposed scheme is robust to various kinds of typical attacks such as contextual truncating, modification, and redundancy addition.
Variations in porcine colostrum oligosaccharide composition between breeds and in association with sow maternal performance
Authors: Trevisi Paolo , Luise Diana , Won Savanna , Salcedo Jaime , Bertocchi Micol , Barile Daniela , Bosi Paolo
Published: March 2020

Background

Oligosaccharides (OS) are indigestible carbohydrates naturally found in milk. The composition of porcine colostrum OS may influence the growth and the health of the neonate and consuming optimal concentrations of OS may reduce piglet susceptibility to illness. In this manner, targeted supplementation of animal feed with OS is being explored as a health management tool in the livestock industry. The variation in OS composition between different breeds of pig and its association with the litter performance is currently unknown. The aim of this study was to characterize the colostrum OS composition from sows of different breed and parity and correlate this data with sow maternal traits.

Methods

Eighty-three colostrum samples from parities 1 to 8 were gathered from 3 different breeds of sow: 44 Large White sows, 27 Landrace sows and 12 Duroc sows. Samples were taken between the birth of the first and the last piglet from sows that were not pharmacologically induced to farrow. OS were purified from the samples and analysed by MALDI-ToF mass spectrometry (21 OS compositions detected). The farrowing season and the maternal data were recorded for each sow, including the number of live piglets and the litter body weight at birth, at day (d) 3 and at weaning.

Results

Five OS compositions, including isomers of the bifidogenic Sialyllactose, Lacto-N-Tetraose and Lacto-N-Hexaose series, were detected in all the samples. Twelve other OS were identified in at least 50% of samples, and their abundances were affected by breed (P < 0.05; 6 of 12), marginally affected by season (P < 0.10; 3 of 12) and never by parity number. The abundances of each OS component were standardized by Z-score scaling (μ = 0 and SD = 1), transformed by principal component analysis, and four similarity clusters were generated. Cluster membership was associated with litter weight gain within 3 days (P = 0.063) and at weaning (P < 0.05), but not with piglet mortality within 3 days.

Conclusions

OS composition of colostrum may partially explain the variability in maternal performance within and between different breeds of sow. The obtained OS data can provide useful information for the development of novel prebiotic food supplements for suckling and weaning pigs.
Comment on Early versus delayed mobilization for in-hospital mortality and health-related quality of life among critically ill patients: a systematic review and meta-analysis (Okada et al., Journal of Intensive Care 2019)
Authors: Kuhn K. Friedrich , Schaller Stefan J.
Published: March 2020

Critical comment on the review by Okada et al. on the effect of early versus delayed mobilization because of their definition of early mobilization as mobilization within a week of ICU admission in contrast to current evidence.
Biomechanical comparison of single-bundle versus double-bundle anterior cruciate ligament reconstruction: a meta-analysis
Authors: Oh Jin-Young , Kim Kun-Tae , Park Young-Jin , Won Hee-Chan , Yoo Jun-Il , Moon Dong-Kyu , Cho Sung-Hee , Hwang Sun-Chul
Published: March 2020

Background

Of the many issues regarding surgical techniques related to anterior cruciate ligament reconstruction (ACLR), single-bundle (SB) or double-bundle (DB) ACLR is one of the most debated topics. However, it is unclear which of the techniques yields better outcomes after ACLR for ACL injury. The purpose of this meta-analysis was to compare the benefits of SB versus DB ACLR in terms of biomechanical outcomes.

Methods

The electronic databases MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and Scopus were searched for relevant articles comparing the outcomes of SB-ACLR versus DB-ACLR that were published until November 2019.

Results

Seventeen biomechanical studies were included. The anterior laxity measured using the anterior drawer test showed significantly better results in DB-ACLR when compared with SB-ACLR. In addition, outcomes of the anterior tibial translation test under a simulated pivot shift presented with better results at low flexion and 30° in DB-ACLR, compared with SB-ACLR. However, there were no significant biomechanical differences between the groups in internal rotation.

Conclusions

The present study demonstrated that both techniques for ACLR are associated with restoration of normal knee kinematics. DB-ACLR is superior to SB-ACLR in terms of restoration of anteroposterior stability. However, which technique yields better improvement in internal rotation laxity, and internal rotation laxity under a simulated pivot shift at a specific angle, remains unclear.

Level of evidence

This is a level II meta-analysis.
A novel serum index for accurate diagnosis of spontaneous bacterial peritonitis in cirrhotic patients without other infections
Authors: Elsadek Hany M. , Elhawari Soha A. , Mokhtar Ahmed
Published: March 2020

Background

The accurate non-invasive diagnosis of spontaneous bacterial peritonitis (SBP) in patients with decompensated liver cirrhosis has not been achieved yet. The aim of the study was to obtain an unmistakable diagnosis of SBP using a new simple serum bioscore, made by combined measurement of procalcitonin (PCT), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), which we called the PEC index. This cross-sectional analytic study comprised 178 cirrhotic patients with ascites (60 patients with SBP and 118 patients with sterile ascites), after excluding non-SBP infection, during the period from March 2019 until September 2019. In all participants, serum levels of PCT, ESR, and CRP were measured, and PEC index was calculated [PEC index = PCT × (ESR + CRP)].

Results

Patients with SBP (n = 60) had significantly higher serum PEC index than those with sterile ascites (n = 118) (41.0/31.2–93.0 vs. 9.9/5.9–15.0, P < 0.001). PEC index distinguished culture positive cases significantly (P < 0.001). Using receiver operating characteristic (ROC) statistics, the sensitivity and specificity of PCT, at a cutoff value of 0.590 ng/mL, for SBP diagnosis, were 81.67% and 93.33%, respectively (area under the curve [AUC] = 0.879; 95% confidence interval [CI] 0.809–0.948). The sensitivity and specificity of ESR, at a cutoff value of 27.0 mm/hour, were 73.33% and 61.67%, respectively (AUC = 0.679; 95% CI 0.581–0.776). The sensitivity and specificity of CRP, at a cutoff value of 21.0 mg/L, were 93.33% and 51.67%, respectively (AUC = 0.736; 95% CI 0.639–0.833). While, the sensitivity and specificity of PEC index, at a cutoff value of 20, were highest (98.33% and 96.67%, respectively, AUC = 0.977; 95% CI 0.940–0.996).

Conclusion

Serum PEC index makes an accurate noninvasive diagnosis of SBP, after excluding other infections.
Seismic full-waveform inversion using minimization of virtual scattering sources
Authors: Lee Donguk , Pyun Sukjoon
Published: March 2020

Full-waveform inversion (FWI) is a powerful tool for imaging underground structures with high resolution; however, this approach commonly suffers from the cycle-skipping issue. Recently, various FWI methods have been suggested to address this problem. Such methods are mainly classified into either data-space manipulation or model-space extension. We developed an alternative FWI method that belongs to the latter class. First, we define the virtual scattering source based on perturbation theory. The virtual scattering source is estimated by minimizing the differences between observed and simulated data with a regularization term penalizing the weighted virtual scattering source. The inverse problem for obtaining the virtual scattering source can be solved by the linear conjugate gradient method. The inverted virtual scattering source is used to update the wavefields; thus, it helps FWI to better approximate the nonlinearity of the inverse scattering problem. As the second step, the virtual scattering source is minimized to invert the velocity model. By assuming that the variation of the reconstructed wavefield is negligible, we can apply an approximated full Newton method to the velocity inversion with reasonable cost comparable to the Gauss-Newton method. From the numerical examples using synthetic data, we confirm that the proposed method performs better and more robust than the simple gradient-based FWI method. In addition, we show that our objective function has fewer local minima, which helps to mitigate the cycle-skipping problem.
Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): Results from the BELIEF trial.
Authors: O'Connor Owen A. , Masszi Tamás , Savage Kerry J. , Pinter-Brown Lauren C. , Foss Francine M. , Popplewell Leslie , Cashen Amanda F. , Doorduijn Jeanette , Chawla Shanta , Knoblauch Poul , Zinzani Pier Luigi , Brown Peter , Hess Georg , Van Hoof Achiel , Horwitz Steven M. , Shustov Andrei R.
Published: March 2020

8507

Background: Therapies approved in US for R/R PTCL have overall response rates (ORR) of 25%-27%. The need for new therapies persists. BELIEF is a pivotal, single-arm study of belinostat in patients with R/R PTCL after failure of ≥1 prior systemic therapies. Methods: Entry criteria were measurable PTCL, platelets ≥ 50,000/µL, no prior HDACi therapy, and adequate organ function. PTCL was confirmed by central pathology review (CPRG). Belinostat 30 min IV infusion at 1000 mg/m2was administered on days 1–5 of a 3 week cycle until progression or unacceptable toxicity. Tumor response was assessed by Cheson 2007 criteria. The primary endpoint was ORR. Results: Patients with R/R PTCL (N=129, 53% male, median age 63 y) received belinostat a median of 2 cycles (range 1–33). The median number of prior therapies was 2 (1-8) including CHOP/CHOP-like (96%) and stem cell transplant (23%). The median administered dose intensity was 98%. One and two dose reductions of 25% occurred in 12% and 1% of patients, respectively, due to adverse events (AEs). For patients with CPRG confirmed PTCL (N=120), the ORR was 26% (n=31; 10% CR; 16% PR). The median time to response was 5.6 weeks (range 4.3-50.4). The median duration of response (DoR) was 8.3 months; longest DoR was 29.4 months. Seven patients remain on study in response. For the subgroup of patients with CPRG confirmed PTCL and baseline platelets ≥100,000/μL (N=100) ORR was 28% (CR 11%; PR 17%). The most frequent (≥ 5%) grade 3-4 treatment emergent AEs were thrombocytopenia (13%), neutropenia (13%), anemia (10%), dyspnea (6%), pneumonia (6%), and fatigue (5%). Patients with platelets <100K tolerated belinostat, with 98% dose intensity. Belinostat was well tolerated with a low incidence of myelosuppression. Discontinuations were due to PD (64%), death (11%), AEs (7%), patient request (8%), and other (4%). Conclusions: Belinostat demonstrated a 26%-28% ORR in BELIEF and was well tolerated with a favorable safety profile in patients with R/R PTCL including those with low platelets. The low incidence of myelosuppression observed warrants further investigation of belinostat combination therapy to develop new treatment paradigms for R/R PTCL. Clinical trial information: NCT00865969.
Effect of CMP, carfilzomib (CFZ) plus melphalan-prednisone (MP), on response rates in elderly patients (pts) with newly diagnosed multiple myeloma (NDMM): Results of a phase (Ph) I/II trial.
Authors: Touzeau Cyrille , Kolb Brigitte , Hulin Cyrille , Caillot Denis , Benboubker Lotfi , Tiab Mourad , Leleu Xavier , Roussel Murielle , Chaleteix Carine , Attal Michel , Facon Thierry , Moreau Philippe
Published: March 2020

8513

Background: MP+thalidomide (MPT) and MP+bortezomib (MPV) have shown significant progression-free survival and overall survival (OS) benefits in NDMM pts > 65 years (y) but are associated with peripheral neuropathy (PN). CFZ, a novel proteasome inhibitor, has shown promising activity and a favorable toxicity profile with low PN rates. Methods: This PhI/II study in NDMM >65y was designed to determine maximum tolerated dose (MTD) of CMP and assess safety and efficacy. In PhI, CFZ was started at 20mg/m2, then escalated to 27, 36, and 45mg/m2, given IV in 42-day (D) cycles (C) on D1/2/8/9/22/23/29/30 for 9C. Melphalan 9mg/m² and prednisone 60mg/m² were given PO D1–4 of every 45-day cycle. MTD was based on dose-limiting toxicity (DLT) in C1 defined as any grade (G) 4 hematologic adverse event (AE), any hematologic AE preventing aministration of ≥ 2 C1 CFZ doses except G4 thrombocytopenia without bleeding or G4 neutropenia ≤7D, ≥G3 febrile neutropenia, or any ≥G3 nonhematologic AE. Results: As of Jan 6, 2013, 24 pts have been enrolled in PhI: 6 for each dose level. There were 2 DLTs at 45mg/m2(fever, hypotension) resulting in a MTD of 36mg/m². In PhII, 45 additional pts received CMP at 36mg/m² CFZ for N=69 total PhI/II pts (median age 74y). ORR was 89% with 51% ≥VGPR. With median follow-up of 12 mo, the projected 2y OS was 89.9%. CMP was well tolerated without PN ≥G2. Conclusions: These results compare favorably to those of MPV, MPT, MP+lenalidomide (R), and R+dex in similar pts (ORR 71% San Miguel NEnglJMed2008, 76% Facon Lancet2007, 80% Palumbo JClinOncol2007 and 85% Rajkumar LancetOncol2010, respectively). CFZ 36mg/m2 +MP is tolerable and effective in elderly NDMM pts. Treatment is ongoing. Final safety and efficacy data will be presented during the meeting. Clinical trial information: NCT01279694.
A phase I study of ISIS 481464 (AZD9150), a first-in-human, first-in-class, antisense oligonucleotide inhibitor of STAT3, in patients with advanced cancers.
Authors: Hong David S. , Younes Anas , Fayad Luis , Fowler Nathan Hale , Hagemeister Fredrick B. , Mistry Reena , Nemunaitis John J. , Borad Mitesh J. , Bryce Alan H. , Yamashita Mason , Hughes Steven George , Kwoh Theodore Jesse , MacLeod A. Robert , Norris Dan , Baldwin Ron , Hung Gene , Monia Brett P. , Kurzrock Razelle
Published: March 2020

8523

Background: ISIS 481464 is a synthetic bicyclic nucleic acid-containing antisense oligonucleotide that is complementary to the mRNA for signal transducer and activator of transcription 3 (STAT3). Methods: Primary objective of the dose-escalation study (3+3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included safety, tumor response, pharmacokinetics (PK), and pharmacodynamics (PD) using IL-6 and tumor markers. Patient (pt) eligibility included : >18 yrs old, solid tumors or lymphomas refractory to at least 1 prior systemic therapy. ISIS 481464 was administered IV as a loading dose on Days 1, 3, and 5 and then weekly. Results: 15 pts were dosed (4 at 2 mg/kg and 11 at 4 mg/kg). 6 pts had advanced lymphoma (3 DLBCL, 2 Hodgkin’s lymphoma, 1 mantle cell lymphoma) and 9 pts solid tumors. There was one dose limiting toxicity (DLT), a possibly related thrombotic microangiopathy at 4 mg/kg. Treatment emergent thrombocytopenia was observed with an average reduction of approximately 70% from baseline. Three pts, 1 at 2 mg/kg and 2 at 4 mg/kg, experienced nadirs in platelet count below 50x109/L (range 16 to 33x109/L). MTD was not reached; however, given the thrombocytopenia at 4mg/kg, the RP2D was 2mg/kg. Partial responses were observed in 2/3 DLBCL pts. The 1st DLBCL pt (2 mg/kg) with 10 prior treatments had a durable 55% reduction in tumor size and is ongoing treatment at 11 months. This pt had a 76% reduction in IL-6. The 2nd DLBCL pt (4 mg/kg) with 2 prior treatments had a 65% reduction for 4 months and was able to undergo autologous stem cell transplantation. There were no responses in the solid tumor pts. PKs revealed increased plasma trough levels (indicative of tissue concentrations) with increased dose. Conclusions: ISIS 481462 was well-tolerated and the RP2D was determined to be 2 mg/kg. Initial tumor activity was observed in DLBCL pts and a dose expansion in advanced lymphomas is ongoing. Clinical trial information: NCT01563302.
Phase Ib dose escalation study of oral quisinostat, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma.
Authors: Leleu Xavier , Touzeau Cyrille , Benboubker Lotfi , Facon Thierry , Delain Martine , Fourneau Nele , Phelps Charles , Forslund Ann , Hellemans Peter , Smit Johan , Badamo-Dotzis Julie , Moreau Philippe
Published: March 2020

8530

Background: Aggresome formation is a mechanism of resistance to agents (e.g., bortezomib) which block proteasome activity. HDACi (e.g., quisinostat) prevents aggresome formation by deacetylation of tubulin that allows the transport of unfolded proteins to lysosomes for degradation. Methods: Patients received quisinostat (Q) at escalated doses (6, 8, 10 and 12 mg) on days 1, 3, and 5 weekly, subcutaneous VELCADE (V) at 1.3 mg/m2on days 1, 4, 8, and 11 of a 3-week cycle, and oral dexamethasone (D) at 20 mg on the day of and the day after VELCADE dosing. The primary endpoint was the maximum tolerated dose (MTD) of Q in the combination (Q+V+D). The secondary endpoints included safety, overall response rate, and pharmacodynamic biomarkers. Results: Eighteen patients (3, 3, 6, and 6 in increasing Q doses) were enrolled: 56% male; median age = 69 (range 50-82) years; multiple myeloma stage: IA = 11% and IIIA = 89%; prior lines of therapy: 1 = 100%, 2 = 55.6%, and 3 = 11.1%; prior VELCADE treatment = 50%. At the highest dose (12 mg) 2 patients had dose-limiting toxicity, 1 with QTc prolongation and 1 with atrial fibrillation. The MTD was established at the 10 mg Q for the Q+V+D regimen. The most common adverse events (≥ 10% of patients) were diarrhea (39%), asthenia (33%), peripheral oedema (22%), nausea (17%), thrombocytopenia (17%), alopecia (11%), constipation (11%), and vomiting (11%); most were grade 2 or lower in toxicity. To date, 13 patients have discontinued treatment, of which 5 completed 11 cycles of treatment. The overall response rate was 87.5% (14/16, 95% CI: 61.7% to 98.5%), including 1 complete response, 2 very good partial response, and 11 partial responses. Most patients (9/11) showed a decrease in number of circulating multiple myeloma cells after 1 cycle. Two of 5 patients showed an increase in acetylated histone 3 from baseline as measured in peripheral blood mononuclear cells. Conclusions: The MTD is 10 mg quisinostat in combination with VELCADE and dexamethasone. The combination is active in the treatment of relapsed multiple myeloma and has an acceptable safety profile. Clinical trial information: NCT01464112.
Long-term follow-up of the GELA LNH 03-7B study: A prospective phase II study of 150 patients over 80 years with diffuse large B-cell lymphoma (DLBCL) treated with RminiCHOP.
Authors: Peyrade Frederic , Fain Olivier , Fabiani Bettina , Bauduer Frederic , Van Den Neste Eric , Macro Margaret , Devidas Alain , Collignon Joelle , Rose Christian , Bonnet Sophie , Maerevoet Marie , Demuynck Hilde , Casasnovas Rene-Olivier
Published: March 2020

8536

Background: We report the outcome of patients included in the LNH 03-7B prospective phase II study of the GELA group which evaluated the tolerance and efficacy of a reduced dosage chemotherapy regimen (miniCHOP) associated with full dose rituximab in patients aged over 80 years with DLBCL. Methods: Patients were between 80 and 95 years (median 83 years), had disease stage I Bulky to IV and 65% had poor risk lymphoma according to IPI. Perfomance status was 0-2 in all cases. The majority of deaths and grade III/IV toxicity occurred during cycle 1 and 2. Response to treatment and early survival analyses were previously presented with 20 months median follow-up (Lancet oncol 2011;12:460-468). Results: At the time of this analysis, The median follow-up time was 41 months and 75 (50%) patients were alive. The 4-year estimated overall survival (OS) was 49.3% [95% CI: 40.8-57.3%] and the median OS was 38 months. The 4-year estimated PFS, EFS and DFS were 41.4% [95% CI: 33.1-49.5%], 39.4% [95% CI : 31.2-47.5%] and 57.9% [95% CI : 47.3-67.2%] respectively.]. During the additional follow-up, 8 patients relapsed (10% of CR patients) and 17 died. No long term toxicity was recorded. In a multivariate analysis an albumin level >35 g/l remained significantly associated with a longer survival. Conclusions: These results show that very old patients with DLBCL treated with RminiCHOP could express long-term survival and probably be cured. Regarding the DFS and despite the early toxicity, it seems crucial to obtain the best possible response. This long term analysis confirm that in patient aged over 80y with DLBCL and with PS from 0 to 2, RminiCHOP is the treatment cornerstone. Clinical trial information: NCT01087424.
Beneficial effect of complete response and type of therapy in multiple myeloma.
Authors: Pandey Shivlal , Rajkumar S. Vincent , Dispenzieri Angela , Lacy Martha , Gertz Morie , Buadi Francis , Dingli David , Hayman Suzanne R. , Russell Stephen J. , Lust John Anthony , Zeldenrust Steven R. , Kapoor Prashant , McCurdy Arleigh Robertson , Kyle Robert A. , Kumar Shaji
Published: March 2020

8541

Background: Achievement of a complete response (CR) to treatment is an important predictor of outcome for patients (pts) with myeloma (MM). The goal of the current study was to assess whether the treatment that resulted in CR has any impact on the outcomes. Methods: We identified 462 pts with MM, who fulfilled the IMWG criteria for CR, seen at Mayo Clinic between 1991 and 2011. The treatment was classified into groups by the regimen that led to CR (Table), and also based on whether an autologous stem cell transplant (ASCT) was part of the regimen. The remaining 21 pts had a variety of regimens and are not included in the Table. Results: The median age at diagnosis was 58.5 yrs (27.1–82.3 yrs) with 56% males. The overall survival (OS) from diagnosis for the entire cohort was 10.7 yrs (95% CI; 9.3, NR). The median interval from diagnosis to the recorded CR was 10.3 mos (range 1- 170), with 272 (58.4%) and 385 (82.7%) obtaining a CR in <12 mos and <24 months from diagnosis. We first compared the outcomes based on whether ASCT was part of the regimen; 328 had an ASCT while 117 pts received only chemotherapy. Median time to progression (TTP) following a CR was 5.1 yrs for the ASCT group compared with 5.5 yrs for the rest (P=0.3). Median OS from CR was 9.1 yrs for the ASCT group and 7.5 yrs for the rest (P=0.5) and OS from diagnosis was 10.1 yrs for the ASCT group and 12.6 for the rest (P=0.5). Examining the outcomes based on the regimen utilized showed that the TTP and OS from CR as well as OS from diagnosis were similar for all the groups (Table). Among pts who had a CR within a year of diagnosis, there were no differences in terms of the TTP or OS from the onset of CR or from diagnosis between the ASCT vs. chemotherapy groups or between the different regimens (P=NS for all comparisons). Conclusions: The current study highlights an important message regarding CR in MM. The results suggest that the prognostic value of CR is independent of the nature of therapy, and likely reflects the contribution of disease biology to obtaining a CR. [Table: see text]
Efficacy of radioimmunotherapy-based conditioning with high-dose chemotherapy and autologous stem cell transplantation for transformed lymphoma.
Authors: Krishnan Amrita Y. , Wondergem Marielle , Palmer Joycelynne , Shimoni Avichai , Raubitschek Andrew Antony , Nademanee Auayporn , Visser Otto , Zijlstra Jose M , Tsai Nicole , Nagler Arnon , Kogut Neil Martin , Simpson Jennifer , Forman Stephen J.
Published: March 2020

8556

Background: Transformed non-Hodgkin lymphoma (TF NHL) has a poor prognosis with median survival of 7-20 months. Studies have suggested the benefit of HDC. The series by Eide showed 47%, 5yr OS in 47 pts treated with HDC and ASCT (Br J Hem 2011). Our multicenter experience with RIT plus HDC (Yttrium 90 ibritumomab tiuxetan plus BEAM; carmustine, etoposide, cytarabine, melphalan "ZBEAM") demonstrated the safety and efficacy of the regimen in diffuse large cell lymphoma (DLCL). Therefore, the regimen was explored in other subtypes of NHL. Herein we report the outcome of 57 pts with TF NHL treated with ZBEAM conditioning and ASCT at three centers (City of Hope USA n=20, VUMC the Netherlands n=31, Chaim Sheba Med Center, Israel n=6.) between 2003- 2011. Methods: Histological confirmation of transformation was defined as dx of DLCL in pts with either a prior history or concomitant dx of follicular NHL. Results: Median age at ASCT was 59.6 yrs (range 41-69). Median number of prior regimens 2 (range 1-6), all pts received rituximab in at least one regimen. Disease status at ASCT: 1st CR 29, 1stPR 7,1st rel 9, IF 5, 2nd CR 5, 2nd rel 1, >3CR 1. Median time from TF NHL dx to ASCT was 7.7 mo (range 2.8-116). Pts engrafted white cells at median of 12 days (range 8-33). Non relapse mortality was 3.5%. There were two second malignancies: 1 MDS and 1 SCC Skin. Median f/u for living pts was 29 mo (range 7-100). Two year PFS was 69.67% (95%CI 59.39 - 77.83) and OS 90.29% (95% CI: 79.63 - 95.52). On univariate analysis, number of prior regimens, time from TF NHL dx to ASCT and history of marrow involvement were not significant for PFS and OS. Disease status at ASCT was significant for PFS in 1st CR vs relapse disease ( p=0.03) The relapsed pts had a significant increase in risk of relapse/progression or death post ASCT compared to the 1CR patients. [HR = 2.9, (95% CI: 1.07 - 7.9)]. Conclusions: ZBEAM conditioning with ASCT is an active treatment for pts with TF NHL, and is particularly efficacious as consolidation for pts in 1st CR.