bluuebunny/crossref_metadata_2025 huggingface dataset:
ESR1 Methylation: A Liquid Biopsy–Based Epigenetic Assay for the Follow-up of Patients with Metastatic Breast Cancer Receiving Endocrine Treatment
Authors: Mastoraki Sophia , Strati Areti , Tzanikou Eleni , Chimonidou Maria , Politaki Eleni , Voutsina Alexandra , Psyrri Amanda , Georgoulias Vassilis , Lianidou Evi
Published: December 2017

Purpose: Liquid biopsy provides real-time monitoring of tumor evolution and response to therapy through analysis of circulating tumor cells (CTCs) and plasma-circulating tumor DNA (ctDNA). ESR1 epigenetic silencing potentially affects response to endocrine treatment. We evaluated ESR1 methylation in CTCs and paired plasma ctDNA. We evaluated ESR1 methylation in CTCs and paired plasma ctDNA as a potential biomarker for response to everolimus/exemestane treatment.

Experimental Design: A highly sensitive and specific real-time MSP assay for ESR1 methylation was developed and validated in (i) 65 primary breast tumors formalin-fixed paraffin-embedded (FFPE), (ii) EpCAM+ CTC fractions (122 patients and 30 healthy donors; HD), (iii) plasma ctDNA (108 patients and 30HD), and (iv) in CTCs (CellSearch) and in paired plasma ctDNA for 58 patients with breast cancer. ESR1 methylation status was investigated in CTCs isolated from serial peripheral blood samples of 19 patients with ER+/HER2− advanced breast cancer receiving everolimus/exemestane.

Results: ESR1 methylation was detected in: (i) 25/65 (38.5%) FFPEs, (ii) EpCAM+ CTC fractions: 26/112 (23.3%) patients and 1/30 (3.3%) HD, and (iii) plasma ctDNA: 8/108 (7.4%) patients and 1/30 (3.3%) HD. ESR1 methylation was highly concordant in 58 paired DNA samples, isolated from CTCs (CellSearch) and corresponding plasma. In serial peripheral blood samples of patients treated with everolimus/exemestane, ESR1 methylation was observed in 10/36 (27.8%) CTC-positive samples, and was associated with lack of response to treatment (P = 0.023, Fisher exact test).

Conclusions: We report for the first time the detection of ESR1 methylation in CTCs and a high concordance with paired plasma ctDNA. ESR1 methylation in CTCs was associated with lack of response to everolimus/exemestane regimen. ESR1 methylation should be further evaluated as a potential liquid biopsy-based biomarker. Clin Cancer Res; 24(6); 1500–10. ©2017 AACR.
Immunotherapy of Myelodysplastic Syndrome: You Can Run, but You Can't Hide
Authors: Fuchs Ephraim Joseph
Published: December 2017

The hypomethylating agent decitabine induces expression of the cancer/testis antigen NY-ESO-1 in the myeloid cells of patients with myelodysplastic syndrome (MDS). Patients with MDS treated with decitabine and an NY-ESO-1 vaccine developed NY-ESO-1–specific T-cell responses directed against their abnormal myeloid cells, raising hopes for combinatorial immunotherapy of this disease. Clin Cancer Res; 24(5); 991–3. ©2017 AACR.

See related article by Griffiths et al., p. 1019
Inhibition of MDM2 by a Rhein-Derived Compound AQ-101 Suppresses Cancer Development in SCID Mice
Authors: Gu Lubing , Zhang Hailong , Liu Tao , Draganov Alexander , Yi Sha , Wang Binghe , Zhou Muxiang
Published: December 2017

A novel small-molecule anthraquinone (AQ) analogue, AQ-101, which was synthesized through chemical modification of the core structures of rhein, exhibited potent anticancer activity. In the present study, we evaluated the cancer-inhibiting mechanism of AQ-101 and tested the therapeutic potential of this compound for treating cancer in mice. We found that AQ-101 was able to induce MDM2 protein degradation through a self-ubiquitination and proteasome-mediated mechanism. This AQ-101–induced MDM2 downregulation led to activation of p53, which contributed to apoptosis of acute lymphoblastic leukemia (ALL), especially those with a wild-type p53 phenotype and MDM2 expression in vitro and in vivo. When given for a period of 2 weeks (20 mg/kg/day, 3×/week), AQ-101 inhibited development of ALL in nude or SCID mice with a human ALL xenograft and achieved cure by the end of the 5-month experiment. Importantly, AQ-101 showed minimal or no inhibitory effect on normal human hematopoiesis in vitro and was well tolerated in vivo in animal models. Given that MDM2-overexpressing cancers are commonly refractory to current treatment options, our study results suggest that further development of AQ-101 is warranted, as it represents a potentially new, safe anticancer drug with a novel strategy for targeting MDM2. Mol Cancer Ther; 17(2); 497–507. ©2017 AACR.
Scavenger Receptor Type B1 and Lipoprotein Nanoparticle Inhibit Myeloid-Derived Suppressor Cells
Authors: Plebanek Michael P. , Bhaumik Debayan , Bryce Paul J. , Thaxton C. Shad
Published: December 2017

Myeloid-derived suppressor cells (MDSC) are innate immune cells that potently inhibit T cells. In cancer, novel therapies aimed to activate T cells can be rendered ineffective due to the activity of MDSCs. Thus, targeted inhibition of MDSCs may greatly enhance T-cell–mediated antitumor immunity, but mechanisms remain obscure. Here we show, for the first time, that scavenger receptor type B-1 (SCARB1), a high-affinity receptor for spherical high-density lipoprotein (HDL), is expressed by MDSCs. Furthermore, we demonstrate that SCARB1 is specifically targeted by synthetic high-density lipoprotein-like nanoparticles (HDL NP), which reduce MDSC activity. Using in vitro T-cell proliferation assays, data show that HDL NPs specifically bind SCARB1 to inhibit MDSC activity. In murine cancer models, HDL NP treatment significantly reduces tumor growth, metastatic tumor burden, and increases survival due to enhanced adaptive immunity. Flow cytometry and IHC demonstrate that HDL NP–mediated suppression of MDSCs increased CD8+ T cells and reduced Treg cells in the metastatic tumor microenvironment. Using transgenic mice lacking SCARB1, in vivo data clearly show that the HDL NPs specifically target this receptor for suppressing MDSCs. Ultimately, our data provide a new mechanism and targeted therapy, HDL NPs, to modulate a critical innate immune cell checkpoint to enhance the immune response to cancer. Mol Cancer Ther; 17(3); 686–97. ©2017 AACR.
Homozygous Familial Hypercholesterolemia Patients With Identical Mutations Variably Express the LDLR (Low-Density Lipoprotein Receptor)
Authors: Thedrez Aurélie , Blom Dirk J. , Ramin-Mangata Stéphane , Blanchard Valentin , Croyal Mikaël , Chemello Kévin , Nativel Brice , Pichelin Matthieu , Cariou Bertrand , Bourane Steeve , Tang Lihua , Farnier Michel , Raal Frederick J. , Lambert Gilles
Published: December 2017

Objective—

Evolocumab, a PCSK9 (proprotein convertase subtilisin kexin type 9)–neutralizing antibody, lowers low-density lipoprotein cholesterol (LDL-C) in homozygous familial hypercholesterolemic (HoFH) patients with reduced LDLR (low-density lipoprotein receptor) function. However, their individual responses are highly variable, even among carriers of identical LDLR genetic defects. We aimed to elucidate why HoFH patients variably respond to PCSK9 inhibition.

Approach and Results—

Lymphocytes were isolated from 22 HoFH patients enrolled in the TAUSSIG trial (Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders). Ten patients were true homozygotes (FH1/FH1) and 5 identical compound heterozygotes (FH1/FH2). Lymphocytes were plated with or without mevastatin, recombinant PCSK9 (rPCSK9), or a PCSK9-neutralizing antibody. Cell surface LDLR expression was analyzed by flow cytometry. All HoFH lymphocytes had reduced cell surface LDLR expression compared with non-FH lymphocytes, for each treatment modality. Lymphocytes from FH1/FH2 patients (LDLR defective/negative) displayed the lowest LDLR expression levels followed by lymphocytes from FH1/FH1 patients (defective/defective). Mevastatin increased, whereas rPCSK9 reduced LDLR expression. The PCSK9-neutralizing antibody restored LDLR expression. Lymphocytes displaying higher LDLR expression levels were those isolated from patients presenting with lowest levels of LDL-C and apolipoprotein B, before and after 24 weeks of evolocumab treatment. These negative correlations remained significant in FH1/FH1 patients and appeared more pronounced when patients with apolipoprotein E3/E3 genotypes were analyzed separately. Significant positive correlations were found between the levels of LDLR expression and the percentage reduction in LDL-C on evolocumab treatment.

Conclusions—

Residual LDLR expression in HoFH is a major determinant of LDL-C levels and seems to drive their individual response to evolocumab.
AMPKα2 Protects Against the Development of Heart Failure by Enhancing Mitophagy via PINK1 Phosphorylation
Authors: Wang Bei , Nie Jiali , Wu Lujin , Hu Yangyang , Wen Zheng , Dong Lingli , Zou Ming-Hui , Chen Chen , Wang Dao Wen
Published: December 2017

Rationale:

Mitochondrial dysfunction plays an important role in heart failure (HF). However, the molecular mechanisms regulating mitochondrial functions via selective mitochondrial autophagy (mitophagy) are poorly understood.

Objective:

We sought to determine the role of AMPK (AMP-activated protein kinase) in selective mitophagy during HF.

Methods and Results:

An isoform shift from AMPKα2 to AMPKα1 was observed in failing heart samples from HF patients and transverse aortic constriction–induced mice, accompanied by decreased mitophagy and mitochondrial function. The recombinant adeno-associated virus Serotype 9-mediated overexpression of AMPKα2 in mouse hearts prevented the development of transverse aortic constriction–induced chronic HF by increasing mitophagy and improving mitochondrial function. In contrast, AMPKα2
−/−
mutant mice exhibited an exacerbation of the early progression of transverse aortic constriction–induced HF via decreases in cardiac mitophagy. In isolated adult mouse cardiomyocytes, AMPKα2 overexpression mechanistically rescued the impairment of mitophagy after phenylephrine stimulation for 24 hours. Genetic knockdown of AMPKα2, but not AMPKα1, by short interfering RNA suppressed the early phase (6 hours) of phenylephrine-induced compensatory increases in mitophagy. Furthermore, AMPKα2 specifically interacted with phosphorylated PINK1 (PTEN-induced putative kinase 1) at Ser495 after phenylephrine stimulation. Subsequently, phosphorylated PINK1 recruited the E3 ubiquitin ligase, Parkin, to depolarized mitochondria, and then enhanced the role of the PINK1–Parkin–SQSTM1 (sequestosome-1) pathway involved in cardiac mitophagy. This increase in cardiac mitophagy was accompanied by the elimination of damaged mitochondria, improvement in mitochondrial function, decrease in reactive oxygen species production, and apoptosis of cardiomyocytes. Finally, Ala mutation of PINK1 at Ser495 partially suppressed AMPKα2 overexpression-induced mitophagy and improvement of mitochondrial function in phenylephrine-stimulated cardiomyocytes, whereas Asp (phosphorylation mimic) mutation promoted mitophagy after phenylephrine stimulation.

Conclusions:

In failing hearts, the dominant AMPKα isoform switched from AMPKα2 to AMPKα1, which accelerated HF. The results show that phosphorylation of Ser495 in PINK1 by AMPKα2 was essential for efficient mitophagy to prevent the progression of HF.
Adenosine-to-Inosine Editing of MicroRNA-487b Alters Target Gene Selection After Ischemia and Promotes Neovascularization
Authors: van der Kwast Reginald V.C.T. , van Ingen Eva , Parma Laura , Peters Hendrika A.B. , Quax Paul H.A. , Nossent A. Yaël
Published: December 2017

Rationale:

Adenosine-to-inosine editing of microRNAs has the potential to cause a shift in target site selection. 2′-O-ribose-methylation of adenosine residues, however, has been shown to inhibit adenosine-to-inosine editing.

Objective:

To investigate whether angiomiR miR487b is subject to adenosine-to-inosine editing or 2′-O-ribose-methylation during neovascularization.

Methods and Results:

Complementary DNA was prepared from C57BL/6-mice subjected to hindlimb ischemia. Using Sanger sequencing and endonuclease digestion, we identified and validated adenosine-to-inosine editing of the miR487b seed sequence. In the gastrocnemius muscle, pri-miR487b editing increased from 6.7±0.4% before to 11.7±1.6% (
P
=0.02) 1 day after ischemia. Edited pri-miR487b is processed into a novel microRNA, edited miR487b, which is also upregulated after ischemia. We confirmed editing of miR487b in multiple human primary vascular cell types. Short interfering RNA–mediated knockdown demonstrated that editing is adenosine deaminase acting on RNA 1 and 2 dependent. Using reverse-transcription at low dNTP concentrations followed by quantitative-PCR, we found that the same adenosine residue is methylated in mice and human primary cells. In the murine gastrocnemius, the estimated methylation fraction increased from 32.8±14% before to 53.6±12% 1 day after ischemia. Short interfering RNA knockdown confirmed that methylation is fibrillarin dependent. Although we could not confirm that methylation directly inhibits editing, we do show that adenosine deaminase acting on RNA 1 and 2 and fibrillarin negatively influence each other’s expression. Using multiple luciferase reporter gene assays, we could demonstrate that editing results in a complete switch of target site selection. In human primary cells, we confirmed the shift in miR487b targeting after editing, resulting in a edited miR487b targetome that is enriched for multiple proangiogenic pathways. Furthermore, overexpression of edited miR487b, but not wild-type miR487b, stimulates angiogenesis in both in vitro and ex vivo assays.

Conclusions:

MiR487b is edited in the seed sequence in mice and humans, resulting in a novel, proangiogenic microRNA with a unique targetome. The rate of miR487b editing, as well as 2′-O-ribose-methylation, is increased in murine muscle tissue during postischemic neovascularization. Our findings suggest miR487b editing plays an intricate role in postischemic neovascularization.
Impact of Prehospital Triage Scales to Detect Large Vessel Occlusion on Resource Utilization and Time to Treatment
Authors: Schlemm Ludwig , Ebinger Martin , Nolte Christian H. , Endres Matthias
Published: December 2017

Background and Purpose—

Prehospital stroke severity scales may help to triage acute ischemic stroke patients with large vessel occlusion (LVO) for direct transportation to a comprehensive stroke center. The impact on resource use and time to reperfusion treatment for patients with and without LVO is unknown.

Methods—

Based on empirical distributions of stroke symptom severity, prehospital delay times, and stroke symptom severity-dependent likelihood of LVO, we simulate prehospital incidents of stroke-like symptoms in abstract geographical environments to estimate the impact of prehospital triage strategies based on different cutoffs of the rapid arterial occlusion evaluation scale.

Results—

Compared with transporting each patient to the nearest stroke center, implementation of a prehospital triage strategy based on a rapid arterial occlusion evaluation scale cutoff score ≥5 is associated with more patients with suspected acute stroke at comprehensive stroke centers and less patients at primary stroke centers (+11.7% [95% confidence interval: +8.1% to +15.3%] and −18.4% [−19.1% to −17.7%], respectively). Mean time to groin puncture is reduced by 29.6 minutes (−35.2 to −24.7 minutes) while mean time to thrombolysis does not change significantly (±0.0 minutes [−0.3 to +0.3 minutes]). The total number of secondary transfers is reduced by 60.9% (−62.8% to −59.0%); mean time of ambulance use per patient is unchanged. Results are robust with regards to variation in model parameters.

Conclusions—

Implementation of prehospital triage based on stroke severity scales would have strong impact on patient flow and distribution. The benefit of earlier thrombectomy for patients with LVO may outweigh the harm associated with delayed access to thrombolysis for some patients without LVO. Randomized trials using clinical stroke severity scales as a triage tool are needed to confirm our findings.
Contact Aspiration Versus Stent Retriever in Patients With Acute Ischemic Stroke With M2 Occlusion in the ASTER Randomized Trial (Contact Aspiration Versus Stent Retriever for Successful Revascularization)
Authors: Gory Benjamin , Lapergue Bertrand , Blanc Raphael , Labreuche Julien , Ben Machaa Malek , Duhamel Alain , Marnat Gautier , Saleme Suzana , Costalat Vincent , Bracard Serge , Desal Hubert , Mazighi Mikael , Consoli Arturo , Piotin Michel , Redjem Hocine , Ciccio Gabriele , Smajda Stanislas , Fahed Robert , Desilles Jean Philippe , Rodesch Georges , Coskun Oguzhan , Maria Federico Di , Bourdain Frédéric , Decroix Jean Pierre , Wang Adrien , Tchikviladze Maya , Evrard Serge , Turjman Francis , Labeyrie Paul Emile , Riva Roberto , Mounayer Charbel , Bonafé Alain , Eker Omer , Gascou Grégory , Dargazanli Cyril , Tonnelet Romain , Derelle Anne Laure , Anxionnat René , Bourcier Romain , Daumas-Duport Benjamin , Berge Jérome , Barreau Xavier , Djemmane Lynda
Published: December 2017

Background and Purpose—

Middle cerebral artery M2-segment occlusions represent an important subgroup of patients with acute stroke with large-vessel occlusion. The safety of mechanical thrombectomy, especially contact aspiration (CA), in such distal intracranial occlusions is still under debate. We compared reperfusion, adverse events, neurological recovery, and functional outcome of patients with isolated M2 occlusions according to the first-line strategy mechanical thrombectomy devices (CA versus stent retriever [SR]).

Methods—

This is a post hoc analysis of the ASTER trial (Contact Aspiration Versus Stent Retriever for Successful Revascularization). The primary outcome was successful reperfusion at the end of all endovascular procedures, defined as modified Thrombolysis in Cerebral Infarction (mTICI) scores 2b/3. Secondary outcomes were mTICI 2c/3 and mTICI 3, 90-day functional outcome, assessed with the modified Rankin Scale score. Safety outcomes included 90-day mortality and any symptomatic intracerebral hemorrhage.

Results—

Seventy-nine patients were included: 48 were allocated to the CA group and 31 to the SR group. There were no significant differences between CA and SR groups in reperfusion after all endovascular procedures regarding mTICI 2b/3 (89.6% versus 83.9%;
P
=0.36), mTICI 2c/3 (54.2% versus 54.8%;
P
=0.90), and mTICI 3 (35.4% versus 41.9%;
P
=0.36) rates. There were no significant differences between CA and SR groups in 90-day modified Rankin Scale ≤2 rate (54.4% versus 50.0%;
P
=0.84), 24-hour change in National Institutes of Health Stroke Scale (mean difference, −3.9; 95% confidence interval, −7.9 to 0.01), and Alberta Stroke Program Early Computed Tomography score (mean difference, 0.9; 95% confidence interval, −0.1 to 2.0) scores. Safety parameters were well balanced between the 2 groups except for a higher 90-day mortality rate in the CA group (19.6% versus 3.3%;
P
=0.078).

Conclusions—

First-line mechanical thrombectomy with CA compared with SR did not result in an increased successful revascularization rate in patients with acute stroke with isolated M2 occlusion.
A comparison of tillage, direct drilling and lime on springtail communities in a long-term field trial in poland
Authors: Olejniczak Izabella , Lenart Stanisław
Published: December 2017

In 2009 and 2010, we examined the effects of different tillage systems on springtail communities. The study was established on the experimental field, in which tillage and no-tillage cultivation had been conducted since 1975, of the Research Station of the Warsaw University of Life Sciences’ Department of Agronomy, located at Chylice, near Warsaw (52005’N, 20033’E).

The treatments considered were conventional tillage with a mouldboard plough (CT) and no-tillage (NT), and each method was divided between with and without liming. In 2009, the fields were sown with winter wheat, and spring barley was planted the following year. During both growing seasons, collembolan densities were higher under NT than CT, but the reverse was true after harvest. However, the time of the season had a significant effect on collembolan densities not only over the whole study period but also in particular years. Additionally, in fields that were limed, collembolan densities varied, with no clear trend. The dominant collembolan species in the CT and NT fields was Isotoma viridis Bourlet, 1839, while Paristoma notabilis (Schäffer, 1896) was prevalent when liming was used. The relative proportion of each of the two species in springtail communities was at least 20 percent. The species diversity of collembolan communities was similar in both study years, and it was higher in CT than in NT fields.

The study was financially supported as part of the MNiSW project No. N N305171136.
Comparison of an InSb Detector and Upconversion Detector for Infrared Polarization Spectroscopy
Authors: Pedersen Rasmus L. , Hot Dina , Li Zongshan
Published: December 2017

This paper compares the signal-to-noise ratio obtained using an InSb photodiode for infrared (IR) polarization spectroscopy to that obtained using an upconversion detector, and shows a factor 64 improvement by the change. Upconversion detection is based on using sum frequency generation to move the IR optical signal to near-visible wavelengths to improve the sensitivity.
Fieldwork in Theban Tomb Kv 39: the 2002 Season
Authors: Buckley Ian M. , Buckley Peter , Cooke Ashley
Published: December 2017

This article describes the survey of KV 39 and the examination of tomb finds carried out in the spring of 2002. The Mission involved a detailed architectural survey and planning programme; the examination and sorting of pottery; continued sieving of the original excavators' outside dump, c. 1900; on-site studies of skeletal and organic material; and the analysis, recording and photography of new finds for publication.
La Conception Du Décor D'Un Temple Au Début Du Règne De Ramsès Ii: Analyse Du Deuxième Registre De La Moitiè Sud Du Mur Ouest De La Grande Salle Hypostyle De Karnak
Authors: Lurson Benoît
Published: December 2017

Before the second year of his reign, the imagemakers of Ramses II drew inspiration from those of Seti I, but from his second year onwards, they instigated a new conception of temple decoration. Were the two first years of Ramses II's reign simply a period of stagnation or rather, one of reflection, and of transition between two manners of conceiving the decoration of a temple? In an attempt to answer this question, the second register of the south half of the west wall of the Great Hypostyle Hall at Karnak is analysed. These scenes were carved around year 2 of Ramses II's reign, and reveal that this period was one of significant innovations in the field of temple iconography.
The Prohibitions: A New Kingdom Didactic Text
Authors: Hagen Fredrik
Published: December 2017

The article presents a little-known wisdom text of the New Kingdom attested on a handful of ostraca from Deir el-Medina. The text is interesting for its rare stichical structure, each line beginning with imi=k, ‘You should not…’, and for the thematically independent nature of the sentences. Included is the hieroglyphic text and a translation with a philological commentary, as well as a discussion of the text's place within the ancient Egyptian didactic literary tradition.
An Inscribed Linen Plea from the Sacred Animal Necropolis, North Saqqara
Authors: Ray John D.
Published: December 2017

Publication of a linen fragment bearing a plea in demotic to Osorapis, the presiding deity of the Saqqara Animal Necropolis, for justice in a legal case. It was discovered by the EES in the Main Temple Enclosure at Saqqara in 1968–9. Two pieces of wood reveal how it was attached to the shrine wall or gate/door frame. Characteristics of the early demotic suggest a date in the fourth century BC, perhaps the Thirtieth Dynasty or Macedonian Period. Comparable pleas and cursive texts on linen, and the link between linen and the hereafter, are discussed.
Pottery from the Spoil Heap in Front of the Tomb of Djehutihotep at Deir Al-Barsha
Authors: De Beeck Lies OP
Published: December 2017

When the Belgian mission started working at Deir al-Barsha in 2002 no pottery from the site had previously been published. The need for a reference collection motivated the clearance of the spoil heap in front of the well-known tomb of Djehutihotep. The present article deals with the pottery retrieved from that dump, which was probably left behind by an earlier excavator. Djehutihotep's tomb dates to the reign of Senwosret II-Senwosret III, a date consistent with the majority of the Middle Kingdom pottery fragments found in the spoil heap. Special remarks are made on the hemispherical cups, concerning their date as well as their occurrence. Several fragments of these cups showed traces of colour pigment. Although the corpus discussed is not large and the burial chamber of Djehutihotep only provides a terminus post quern, the material is important as it provides an overview of Middle Kingdom pottery from a site in a region where the pottery corpus is not well documented.
A Battered Statue of Shedsunefertem, High Priest of Memphis (BM EA 25)
Authors: Leahy Anthony
Published: December 2017

Publication of a kneeling naophorous statue in the British Museum (EA 25), now headless and much damaged. It has previously been recognised as belonging to an unidentified official, son of a high priest of Memphis called Ankhefensekhmet, and has been associated with an uninscribed head now in the Metropolitan Museum of Art, 66.99.64. Study of the fragmentary text shows that this son was the high priest of Memphis in the time of Sheshonq I, Shedsunefertem, for whom it records some unusual epithets. It is argued that the text is secondary and that the statue, which has a regal belt motif, was originally made for Khaemwese, son of Ramesses II. The hiatus in the production of statues during the Twenty-first Dynasty, and the extent of usurpation when interest in this medium revived at the start of the Twenty-second, are discussed, as are the implications for the Metropolitan Museum of Art head.
Priests of Soknebtunis and Sokonopis: P. BM EA 10647
Authors: Monson Andrew
Published: December 2017

The text edited here is a Demotic document from the Ptolemaic Period used for the administration of the temple of Soknebtunis in Tebtunis. It contains a list of the priests of Soknebtunis who were also serving as priests in the cult of Sokonopls. The document was probably given to the lesonis or ‘chief priest’ of Sokonopis who would be responsible for dividing temple revenue into offering-shares for the priests. The document provides the first evidence for the organization of the cult of the god Sokonopis in the Fayyum and shows that he shared the priesthood and probably the temple of the god Soknebtunis.
A Conservation History of the Ramesseum Papyri
Authors: Leach Bridget
Published: December 2017

In 2004 the British Museum instigated a project to re-evaluate fully the group of Thirteenth Dynasty papyri known as the Ramesseum Papyri, the majority of which are now housed in the Department of Ancient Egypt and Sudan at the Museum. This article records the treatment of the find from the time of discovery in 1896 until the present day. The materials and methods used to preserve the manuscripts are presented in the light of our current knowledge, in order to have a better understanding of their condition and evaluate future conservation. Examination and analysis, primarily based on work carried out at the British Museum since the 1980s, is reported. For reference purposes, a detailed list is given containing descriptions, known conservation treatments and the condition of each manuscript.
Angular Harps in the Amarna Period
Authors: Manniche Lise
Published: December 2017

Four additional representations of musicians playing the angular harp are added to the three Amarna Period examples previously identified by the author.
How Mr Anytime has gone Unnoticed—Every Time
Authors: Haring Ben
Published: December 2017

The name of the Necropolis workman Nw-nb of the early Nineteenth Dynasty has so far been misread by Deir el-Medina specialists, as is demonstrated by the following examination of several ostraca and shabtis.
Recent Identification of Greek Imports from Kom Firin
Authors: Smoláriková Květa
Published: December 2017

Discussion of Greek imported ceramics collected by the British Museum team during the 2005 field season at Kom Firin, an extensive settlement site in the Western Delta.i
Marsa Matruh: Two Iron Age Notes
Authors: Johnston Alan
Published: December 2017

A sherd previously ascribed to an Attic amphora type and dated to c. 700 BC is reascribed to a vessel type, possibly Laconian, from c. 600 BC. An enigmatic graffito on another fragment is discussed.
Acute Central Infusion of Leptin Modulates Fatty Acid Mobilization by Affecting Lipolysis and mRNA Expression for Uncoupling Proteins
Authors: Tajima Daisuke , Masaki Takayuki , Hidaka Shuji , Kakuma Tetsuya , Sakata Toshiie , Yoshimatsu Hironobu
Published: December 2017

Chronic administration of leptin has been shown to reduce adiposity through energy intake and expenditure. The present study alms to examine how acute central infusion of leptin regulates peripheral lipid metabolism, as assessed by markers indicative of their mobilization and utilization. A bolus infusion of 1 μg/rat leptin into the third cerebroventricle increased the expression of mRNA for hormone-sensitive lipase (HSL), an indicator of lipolysis, in white adipose tissue (WAT). This was accompanied by elevation of plasma levels of glycerol, but not of free fatty acids, as compared to the saline control (P < 0.03). The same treatment with leptin decreased plasma insulin levels but did not affect the plasma glucose level (P < 0.05 for insulin). Among the major regulators of the transportation or utilization of energy substrates, leptin treatment increased expression of mRNA for uncoupling protein 1 (UCP1) in brown adipose tissue (BAT), UCP2 in WAT, and UCP3 in quadriceps skeletal muscle, but not those for fatty acid–binding protein in WAT, carnitine phosphate transferase-1, a marker for β oxidation of fatty acids in muscle, nor glucose transporter 4 in WAT and muscle (P < 0.01 for HSL, P < 0.05 for UCP1, and P < 0.005 for UCP2 and UCP3). These results indicate that, even in a single bolus, leptin may regulate the mobilization and/or utilization of energy substrates such as fatty acids by affecting lipolytic activity in WAT and by increasing the expression of UCPs in BAT, WAT, and muscle.
Prognostic significance of cytogenetic heterogeneity in patients with newly diagnosed multiple myeloma
Authors: Merz Maximilian , Jauch Anna , Hielscher Thomas , Bochtler Tilmann , Schönland Stefan Olaf , Seckinger Anja , Hose Dirk , Bertsch Uta , Neben Kai , Raab Marc Steffen , Hillengass Jens , Salwender Hans , Blau Igor Wolfgang , Lindemann Hans-Walter , Schmidt-Wolf Ingo G. H. , Scheid Christof , Haenel Mathias , Weisel Katja C. , Goldschmidt Hartmut
Published: December 2017

Key Points

Clonal heterogeneity detected by iFISH is common in newly diagnosed MM. Treatment with bortezomib overcomes the negative impact of high-risk cytogenetic abnormalities if no further subclones are detected.
The clinical diagnosis of symptomatic forefoot neuroma in the general population: a Delphi consensus study
Authors: Dando Charlotte , Cherry Lindsey , Jones Lyndon , Bowen Catherine
Published: December 2017

Background

There is limited evidence for defining what specific method or methods should be used to clinically influence clinical decision making for forefoot neuroma. The aim of this study was to develop a clinical assessment protocol that has agreed expert consensus for the clinical diagnosis of forefoot neuroma.

Methods

A four‐round Delphi consensus study was completed with 16 expert health professionals from either a clinical or clinical academic background, following completion of a structured literature review. Clinical experience ranged from 5 to 34 years (mean: 19.5 years). Consensus was sought on the optimal methods to achieve the clinical diagnosis of forefoot neuroma. Round 1 sought individual input with an open ended question. This developed a list of recommendations. Round 2 and 3 asked the participants to accept or reject each of the recommendations in the list in relation to the question: “What is the best way to clinically diagnose neuroma in the forefoot?” Votes that were equal to or greater than 60% were accepted into the next round; participant's votes equal to or less then 20% were excluded. The remaining participant's votes between 20 to 60% were accepted and placed into the following round for voting. Round 4 asked the participants to rank the list of recommendations according to the strength of recommendation they would give in relation to the question: “What is the best way to clinically diagnose neuroma in the forefoot?” The recruitment and Delphi rounds were conducted through email.

Results

In round 1, the 16 participants identified 68 recommendations for the clinical diagnosis of forefoot neuroma. In round 2, 27 recommendations were accepted, 11 recommendations were rejected and 30 recommendations were assigned to be re‐voted on. In round 3, 36 recommendations were accepted, 22 recommendations were rejected and 11 recommendations were assigned to be re‐voted on. In round 4, 21 recommendations were selected by the participants to form the expert derived clinical assessment protocol for the clinical diagnosis of forefoot neuroma. From these 21 recommendations, a set of themes were established: location of pain, non weight bearing sensation, weight bearing sensation, observations, tests and imaging.

Conclusion

Following the identification of 21 method recommendations, a core set of clinical diagnostic methods have been prepared as a clinical assessment protocol for the diagnosis of forefoot neuroma. Based on expert opinion, the core set will assist clinicians in forming a clearer diagnosis of forefoot neuroma.
Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma
Authors: Robert Caroline , Ribas Antoni , Hamid Omid , Daud Adil , Wolchok Jedd D. , Joshua Anthony M. , Hwu Wen-Jen , Weber Jeffrey S. , Gangadhar Tara C. , Joseph Richard W. , Dronca Roxana , Patnaik Amita , Zarour Hassane , Kefford Richard , Hersey Peter , Zhang Jin , Anderson James , Diede Scott J. , Ebbinghaus Scot , Hodi F. Stephen
Published: December 2017

Purpose

Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827).

Patients and Methods

Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses.

Results

Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis.

Conclusion

Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.
Peripheral Endocannabinoids Associated With Energy Expenditure in Native Americans of Southwestern Heritage
Authors: Heinitz Sascha , Basolo Alessio , Piaggi Paolo , Piomelli Daniele , Jumpertz von Schwartzenberg Reiner , Krakoff Jonathan
Published: December 2017

Context

The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), as well as the related acylethanolamide oleoylethanolamide (OEA), have been implicated in energy expenditure (EE) regulation and metabolic diseases. Muscle (fat-free mass) and fat (fat mass) are metabolically active compartments and main determinants of EE.

Objective

To assess whether human muscle, adipose, and plasma endocannabinoids correlate with EE.

Design

Muscle, adipose, and plasma AEA, 2-AG, and OEA concentrations were measured via liquid chromatography–mass spectrometry. EE was assessed by indirect whole-room calorimetry.

Setting

Clinical trial.

Participants

Obese/overweight Native Americans of full (n = 35) and at least half (n = 21) Southwestern heritage.

Main Outcome Measures

Twenty-four-hour EE, sleeping EE (SLEEP), resting EE (REE), respiratory quotient (RQ), and macronutrient oxidation.

Results

In full Natives, muscle AEA concentration correlated with SLEEP (r = −0.65, P = 0.004) and REE (r = −0.53, P = 0.02). Muscle 2-AG was associated with SLEEP (r = −0.75, P = 0.0003). Adipose OEA concentration correlated with RQ (r = −0.47, P = 0.04) and lipid oxidation (r = 0.51, P = 0.03). Plasma OEA concentration was associated with SLEEP (r = −0.52, P = 0.04). After adjustment for major determinants, these lipids explained nearly 20% of the additional variance of the respective measure. Similarly, in Native Americans of at least half Southwestern heritage, investigated lipids correlated with EE measures.

Conclusion

Endocannabinoids in metabolically relevant peripheral tissues explained a large part of EE variation and may be involved in regulating EE. Dysregulation of peripheral endocannabinoids may predispose people to metabolic diseases via an effect on EE and lipid oxidation.
Progesterone-Mediated Inhibition of the GnRH Pulse Generator: Differential Sensitivity as a Function of Sleep Status
Authors: Kim Su Hee , Lundgren Jessica A , Bhabhra Ruchi , Collins Jessicah S , Patrie James T , Burt Solorzano Christine M , Marshall John C , McCartney Christopher R
Published: December 2017

Context

During normal, early puberty, luteinizing hormone (LH) pulse frequency is low while awake but increases during sleep. Mechanisms underlying such changes are unclear, but a small study in early pubertal girls suggested that differential wake-sleep sensitivity to progesterone negative feedback plays a role.

Objective

To test the hypothesis that progesterone acutely reduces waking LH pulse frequency more than sleep-associated pulse frequency in late pubertal girls.

Design

Randomized, placebo-controlled, double-blinded crossover study.

Setting

Academic clinical research unit.

Participants

Eleven normal, postmenarcheal girls, ages 12 to 15 years.

Intervention

Subjects completed two 18-hour admissions in separate menstrual cycles (cycle days 6 to 11). Frequent blood sampling for LH assessment was performed at 1800 to 1200 hours; sleep was encouraged at 2300 to 0700 hours. Either oral micronized progesterone (0.8 mg/kg/dose) or placebo was given at 0700, 1500, 2300, and 0700 hours, before and during the first admission. A second admission, performed at least 2 months later, was identical to the first except that placebo was exchanged for progesterone or vice versa (treatment crossover).

Main Outcome Measures

LH pulse frequency during waking and sleeping hours.

Results

Progesterone reduced waking LH pulse frequency by 26% (P = 0.019), with no change observed during sleep (P = 0.314). The interaction between treatment condition (progesterone vs placebo) and sleep status (wake vs sleep) was highly significant (P = 0.007).

Conclusions

In late pubertal girls, progesterone acutely reduced waking LH pulse frequency more than sleep-associated pulse frequency. Differential wake-sleep sensitivity to progesterone negative feedback may direct sleep-wake LH pulse frequency changes across puberty.
A 6-Year Follow-Up of Fracture Incidence and Volumetric Bone Mineral Density Development in Girls With Turner Syndrome
Authors: Soucek Ondrej , Schönau Eckhard , Lebl Jan , Willnecker Johannes , Hlavka Zdenek , Sumnik Zdenek
Published: December 2017

Context

Patients with Turner syndrome (TS) are at risk for osteoporotic fractures.

Objective

The aims of this study were to assess the incidence of clinically important fractures in girls with TS and prospectively describe the development of volumetric bone mineral density (BMD).

Design

Peripheral quantitative computerized tomography (pQCT) of the radius every other year over the 6 years of observation.

Setting

Government-funded university referral center.

Participants

Thirty-two girls with TS, aged 6 to 16 years, were included in the analyses. Fracture incidence was compared with the data in the general population. Bone density and strength were compared with data from 185 healthy girls.

Outcomes

The main clinical outcome was the fracture occurrence. The secondary outcomes were the changes in Z-scores of the bone parameters.

Results

Three girls with TS sustained four fractures during 6 years of observation. The fracture rate in TS was not substantially higher than the downward-biased fracture-rate estimate from age-matched, healthy controls (P = 0.48). Whereas the trabecular BMD Z-score decreased with age (β estimate −0.21 ± 0.04, P < 0.001), total bone cross-sectional area correspondingly increased (+0.16 ± 0.04, P < 0.001), which led to normal bone strength. A positive history of incident fractures was not significantly associated with any of the pQCT-derived bone parameters.

Conclusions

Current pediatric TS patients that are treated with growth hormone and estrogens are not at risk for osteoporotic fractures. Low BMD in TS may be counterweighted by enlarged bone radius, which leads to normal bone strength at the appendicular skeleton.
Embryonic Exposure to Dexamethasone Affects Nonneuronal Cells in the Adult Paraventricular Nucleus of the Hypothalamus
Authors: Frahm Krystle A , Handa Robert J , Tobet Stuart A
Published: December 2017

Neurons in the paraventricular nucleus of the hypothalamus (PVN) integrate peripheral signals and coordinate responses that maintain numerous homeostatic functions. An excess of glucocorticoids during fetal development results in long-lasting consequences tied to disrupted PVN development. The PVN contains a distinct neuronal population and a threefold greater vascular density than the surrounding brain regions that prepubertally is reduced in offspring exposed to excess glucocorticoids in utero. This study expands the examination of sex-specific nonneuronal PVN composition by examining astrocytes, astrocytic endfeet, and pericytes. Blood-brain barrier (BBB) competency and composition were examined along with depressive-like behavior and hypothalamic-pituitary-adrenal function in male and female mice. For PVN vasculature, female offspring of vehicle (veh)-treated mothers had significantly more astrocytes and pericytes than male offspring from the same litters. Female offspring from dexamethasone (dex)-treated mothers had significantly lower levels of astrocytes than female offspring from veh-treated mothers, whereas male offspring from dex-treated mothers had greater levels of pericytes compared with veh-treated male offspring. Using the tail-suspension test, male and female offspring from dex-treated mothers had significantly shorter latencies to immobility, indicating an increase in depression-like behavior, and showed greater plasma corticosterone after restraint stress, which was significantly greater in female offspring from dex-treated mothers even after recovery. Therefore, in addition to long-term sex differences in cellular components of the BBB in the PVN that were differentially regulated by fetal glucocorticoid exposure, there were behavioral differences observed into early adulthood in a sex-specific manner.
Clinical Utility of Intraoperative Motor-Evoked Potential Monitoring to Prevent Postoperative Spinal Cord Injury in Thoracic and Thoracoabdominal Aneurysm Repair: An Audit of the Japanese Association of Spinal Cord Protection in Aortic Surgery Database
Authors: Yoshitani Kenji , Masui Kenichi , Kawaguchi Masahiko , Kawamata Mikito , Kakinohana Manabu , Kato Shinya , Hasuwa Kyoko , Yamakage Michiaki , Yoshikawa Yusuke , Nishiwaki Kimitoshi , Aoyama Tadashi , Inagaki Yoshimi , Yamasaki Kazumasa , Matsumoto Mishiya , Ishida Kazuyoshi , Yamashita Atsuo , Seo Katsuhiro , Kakumoto Shinichi , Hayashi Hironobu , Tanaka Yuu , Tanaka Satoshi , Ishida Takashi , Uchino Hiroyuki , Kakinuma Takayasu , Yamada Yoshitsugu , Mori Yoshiteru , Izumi Shunsuke , Nishimura Kunihiro , Nakai Michikazu , Ohnishi Yoshihiko
Published: December 2017

BACKGROUND:

Spinal cord ischemic injury is the most devastating sequela of descending and thoracoabdominal aortic surgery. Motor-evoked potentials (MEPs) have been used to intraoperatively assess motor tract function, but it remains unclear whether MEP monitoring can decrease the incidence of postoperative motor deficits. Therefore, we reviewed multicenter medical records of patients who had undergone descending and thoracoabdominal aortic repair (both open surgery and endovascular repair) to assess the association of MEP monitoring with postoperative motor deficits.

METHODS:

Patients included in the study underwent descending or thoracoabdominal aortic repair at 12 hospitals belonging to the Japanese Association of Spinal Cord Protection in Aortic Surgery between 2000 and 2013. Using multivariable mixed-effects logistic regression analysis, we investigated whether intraoperative MEP monitoring was associated with postoperative motor deficits at discharge after open and endovascular aortic repair.

RESULTS:

We reviewed data from 1214 patients (open surgery, 601 [49.5%]; endovascular repair, 613 [50.5%]). MEP monitoring was performed in 631 patients and not performed in the remaining 583 patients. Postoperative motor deficits were observed in 75 (6.2%) patients at discharge. Multivariable logistic regression analysis revealed that postoperative motor deficits at discharge did not have a significant association with MEP monitoring (adjusted odds ratio [OR], 1.13; 95% confidence interval [CI], 0.69–1.88; P = .624), but with other factors: history of neural deficits (adjusted OR, 6.08; 95% CI, 3.10–11.91; P < .001), spinal drainage (adjusted OR, 2.14; 95% CI, 1.32–3.47; P = .002), and endovascular procedure (adjusted OR, 0.45; 95% CI, 0.27–0.76; P = .003). The sensitivity and specificity of MEP <25% of control value for motor deficits at discharge were 37.8% (95% CI, 26.5%–49.5%) and 95.5% (95% CI, 94.7%–96.4%), respectively.

CONCLUSIONS:

MEP monitoring was not significantly associated with motor deficits at discharge.