bluuebunny/crossref_metadata_2025 huggingface dataset:
Normative data for flow cytometry immunophenotyping of benign lymph nodes sampled by surgical biopsy
Authors: Scott Gregory David , Atwater Susan K , Gratzinger Dita A
Published: September 2017

Aims

To create clinically relevant normative flow cytometry data for understudied benign lymph nodes and characterise outliers.

Methods

Clinical, histological and flow cytometry data were collected and distributions summarised for 380 benign lymph node excisional biopsies. Outliers for kappa:lambda light chain ratio, CD10:CD19 coexpression, CD5:CD19 coexpression, CD4:CD8 ratios and CD7 loss were summarised for histological pattern, concomitant diseases and follow-up course.

Results

We generated the largest data set of benign lymph node immunophenotypes by an order of magnitude. B and T cell antigen outliers often had background immunosuppression or inflammatory disease but did not subsequently develop lymphoma.

Conclusions

Diagnostic immunophenotyping data from benign lymph nodes provide normative ranges for clinical use. Outliers raising suspicion for B or T cell lymphoma are not infrequent (26% of benign lymph nodes). Caution is indicated when interpreting outliers in the absence of excisional biopsy or clinical history, particularly in patients with concomitant immunosuppression or inflammatory disease.
SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family
Authors: Roeben Benjamin , Schüle Rebecca , Ruf Susanne , Bender Benjamin , Alhaddad Bader , Benkert Tanja , Meitinger Thomas , Reich Selina , Böhringer Judith , Langhans Claus-Dieter , Vaz Frédéric M , Wortmann Saskia B , Marquardt Thorsten , Haack Tobias B , Krägeloh-Mann Ingeborg , Schöls Ludger , Synofzik Matthis
Published: September 2017

Objective

To demonstrate that mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters, thus adding SERAC1 to the increasing number of complex lipid cHSP genes.

Methods

Combined genomic and functional validation studies (whole-exome sequencing, mRNA, cDNA and protein), biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1), and clinical and imaging phenotyping were performed in six affected subjects from two different branches of a large consanguineous family.

Results

5 of 6 affected subjects shared cHSP as a common disease phenotype. Three subjects presented with juvenile-onset oligosystemic cHSP, still able to walk several miles at age >10–20 years. This benign phenotypic cluster and disease progression is strikingly divergent to the severe infantile phenotype of all SERAC1 cases reported so far. Two family members showed a more multisystemic juvenile-onset cHSP, indicating an intermediate phenotype between the benign oligosystemic cHSP and the classic infantile SERAC1 cluster. The homozygous splice mutation led to loss of the full-length SERAC1 protein and impaired phosphatidylglycerol PG34:1/PG36:1 remodelling. These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype.

Conclusions

Our findings add SERAC1 to the increasing list of complex lipid cHSP genes. At the same time they redefine the phenotypic spectrum of SERAC1 deficiency. It is associated not only with the severe infantile-onset ‘Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like’ syndrome (MEGDEL syndrome), but also with oligosystemic juvenile-onset cHSP as part of the now unfolding SERAC1 deficiency spectrum.
A balance and proprioception intervention programme to enhance combat performance in military personnel
Authors: Funk Shany , Jacob T , Ben-Dov D , Yanovich E , Tirosh O , Steinberg N
Published: September 2017

Background

Optimal functioning of the lower extremities under repeated movements on unstable surfaces is essential for military effectiveness. Intervention training to promote proprioceptive ability should be considered in order to limit the risk for musculoskeletal injuries. The aim of this study was to assess the effect of a proprioceptive intervention programme on static and dynamic postural balance among Israel Defense Forces combat soldiers.

Methods

Twenty-seven male soldiers, aged 18–20 years, from a physical fitness instructor’s course, were randomly divided into two groups matched by age and army unit. The intervention group (INT) underwent 4 weeks of proprioceptive exercises for 10 min daily; the control group underwent 4 weeks of upper body stretching exercises for 10 min daily. All participants were tested pre and postintervention for both static and dynamic postural balance.

Results

Significant interaction (condition*pre-post-test*group) was found for static postural balance, indicating that for the INT group, in condition 3 (on an unstable surface—BOSU), the post-test result was significantly better compared with the pretest result (p<0.05). Following intervention, the INT group showed significant correlations between static postural stability in condition 2 (eyes closed) and the dynamic postural stability (length of time walked on the beam following fatigue) (r ranged from 0.647 to 0.822; p<0.05).

Conclusions

The proprioceptive intervention programme for combat soldiers improved static postural balance on unstable surfaces, and improved the correlation between static postural balance in the eyes closed condition and dynamic postural balance following fatigue. Further longitudinal studies are needed to verify the relationship between proprioception programmes, additional weight bearing and the reduction of subsequent injuries in combat soldiers.
Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis
Authors: Boedigheimer Michael J , Martin David A , Amoura Zahir , Sánchez-Guerrero Jorge , Romero-Diaz Juanita , Kivitz Alan , Aranow Cynthia , Chan Tak Mao , Chong Yip Boon , Chiu Kit , Wang Christine , Sohn Winnie , Arnold Gregory E , Damore Michael A , Welcher Andrew A , Sullivan Barbara A , Kotzin Brian L , Chung James B
Published: September 2017

Objective

To evaluate safety, pharmacokinetics and pharmacodynamics of anti-interferon (IFN)-γ monoclonal antibody AMG 811 in subjects with SLE without or with lupus nephritis (LN).

Methods

In this phase Ib, randomised, multiple-dose escalation study (NCT00818948), subjects without LN were randomised to subcutaneous AMG 811 (6, 20 or 60 mg) or placebo and subjects with LN were randomised to subcutaneous AMG 811 (20, 60 or 120 mg) or placebo every four weeks for three total doses. Outcomes included incidence of adverse events (AEs); pharmacokinetics; levels of serum proteins (CXCL-10, interleukin 18, monocyte chemotactic protein-1); changes in gene transcript profiles and clinical parameters (Safety of Estrogen in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores, proteinuria, anti-double-stranded DNA (anti-dsDNA) antibodies, C3 complement, C4 complement).

Results

Fifty-six subjects enrolled (28 SLE without LN; 28 with LN). Baseline mean SELENA-SLEDAI scores were 2.2 and 12.0 for SLE subjects without and with LN, respectively. Most subjects reported an AE; no meaningful imbalances were observed between AMG 811 and placebo. Pharmacokinetic profiles were similar and mostly dose-proportional in subjects without or with LN. AMG 811 treatment reduced CXCL-10 protein levels and blood-based RNA IFN-γ Blockade Signature compared with placebo. Reductions were less pronounced and not sustained in subjects with LN, even at the highest dose tested, compared with subjects without LN. No effect on SELENA-SLEDAI scores, proteinuria, C3 or C4 complement levels, or anti-dsDNA antibodies was observed.

Conclusion

AMG 811 demonstrated favourable pharmacokinetics and acceptable safety profile but no evidence of clinical impact. IFN-γ-associated biomarkers decreased with AMG 811; effects were less pronounced and not sustained in LN subjects.

Trial registration number

NCT00818948; results.
Impact of coil price knowledge by the operator on the cost of aneurysm coiling. A single center study
Authors: Finitsis Stephanos , Fahed Robert , Gaulin Ian , Roy Daniel , Weill Alain
Published: September 2017

Background

Endovascular treatment of aneurysms with coils is among the most frequent treatments in interventional neuroradiology, and represents an important expense. Each manufacturer has created several types of coils, with prices varying among brands and coil types. The objective of this study was to assess the impact of cost awareness of the exact price of each coil by the operating physician on the total cost of aneurysm coiling.

Materials and methods

This was a comparative study conducted over 1 year in a single tertiary care center. The reference cohort and the experimental cohort consisted of all aneurysm embolization procedures performed during the first 6 months and the last 6 months, respectively. During the second period, physicians were given an information sheet with the prices of all available coils and were requested to look at the sheet during each procedure with the instruction to try to reduce the total cost of the coils used. Expenses related to the coiling procedures during each period were compared.

Results

77 aneurysms (39 ruptured) in the reference cohort and 73 aneurysms (36 ruptured) in the experimental cohort were treated, respectively. There was no statistically significant difference regarding aneurysm location and mean size. The overall cost of the coiling procedures, the mean number of coils used per procedure, and the median cost of each procedure did not differ significantly between the two cohorts.

Conclusion

Awareness of the precise price of coils by operators without any additional measure did not have a scientifically proven impact on the cost of aneurysm embolization.
Study of fall risk-increasing drugs in elderly patients before and after a bone fracture
Authors: Beunza-Sola Mónica , Hidalgo-Ovejero Ángel M , Martí-Ayerdi Jon , Sánchez-Hernández José Germán , Menéndez-García Miguel , García-Mata Serafín
Published: September 2017

Background

Accidental falls have a significant economic and human impact. The use of certain drugs is one of the modifiable risk factors associated with these events.

Objective

The aim of this study was to determine the prevalence of use and to explore changes in treatment with fall-related drugs in patients over 65 years of age admitted as a result of a fall-related fracture.

Methods

Observational and prospective study performed in a tertiary level hospital. A list of fall risk-increasing drugs (FRIDs) was drawn up. The main study variables were number and type of FRIDs prescribed at admission and 1 month after the fracture and number, type, treating physician and place where changes in FRIDs were implemented.

Results

In total, 252 patients were included. At admission, 91.3% were receiving at least one FRID, mean daily use was 3.1 FRIDs and the most frequently prescribed FRIDs were diuretics (18%), renin–angiotensin system-acting agents (15.8%) and antidepressants (15%). One month later, mean daily use was 3.4 FRIDs (p=0.099) and a significant increase was detected in the use of hypnotics (p=0.003) and antidepressants (p=0.042). A total of 327 changes in treatment were recorded (1.3 changes/patient). Of the changes, 52.6% were new prescriptions, 72.2% occurred at discharge and 56.6% were ordered by a geriatrician.

Conclusions

The use of FRIDs among patients with a fall-related fracture is very high. This use rises 1 month after the fracture, significantly in the case of hypnotics and antidepressants.
Effect of celastrol on bone structure and mechanics in arthritic rats
Authors: Cascão Rita , Vidal Bruno , Jalmari Finnilä Mikko Arttu , Lopes Inês Pascoal , Teixeira Rui Lourenço , Saarakkala Simo , Moita Luis Ferreira , Fonseca João Eurico
Published: September 2017

Objective

Rheumatoid arthritis (RA) is characterised by chronic inflammation leading to articular bone and cartilage damage. Despite recent progress in RA management, adverse effects, lack of efficacy and economic barriers to treatment access still limit therapeutic success. Therefore, safer and less expensive treatments that control inflammation and bone resorption are needed. We have previously shown that celastrol is a candidate for RA treatment. We have observed that it inhibits both interleukin (IL)-1β and tumor necrosis factor (TNF) in vitro, and that it has anti-inflammatory properties and ability to decrease synovial CD68+ macrophages in vivo. Herein our goal was to evaluate the effect of celastrol in local and systemic bone loss.

Methods

Celastrol was administrated intraperitoneally at a dose of 1 µg/g/day to female Wistar adjuvant-induced arthritic rats. Rats were sacrificed after 22 days of disease progression, and blood, femurs, tibiae and paw samples were collected for bone remodelling markers quantification, 3-point bending test, micro-CT analysis, nanoindentation and Fourier transform infrared spectroscopy measurements, and immunohistochemical evaluation.

Results

We have observed that celastrol preserved articular structures and decreased the number of osteoclasts and osteoblasts present in arthritic joints. Moreover, celastrol reduced tartrate-resistant acid phosphatase 5b, procollagen type 1 amino-terminal propeptide and C terminal crosslinked telopeptide of type II collagen serum levels. Importantly, celastrol prevented bone loss and bone microarchitecture degradation. Celastrol also preserved bone nanoproperties and mineral content. Additionally, animals treated with celastrol had less fragile bones, as depicted by an increase in maximum load and yield displacement.

Conclusions

These results suggest that celastrol reduces both bone resorption and cartilage degradation, and preserves bone structural properties.
Patient burden of Sjögren’s: a comprehensive literature review revealing the range and heterogeneity of measures used in assessments of severity
Authors: Hammitt Katherine M , Naegeli April N , van den Broek Remon W M , Birt Julie A
Published: September 2017

Context

The severity of Sjögren’s syndrome has been evaluated using a wide variety of clinical measures and patient-reported outcomes (PROs). This may contribute to the lack of clarity concerning the burden of Sjögren’s from the patient perspective.

Objective

To perform a comprehensive peer-reviewed literature analysis of the patient aspects of Sjögren’s, focusing on PROs, to investigate the complexity underlying the evaluation of the syndrome and to elucidate the discordance between the different measures.

Methods

We searched Embase for articles published between January 2005 and September 2015. Research articles, clinical and diagnostic reviews, and validation studies with a focus on patient aspects of Sjögren’s were selected as the primary information source.

Results

157 articles met the eligibility criteria. A wide variety of assessment measures used to evaluate glandular, extraglandular and functional domains were observed. Many different, non-validated Visual Analogue Scales, with a wide range of anchor words, were used in the quantification of Sjögren’s disease burden, impeding comparisons between studies. Relatively few clinical trials of drug therapies used validated scales: European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index was used most often for symptom assessment and 36 Item Short Form Survey for quality of life (QoL).

Conclusion

A wide range and diversity of measures are used to evaluate the patient burden of Sjögren’s; most are not validated for use in this disease. PRO endpoints, validated specifically in Sjögren’s, that demonstrate improvement are needed. These measures should focus on QoL aspects important to patients and will most likely involve gauging change in function rather than patient-reported symptoms.
Pneumococcal vaccination in autoimmune rheumatic diseases
Authors: Rákóczi Éva , Szekanecz Zoltan
Published: September 2017

Streptococcus pneumoniaeis the leading cause of the community-acquired pneumonia. The mortality rate of invasive pneumococcal infections is high. Immunocompromised patients suffering from autoimmune inflammatory rheumatic diseases (AIRD) have a high risk for acquiring these infections. Protection against infection can be improved with vaccination. After using polysaccharide vaccines (PPV-23), in July 2013, a 13-valent conjugate vaccine (PCV-13) was approved for adults. Due to its conjugate form, this vaccine is the recommended choice in pneumococcal vaccine-naive patients. PCV-13 is also recommended in patients previously receiving PPV-23. Vaccination in AIRD is very important and needs deliberate scheduling to coordinate with the immunosuppressive therapy. Here, based on international and national vaccine guidelines, we provide a current review of PPV-23 and PCV-13 vaccines for specialists following patients with AIRD.
Impact of tocilizumab monotherapy on patient-reported outcomes in patients with rheumatoid arthritis from two randomised controlled trials
Authors: Strand Vibeke , Michalska Margaret , Birchwood Christine , Pei Jinglan , Tuckwell Katie , Finch Rebecca , Gabay Cem , Kavanaugh Arthur , Jones Graeme
Published: September 2017

Objective

Two randomised controlled trials, AMBITION (NCT00109408) and ADACTA (NCT01119859), showed tocilizumab (TCZ) monotherapy superior to methotrexate (MTX) and adalimumab (ADA) monotherapy, respectively, for improving rheumatoid arthritis (RA) disease activity. This study compared the benefit of TCZ versus MTX or ADA monotherapy for improving patient-reported outcomes (PROs) in patients with RA.

Methods

PROs included patient global assessment (PtGA), pain, Health Assessment Questionnaire Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and Short Form-36 (SF-36) physical component summary (PCS) and mental component summary (MCS) and eight domain scores. Outcomes included proportions of patients reporting changes from baseline in PRO scores ≥minimum clinically important differences (MCID) and ≥age-matched and gender-matched normative values at 24 weeks.

Results

In AMBITION, TCZ-treated patients reported significantly greater mean improvements in HAQ (−0.7 vs −0.5), FACIT-Fatigue (8.7 vs 5.7), SF-36 PCS (9.8 vs 7.8) and five SF-36 domains at week 24 than with MTX; 45.0%–84.0% of TCZ-treated patients reported improvements ≥MCID, and 24.3%–52.1% reported scores ≥normative values across all PROs versus 39.4%–81.8% and 14.5%–45.0%, respectively, with MTX. In ADACTA, TCZ-treated patients reported significantly greater improvements in PtGA (−42.3 vs −31.8), pain (−40.1 vs −28.7), SF-36 MCS (7.9 vs 5.0) and three SF-36 domains than with ADA; 57.7%–83.3% of TCZ-treated patients reported improvements ≥MCID, and 22.1%–49.3% reported scores ≥normative values across all PROs versus 13.6%–37.8%, respectively, with ADA.

Conclusions

TCZ monotherapy resulted in more patients reporting clinically meaningful PRO improvements and PRO scores ≥normative values compared with MTX or ADA monotherapy.

Trial registration numbers

NCT00109408andNCT01119859; Post-results.
Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis
Authors: Gray Robert D , Hardisty Gareth , Regan Kate H , Smith Maeve , Robb Calum T , Duffin Rodger , Mackellar Annie , Felton Jennifer M , Paemka Lily , McCullagh Brian N , Lucas Christopher D , Dorward David A , McKone Edward F , Cooke Gordon , Donnelly Seamas C , Singh Pradeep K , Stoltz David A , Haslett Christopher , McCray Paul B , Whyte Moira K B , Rossi Adriano G , Davidson Donald J
Published: September 2017

Background

Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation. We hypothesised that the delay in apoptosis in CF is a primary defect and preferentially allows CF neutrophils to form NETs, contributing to inflammation.

Methods

Blood neutrophils were isolated from patients with CF, CF pigs and appropriate controls. Neutrophils were also obtained from patients with CF before and after commencing ivacaftor. Apoptosis was assessed by morphology and flow cytometry. NET formation was determined by fluorescent microscopy and DNA release assays. NET interaction with macrophages was examined by measuring cytokine generation with ELISA and qRT-PCR.

Results

CF neutrophils live longer due to decreased apoptosis. This was observed in both cystic fibrosis transmembrane conductance regulator (CFTR) null piglets and patients with CF, and furthermore was reversed by ivacaftor (CFTR potentiator) in patients with gating (G551D) mutations. CF neutrophils formed more NETs and this was reversed by cyclin-dependent kinase inhibitor exposure. NETs provided a proinflammatory stimulus to macrophages, which was enhanced in CF.

Conclusions

CF neutrophils have a prosurvival phenotype that is associated with an absence of CFTR function and allows increased NET production, which can in turn induce inflammation. Augmenting neutrophil apoptosis in CF may allow more appropriate neutrophil disposal, decreasing NET formation and thus inflammation.
Lower extremity compartment syndrome
Authors: Cone Jennifer , Inaba Kenji
Published: September 2017

Lower extremity compartment syndrome is a devastating complication if not rapidly diagnosed and properly managed. The classic symptoms of compartment syndrome can be deceiving as they occur late. Any concern for compartment syndrome based on mechanism, or the presence of pain in the affected extremity, should prompt a compartment pressure check. Both absolute compartment pressures above 30 mm Hg and a pressure differential of less than 30 mm Hg are used to make the diagnosis. The treatment goal is first to save the patient’s life and second to salvage the affected limb. Fasciotomy is the only accepted treatment of compartment syndrome and should be performed quickly after the diagnosis is made. Outcomes after fasciotomy are best when there is no delay in treatment.
CT scan incidental findings in trauma patients: does it impact hospital length of stay?
Authors: Andrawes Peter , Picon Antonio I , Shariff Masood A , Azab Basem , von Waagner Wolf , Demissie Seleshi , Fasanya Charles
Published: September 2017

Background

CT scans are heavily relied on for assessment of solid organ injuries complementing clinical examination. These CT scans could also reveal pathologies not related to trauma called incidental findings. We aimed to evaluate the frequency of these findings and their outcome on hospital services.

Methods

A retrospective chart review of prospectively collected data of the emergency department’s trauma database from January 2005 to December 2011 to evaluate incidental findings on CT scans on trauma admissions. These incidental findings were divided into three classes: class 1—minor degenerative, non-degenerative, normal variants or congenital finding that does not require further investigation or workup; class 2—findings not requiring urgent intervention with scheduled outpatient follow-up and class 3—all findings that require urgent evaluation/further investigation during the same hospital admission. One-year follow-up was done to review hospital length of stay, trauma clinic follow-up and post-trauma surgery.

Results

Of 1000 charts reviewed, 957 were selected after 43 patients were excluded due to incomplete documentation. Of the 957 patients, 385 (40%) were found to have incidental findings. A total of 560 incidental findings were found on the CT scan reports with one-third of patients having multiple findings (144 patients, 37.4%). The largest number of incidental findings were in class 2. The incidental group had significantly longer length of stay after adjusted multivariate analysis (8.7±0.48 vs 6.7±0.55, p=0.005).

Conclusion

The incidental findings are commonly found during CT imaging in trauma centers and our rate was 40%. Appropriate documentation, communication and follow-up of those findings is necessary. A classification system for these findings practiced nationwide will aid in categorizing the urgency of continued follow-up. This also will help decrease the length of hospital stay and healthcare cost.

Level of evidence

Level 4
Role of the gastrointestinal microbiota in small animal health and disease
Authors: Redfern Alana , Suchodolski Jan , Jergens Albert
Published: September 2017

There is a large and emerging interest in the role of the gastrointestinal microbiota in health and disease. This paper serves to review the current knowledge and recommendations of the gastrointestinal microbiota in health and gastrointestinal disease. Further, this review evaluates the current literature and suggests guidelines for faecal microbial transplantation, a novel therapy for dysbiosis in veterinary medicine.
Evidence for the early onset of the Ipswichian thermal optimum: palaeoecology of Last Interglacial deposits at Whittlesey, eastern England
Authors: Langford H. E. , Boreham S. , Briant R. M. , Coope G. R. , Horne D. J. , Penkman K. E. H. , Schreve D. C. , Whitehouse N. J. , Whittaker J. E.
Published: September 2017

Fossiliferous deposits infilling a channel at Whittlesey, eastern England, are dated by amino acid racemization to the Last Interglacial, and pollen analysis indicates deposition in Ipswichian biozones Ip Ib and Ip IIb. Multidisciplinary palaeoenvironmental analyses of these deposits provide a rare insight into Ip Ib subzone conditions. Specifically, the Ip Ib deposits contain exotic thermophiles
Naias minor
,
Belgrandia marginata
,
Bembidion elongatum
,
Pelochares versicolor
,
Caccobius schreberi, Onthophagus massai
and
Emys orbicularis
, usually associated with Ip IIb. Combined palaeotemperature reconstructions based on beetle, ostracod and vertebrate assemblages of the Ip Ib deposits indicate that summers (mean July range +19 to +22°C) were at least 2°C warmer than at present, whereas winters (mean January air temperature range 0 to +7°C) were probably similar to those of today. These palaeotemperature ranges encompass those for Ip IIb deposits at Trafalgar Square (+20 to +21°C and +1.5 to +3°C), previously considered the only Ipswichian site to record temperatures significantly warmer than Holocene temperatures. Of particular significance is that thermal optimal conditions commenced in Ip Ib, rather than being confined to Ip IIb. This demonstrates rapid warming and biological response to early Ipswichian climate amelioration, which accords with the deep-sea Last Interglacial and European Eemian records.

Supplementary material:
Supplementary Tables S1-S7 are available at
http://doi.org/10.6084/m9.figshare.c.3830221
.
Deep-water plays in the western Black Sea: insights into sediment supply within the Maykop depositional system
Authors: Rees E. V. L. , Simmons M. D. , Wilson J. W. P.
Published: September 2017

The Oligocene–Early Miocene Maykop depositional system of the Western Black Sea Basin is investigated in terms of sediment supply and provenance. Potential sediment source regions and conduits for sediment supply into the deep-water portion of the basin are evaluated based on the tectonic history and framework of the region, and are supported by observations from published well, reflection seismic and isopach data. The outcrop geology of the present-day land areas adjacent to the basin is used as a guide to the likely provenance and, hence, quality of potential siliciclastic reservoirs. Reservoir presence and reservoir quality are key subsurface risks for exploration in deep-water plays involving Maykop turbidite sandstones and charge from the well-known Maykop organic carbon-rich mudstones that are widespread across the basin.

Sediments sourced from the NE Moesian Platform and Dobrogea, channelled into the offshore Black Sea via the Histria Trough, are considered moderate risk in terms of primary reservoir quality, as evidenced by thick packages of fine-grained sediment. In contrast, sediments derived from the southern Strandja Massif fed into the Burgas Basin, and potentially into the deeper-water Turkish Black Sea, are relatively low risk in terms of reservoir quality, given the abundance of acidic intrusions within the massif. Sediment derived from parts of the northern Strandja Massif, especially the volcaniclastics of the Srednogornie region, are likely to have poorer reservoir quality characteristics. Sediments derived from the granitic Bolu Massif within the Pontides might be of good reservoir quality but are likely to be ponded behind the offshore Kozlu Ridge. An important sediment source-to-sink system was derived from the Balkanides and entered the deeper-water western Black Sea via the Kamchia Trough. The present-day Kamchia river is a relatively minor sediment supplier to the Black Sea, but the palaeo-Kamchia river of the Oligocene–Early Miocene would have exploited a much greater drainage area consisting of an axial trunk stream, occupying the newly formed Kamchia Foredeep to the north of the Balkanides, and transverse rivers sourcing sediment from the granitic and gneissic bodies of the Balkan Mountains and from Early Cretaceous and Palaeogene sandstones. These would provide reasonable reservoir quality, and it is estimated from reference source-to-sink relationships that offshore sediment flux via this system was probably at least eight times greater than at present. Known shelf-edge canyons in offshore Bulgaria facilitated this sediment reaching the deep water offshore, where a sedimentary fan with a length in excess of 150 km is likely to have developed. This suggests that the potential is good for encountering good-quality reservoir sands in the Maykop succession deep water of the western Black Sea, and this aspect of regional play risk could be of less concern than was previously considered.
Geological evolution of the Central Pontides
Authors: Okay Aral I. , Altiner Demir , Sunal Gürsel , Aygül Mesut , Akdoğan Remziye , Altiner Sevinç , Simmons Mike
Published: September 2017

Before the Late Cretaceous opening of the Black Sea, the Central Pontides constituted part of the southern margin of Laurasia. Two features that distinguish the Central Pontides from the neighbouring Pontide regions are the presence of an extensive Lower Cretaceous submarine turbidite fan (the Çağlayan Formation) in the north, and a huge area of Jurassic–Cretaceous subduction–accretion complexes in the south.

The Central Pontides comprise two terranes, the Istanbul Zone in the west and the Sakarya Zone in the east, which were amalgamated before the Late Jurassic (Kimmeridgian), most probably during the Triassic. The basement in the western Central Pontides (the Istanbul Zone) is made up of a Palaeozoic sedimentary sequence, which ends with Carboniferous coal measures and Permo-Triassic red beds. In the eastern Central Pontides, the basement consists of Permo-Carboniferous granites and an Upper Triassic forearc sequence of siliciclastic turbidites with tectonic slivers of pre-Jurassic ophiolite (the Küre Complex). The Küre Complex is intruded by Middle Jurassic granites and porphyries, which constitute the western termination of a major magmatic arc.

Upper Jurassic–Lower Cretaceous shallow-marine limestones (the İnaltı Formation) lie unconformably over both the Istanbul and Sakarya sequences in the Central Pontides. Two new measured stratigraphic sections from the İnaltı Formation constrain the age of the İnaltı Formation as Kimmeridgian–Berriasian. After a period of uplift and erosion during the Valanginian and Hauterivian, the İnaltı Formation is unconformably overlain by an over 2 km-thick sequence of Barremian–Aptian turbidites. Palaeocurrent measurements and detrital zircons indicate that the major part of the turbidites was derived from the East European Platform, implying that the Black Sea was not open before the Aptian. The Çağlayan turbidites pass northwards to a coeval carbonate–clastic shelf exposed along the present Black Sea coast. In the southern part of the Central Pontides, the Lower Cretaceous turbidites were deformed and metamorphosed in the Albian. Albian times also witnessed accretion of Tethyan oceanic crustal and mantle sequences to the southern margin of Laurasia, represented by Albian eclogites and blueschists in the Central Pontides.

A new depositional cycle started in the Late Cretaceous with Coniacian–Santonian red pelagic limestones, which lie unconformably over the older units. The limestones pass up into thick sequences of Santonian–Campanian arc volcanic rocks. The volcanism ceased in the middle Campanian, and the interval between late Campanian and middle Eocene is represented by a thick sequence of siliciclastic and calciclastic turbidites in the northern part of the Central Pontides. Coeval sequences in the south are shallow marine and are separated by unconformities. The marine deposition in the Central Pontides ended in the Middle Eocene as a consequence of collision of the Pontides with the Kırşehir Massif.
Pharmacological and physiological assessment of serotonin formation and degradation in isolated preparations from mouse and human hearts
Authors: Gergs Ulrich , Jung Franziska , Buchwalow Igor B. , Hofmann Britt , Simm Andreas , Treede Hendrik , Neumann Joachim
Published: September 2017

Using transgenic (TG) mice that overexpress the human serotonin (5-HT)4areceptor specifically in cardiomyocytes, we wanted to know whether 5-HT can be formed and degraded in the mammalian heart and whether this can likewise lead to inotropic and chronotropic effects in this TG model. We noted that the 5-HT precursor 5-hydroxy-tryptophan (5-HTP) can exert inotropic and chronotropic effects in cardiac preparations from TG mice but not from wild-type (WT) mice; similar results were found in human atrial preparations as well as in intact TG animals using echocardiography. Moreover, by immunohistochemistry we could detect 5-HT metabolizing enzymes and 5-HT transporters in mouse hearts as well as in human atria. Hence, in the presence of an inhibitor of aromatic l-amino acid decarboxylase, the positive inotropic effects of 5-HTP were absent in TG and isolated human atrial preparations, and, moreover, inhibitors of enzymes involved in 5-HT degradation enhanced the efficacy of 5-HT in TG atria. A releaser of neurotransmitters increased inotropy in the isolated TG atrium, and this effect could be blocked by a 5-HT4areceptor antagonist. Fluoxetine, an inhibitor of 5-HT uptake, elevated the potency of 5-HT to increase contractility in the TG atrium. In addition, inhibitors of organic cation and monoamine transporters apparently reduced the positive inotropic potency of 5-HT in the TG atrium. Hence, we tentatively conclude that a local production and degradation of 5-HT in the mammalian heart and more specifically in mammalian myocytes probably occurs. Conceivably, this formation of 5-HT and possibly impaired degradation may be clinically relevant in cases of unexplained tachycardia and other arrhythmias.

NEW & NOTEWORTHY The present work suggests that inotropically active serotonin (5-HT) can be formed in the mouse and human heart and probably by cardiomyocytes themselves. Moreover, active degradation of 5-HT seems to occur in the mammalian heart. These findings may again increase the interest of researchers for cardiac effects of 5-HT.
A Large Lumbar Adnexal Neoplasm Presenting Characteristics of Eccrine Poroma and Poroid Hidradenoma
Authors: Michalinos Adamantios , Schizas Dimitrios , Sarakinos Antonios , Athanasiadis Georgios , Spartalis Eleftherios , Vlachodimitropoulos Dimitrios , Troupis Theodore
Published: September 2017

Poroma is a rare benign neoplasm that derives from eccrine sweat glands epithelium. Its histological subtypes, with respect to its position within skin layers, are eccrine poroma, hidroacanthoma simplex, poroid hidradenoma, and dermal duct tumor. Poromas commonly exhibit benign clinical behavior as they are usually small and asymptomatic and do not exhibit malignant behavior. Although their histological subtypes share similar histological characteristics, they rarely coexist in the same tumor. In this report we present the case of an unusual poroma in terms of histological and clinical behavior as it was large and presented histological characteristic of both eccrine poroma and poroid hidradenoma. Coexistence of different histologic subtypes in the same tumor indicates simultaneous tumorigenesis, differentiation from one cell type to another, or parallel differentiation from a common progenitor cell. Implications in treatment remain unknown partly due to the rarity of such cases.
Tenascin-C and Integrin α9 Mediate Interactions of Prostate Cancer with the Bone Microenvironment
Authors: San Martin Rebeca , Pathak Ravi , Jain Antrix , Jung Sung Yun , Hilsenbeck Susan G. , Piña-Barba María C. , Sikora Andrew G. , Pienta Kenneth J. , Rowley David R.
Published: September 2017

Deposition of the extracellular matrix protein tenascin-C is part of the reactive stroma response, which has a critical role in prostate cancer progression. Here, we report that tenascin C is expressed in the bone endosteum and is associated with formation of prostate bone metastases. Metastatic cells cultured on osteo-mimetic surfaces coated with tenascin C exhibited enhanced adhesion and colony formation as mediated by integrin α9β1. In addition, metastatic cells preferentially migrated and colonized tenascin-C–coated trabecular bone xenografts in a novel system that employed chorioallantoic membranes of fertilized chicken eggs as host. Overall, our studies deepen knowledge about reactive stroma responses in the bone endosteum that accompany prostate cancer metastasis to trabecular bone, with potential implications to therapeutically target this process in patients. Cancer Res; 77(21); 5977–88. ©2017 AACR.
YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63–GPX2 Axis and ROS Accumulation
Authors: Huang Hsinyi , Zhang Wenjing , Pan Yafang , Gao Yijun , Deng Lei , Li Fuming , Li Fei , Ma Xueyan , Hou Shenda , Xu Jing , Li Peixue , Li Xiaoxun , Hu Guohong , Li Cheng , Chen Haiquan , Zhang Lei , Ji Hongbin
Published: September 2017

Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non–small cell lung cancer, is often refractory to therapy. Screening a small-molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo. Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft models, digitoxin treatment efficiently inhibited lung SCC progression in correlation with reduced expression of YAP. Collectively, our results highlight a novel tumor-suppressor function of YAP via downregulation of GPX2 and ROS accumulation, with potential implications to improve precision medicine of human lung SCC. Cancer Res; 77(21); 5769–81. ©2017 AACR.
LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression
Authors: Liang Yi , Ahmed Musaddeque , Guo Haiyang , Soares Fraser , Hua Junjie T. , Gao Shuai , Lu Catherine , Poon Christine , Han Wanting , Langstein Jens , Ekram Muhammad B. , Li Brian , Davicioni Elai , Takhar Mandeep , Erho Nicholas , Karnes R. Jeffrey , Chadwick Dianne , van der Kwast Theodorus , Boutros Paul C. , Arrowsmith Cheryl H. , Feng Felix Y. , Joshua Anthony M. , Zoubeidi Amina , Cai Changmeng , He Housheng H.
Published: September 2017

Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479–90. ©2017 AACR.
Tethering IL2 to Its Receptor IL2Rβ Enhances Antitumor Activity and Expansion of Natural Killer NK92 Cells
Authors: Jounaidi Youssef , Cotten Joseph F. , Miller Keith W. , Forman Stuart A.
Published: September 2017

IL2 is an immunostimulatory cytokine for key immune cells including T cells and natural killer (NK) cells. Systemic IL2 supplementation could enhance NK-mediated immunity in a variety of diseases ranging from neoplasms to viral infection. However, its systemic use is restricted by its serious side effects and limited efficacy due to activation of T regulatory cells (Tregs). IL2 signaling is mediated through interactions with a multi-subunit receptor complex containing IL2Rα, IL2Rβ, and IL2Rγ. Adult natural killer (NK) cells express only IL2Rβ and IL2Rγ subunits and are therefore relatively insensitive to IL2. To overcome these limitations, we created a novel chimeric IL2-IL2Rβ fusion protein of IL2 and its receptor IL2Rβ joined via a peptide linker (CIRB). NK92 cells expressing CIRB (NK92CIRB) were highly activated and expanded indefinitely without exogenous IL2. When compared with an IL2-secreting NK92 cell line, NK92CIRB were more activated, cytotoxic, and resistant to growth inhibition. Direct contact with cancer cells enhanced the cytotoxic character of NK92CIRB cells, which displayed superior in vivo antitumor effects in mice. Overall, our results showed how tethering IL2 to its receptor IL2Rβ eliminates the need for IL2Rα and IL2Rβ, offering a new tool to selectively activate and empower immune therapy. Cancer Res; 77(21); 5938–51. ©2017 AACR.
Biallelic Dicer1 Loss Mediated by aP2-Cre Drives Angiosarcoma
Authors: Hanna Jason A. , Drummond Catherine J. , Garcia Matthew R. , Go Jonathan C. , Finkelstein David , Rehg Jerold E. , Hatley Mark E.
Published: September 2017

Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Because of the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to miRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Here, we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma. miR-23 target genes, including the oncogenes Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis, were enriched in mouse and human angiosarcoma. These studies illustrate that Dicer1 can function as a traditional loss-of-function tumor suppressor gene, and they provide a fully penetrant animal model for the study of angiosarcoma development and metastasis. Cancer Res; 77(22); 6109–18. ©2017 AACR.
Chemotherapy-Induced Macrophage Infiltration into Tumors Enhances Nanographene-Based Photodynamic Therapy
Authors: Zhao Yang , Zhang Chenran , Gao Liquan , Yu Xinhe , Lai Jianhao , Lu Dehua , Bao Rui , Wang Yanpu , Jia Bing , Wang Fan , Liu Zhaofei
Published: September 2017

Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here, we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission CT imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach. Cancer Res; 77(21); 6021–32. ©2017 AACR.
Monoclonal Antibodies Directed against Cadherin RGD Exhibit Therapeutic Activity against Melanoma and Colorectal Cancer Metastasis
Authors: Bartolomé Rubén A. , Aizpurua Carmen , Jaén Marta , Torres Sofía , Calviño Eva , Imbaud Juan I. , Casal J. Ignacio
Published: September 2017

Purpose: New targets are required for the control of advanced metastatic disease. We investigated the use of cadherin RGD motifs, which activate the α2β1integrin pathway, as targets for the development of therapeutic monoclonal antibodies (mAb).

Experimental Design: Cadherin 17 (CDH17) fragments and peptides were prepared and used for immunization and antibody development. Antibodies were tested for inhibition of β1 integrin and cell adhesion, proliferation, and invasion assays using cell lines from different cancer types (colorectal, pancreatic, melanoma, and breast cancer). Effects of the mAbs on cell signaling were determined by Western blot analysis. Nude mice were used for survival analysis after treatment with RGD-specific mAbs and metastasis development.

Results: Antibodies against full-length CDH17 failed to block the binding to α2β1 integrin. However, CDH17 RGD peptides generated highly selective RGD mAbs that blocked CDH17 and vascular-endothelial (VE)-cadherin–mediated β1 integrin activation in melanoma and breast, pancreatic, and colorectal cancer cells. Antibodies provoked a significant reduction in cell adhesion and proliferation of metastatic cancer cells. Treatment with mAbs impaired the integrin signaling pathway activation of FAK in colorectal cancer, of JNK and ERK kinases in colorectal and pancreatic cancers, and of JNK, ERK, Src, and AKT in melanoma and breast cancer. In vivo, RGD-specific mAbs increased mouse survival after inoculation of melanoma and colorectal cancer cell lines to cause lung and liver metastasis, respectively.

Conclusions: Blocking the interaction between RGD cadherins and α2β1 integrin with highly selective mAbs constitutes a promising therapy against advanced metastatic disease in colon cancer, melanoma, and, potentially, other cancers. Clin Cancer Res; 24(2); 433–44. ©2017 AACR.

See related commentary by Marshall, p. 253