bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurosurgical delivery of the poly ADP ribose polymerase-1 inhibitor olaparib from a thermo-responsive biodegradable paste potentiates radiotherapy and prolongs survival
Authors: Smith Stuart , Serra Riccardo , Rowlinson Jonathan , Gorelick Noah , Veal Gareth , Shakesheff Kevin , Brem Henry , Grundy Richard , Tyler Betty , Rahman Ruman
Published: October 2019

There has been considerable interest in repurposing the poly ADP ribose polymerase inhibitor and purported radiosensitiser olaparib (Lynparza), with a recent dose escalation study of olaparib plus temozolomide in recurrent GBM showing good tolerance. Due to systemic therapy-associated caveats such as dose-limiting toxicities and blood-brain-barrier penetration, here we assess localised post-surgical delivery of olaparib from our previously developed PLGA/PEG thermo-sensitive biodegradable paste.

Metabolic and clonogenic assays revealed impaired proliferation and clonal growth respectively, upon acute exposure of high-grade glioma cells to olaparib (3–5µM), an effect dramatically potentiated with 3Gy radiation. Flow cytometry of Annexin V+/Propidium iodide+ rodent and human high-grade glioma cells, revealed a significant cell proportion increase at late stage apoptosis when exposed to 2–3µM olaparib and 3Gy radiation (relative to untreated, olaparib alone or radiation alone).

A high-grade glioma orthotopic allograft study is ongoing where we already observe a significant overall survival benefit of locally-delivered 10% and 20% w/w (drug:polymer ratio) olaparib via PLGA/PEG paste post-surgery with adjuvant radiotherapy, compared to surgery/oral temozolomide/radiotherapy (GBM standard-of-care) and surgery/systemic olaparib (50 days vs. 44 vs 30 respectively). A more pronounced survival benefit was observed with combined PLGA/PEG/olaparib/temozolomide/radiotherapy or PLGA/PEG/olaparib/etoposide/radiotherapy.

RNAseq data from 10 GBM patients show significantly elevated levels of apoptosis-inducing factor-1 in 5-aminolevulinic acid (5ALA)+ fluorescence–activated cell sorted populations (i.e. purified tumour cells from the invasive margin), relative to 5ALA- cells, confirming PARP-1 activity in infiltrative tumour cells. Collectively our data supports a clinical rationale for localised olaparib delivery with adjuvant radiotherapy.
Neurocognition and quality of life in patients with intracranial metastases – contributing factors and impact on clinical outcome
Authors: Iqbal Najmus , Daisley-Devoy Tara , Smalley Michelle , Johnson Anne , Staffurth John , Wise Richard , Powell James
Published: October 2019

Cognitive impairment at diagnosis is prevalent in patients with brain metastases (BM). Neurocognitive function (NCF) decline following radiotherapy is well described in this patient cohort, but the impact of baseline NCF on clinical outcome and survival is less well understood. In this study we describe NCF in patients at baseline before undergoing stereotactic radiosurgery without whole brain radiotherapy and explore its impact on overall survival and explore possible causative factors.

Baseline NCF data was collected in patients with 1–3 BM and WHO performance status 0–2. Patients underwent NCF assessments according to the RANO group and included Hopkin’s verbal learning test, controlled oral word association test, trail making test A and B and digit span. We collected quality of life (QoL) data using EORTC QLQ30/BN20 questionnaires and recorded functional assessment of cancer therapy scores.

31 patients underwent neurocognitive testing with mean age of 65 years and median overall survival was 10 months. 21 patients had a single metastasis. The most common primary site was lung (12) followed by melanoma (7). 64% of patients exhibited impaired NCF at baseline in at least 1 domain with a Z-score of >1 and this was associated with lower overall survival. Other factors associated with lower overall survival were presence of seizures, steroid use and larger tumour volume.

In this study impaired NCF at baseline was associated with lower overall survival. Intracranial disease burden and the presence of seizures were also associated with worse NCF and worse survival indicating that these may be important causative factors to consider.
Determination of meningioma brain tissue grades using Raman hyperspectral imaging
Authors: De Lelis Medeiros De Morais Camilo , Lilo Taha , Ashton Katherine , Davis Charles , Dawson Timothy , Gurusinghe Nihal , Martin Francis
Published: October 2019

Raman spectroscopy is a powerful tool used to analyse biological materials, where spectral biomarkers such as proteins (1500–1700 cm-1), carbohydrates (470–1200 cm-1) and phosphate groups of DNA (980, 1080–1240 cm-1) can be detected. A major advantage is that it is reagent-free and unaffected by water interference, which is ideal for biological applications. Raman hyperspectral imaging combines the chemical sensitivity of this spectrochemical technique with spatially distributed information. Herein, Raman microspectroscopy imaging (50 × 50 μm tissue area, 50× magnification, 50% laser power, 0.1 ms exposure time, 780–1858 cm-1 spectral range) was used to investigate 79 brain tissue samples (sourced from the Brain Tumour North West) in order to differentiate meningioma Grade I (n=55) versus Grade II (n=24). Meningioma is the commonest type of brain tumour with the majority of them being benign tumours (Grade I) whilst a few are aggressive or malignant (Grade II). Grade II tumours have a poor prognosis by their nature, hence new sensitive diagnostic tools are essential. Using partial least squares discriminant analysis (PLS-DA) with 20 LVs (99% explained variance), we were able to differentiate Grade I versus Grade II meningioma with a classification accuracy of 99% in an internal validation set of 23 samples (16 Grade I, seven Grade II); this was with an accuracy of 85% for an external test set of similar size. These findings highlight the potential of Raman hyperspectral imaging for differentiation of meningioma tumours.
A pilot study to establish non-invasive biomarkers for higher-grade meningioma
Authors: Baiz Daniele , Negroni Caterina , Ercolano Emanuela , L Adams Claire , Kurian Kathreena M , A Hilton David , Hanemann Oliver C
Published: October 2019

Introduction

Meningioma brain tumours are the most common primary tumour in adults. Despite surgery and/or radiation therapy, meningioma may recur. The 5-year recurrence rate in benign meningioma is estimated in about 10% while much greater in atypical and malignant tumours. MicroRNAs (miRNAs) represent a large class of small RNAs driving regulation of gene expression and playing a role in tumour progression and therefore proposed as diagnostic tools. Moreover, miRNAs can be released from tumour cells into the blood stream via exosomes, showing potential to be used as liquid biopsies.

Methods

Identification of novel circulating biomarkers was conducted by performing an unbiased Cancer MicroRNA qPCR Array, followed by bioinformatics analysis. In parallel, we conducted a biased in silico analysis of the miRNAs targeting Cyclin D1 and E1, recently proposed as immunohistochemical meningioma biomarkers. Validation studies performed using TaqMan® reagents.

Results

Stringent unbiased (p<0.01) miRNA profiling followed by validation in ex vivo samples revealed that the miR-9-1 is upregulated in higher-grade meningioma tissues and serum exosomes, controlled by the EGFR/AP-1 axis and correlated with lower levels of E-Cadherin, a proposed biomarker for malignant meningioma. On the contrary, biased analysis, followed by validation in vitro and ex vivo, showed that the miR-497~195 cluster is downregulated in higher-grade meningioma tissues and serum exosomes, correlating with the overexpression of GATA-4, a novel meningioma tissue biomarker.

Conclusion

Our data demonstrated that both miR-497~195 and miR-9-1 show potential to become promising non-invasive biomarkers for higher-grade meningioma, reflecting their expression status in tissues.

(DB and CN contributed equally).
Patient engagement in the design of a randomised trial of proton beam radiotherapy versus photon radiotherapy for good prognosis glioma
Authors: Powell James R , Murray Louise , Burnet Neil , Fernandez Sharon , McParland Lucy , O’Hara Daniel , Lingard Zoe , Whitfield Gillian , Short Susan C
Published: October 2019

Introduction

UK Neuro-Oncologists and multidisciplinary colleagues are developing one of the first randomised clinical trials of proton beam radiotherapy(PBT) to compare quality of life(QOL), cognitive function and other late effects in adults with good prognosis glioma following either PBT or photon radiotherapy. The feasibility of running randomised studies with PBT is an important consideration, particularly in respect of participants’ views of a randomised design requiring treatment at national centres. We sought patient and carer engagement on our proposals to ensure we incorporate their views.

Methods

To explore these issues, we invited patients who had previously completed radiotherapy for oligodendroglioma and their carers to attend a focus group in Manchester in November 2018. Fifteen participants attended. We sought views on our trial proposal through small group discussions centred around 5 questions, led and facilitated by neuro-oncologists, a research radiographer, neuro-psychologist and statistician.

Results

Participants strongly endorsed the trial proposal and positively highlighted the opportunity to access PBT within a clinical trial and the group recognised and supported the need for randomisation and stated this should be 1:1. Patients disliked some traditional terminology such as ‘trial’ and ‘neurocognitive tests’ and preferred ‘research study’ and ‘neurocognitive assessments’. Patient and carers expressed the need for careful consideration of issues around travel and accommodation during PBT away from home. Interestingly, participants considered that standard QOL questionnaires fail to address some important areas reflecting daily wellbeing.

Conclusion

We acknowledge and will now incorporate these important patient and carer observations to strengthen our study and add validity to the key study endpoints.
The Collagen-Prolyl Hydroxylases promote proliferation and invasion in GBM
Authors: Castellano Elena , Atkinson Aithne , O’Neill Kevin , Syed Nelofer
Published: October 2019

Glioblastoma Multiforme (GBM) is the most aggressive form of brain tumour, with a median survival time of just 14 months. Current standard therapy includes surgical excision, followed by chemotherapy and radiotherapy, however complete surgical excision is not usually possible due to the diffuse and infiltrative nature of the disease. To combat this, therapies inhibiting the invasion of leader migratory cells are an attractive area of research. The collagen prolyl-4 hydroxylases (C-P4Hs) are a family of proteins which catalyse the hydroxylation of proline residues on pre-pro-collagen, leading to the formation of the stable triple-helical structure of functional collagen. Collagen is a highly abundant protein, and important in several oncogenic cellular processes including proliferation, invasion and migration. We hypothesis that by inhibiting the C-P4Hs, the pro-tumorigenic effect of collagen will be inhibited in GBM. To explore this, we treated cells with ethyl 3,4-dihydroxybenzoate (EDHB) (a C-P4H inhibitor) and observed the resultant effect in GBM cells lines and primary cells through proliferation assays and 3D tumour spheroid invasion assays. Our results indicate that the addition of EDHB significantly reduces proliferation and invasion in both cell lines and primary GBM samples. Furthermore, we show that the C-P4Hs are upregulated in hypoxic conditions, which are commonly found in the clinical tumour microenvironment. Our study reveals that the C-P4H proteins may be an attractive therapeutic target to reduce invasion and proliferation and may be especially attractive as adjuvants with a cytotoxic agent such as temozolomide.
Real-world experience with Temozolomide & Sativex in patients with recurrent High Grade Gliomas
Authors: Shahabi Lillie , Le Calvez Kerlann , Dadhania Seema , Blake Catherine , Wang James , Ingle Manasi , Anichini Giulio , Peterson David , Nandi Dipankar , Camp Sophie , Saleem Waqar , Falconer Alison , O’Neill Kevin , Williams Matt
Published: October 2019

Background

Glioblastoma (GBM) is the most common malignant brain tumour in adults with a median survival from progression of 8 months. A recent phase 1 study of temozolomide (TMZ) and 1:1 CBD:THC (Sativex) offers evidence of efficacy in patients with recurrent GBM (NCT01812603).

Methods

All patients receiving TMZ & Sativex (75mg/m2 daily d1 – 21 q28; Sativex continuously) for relapsed GBM or grade 3 astrocytoma at our centre were identified. Patient, tumor and treatment characteristics were recorded, and response based on sequential MRI scans using modified RANO criteria assessed.

Results

13 patients were treated over 18 months. The median age was 56; 69% were male. All had received initial chemo-radiotherapy (12 patients: 60 or 59.4Gy/30–33#; 1 patient: 45Gy/15#). 6 patients underwent reresection at recurrence. 4 patients were treated at first progression, 7 at second progression, and 2 at third or later progression. The median number of cycles of TMZ and sativex was 2. The combination treatment was tolerated well by all patients treated, with no Grade 3 or 4 toxicities, the only complaints being of discomfort in mouth after spray and ‘spaced out feeling’. Patients stopped treatment due to evidence of progressive disease on sequential MRI sign or physical deterioration. Median Overall Survival (OS) from initiation was 5.9 months (177 days); Progression Free Surival (PFS) at 3 months was 50%.

Conclusion

These results highlight some discrepancies in OS in comparison to the previous trial (NCT01812603), but our patients were treated at second/ third recurrence. We agree that the combination is well tolerated.
Effectiveness of BRAF inhibitors in patients with BRAF V600 mutation positive glioma: a systematic review
Authors: Yao Ian , Dawson Sarah , Higgins Julian , McGuinness Luke , McAleenan Alexandra , Kurian Kathreena M
Published: October 2019

Background

BRAF inhibitor treatment with vemurafenib and dabrafenib have produced significant increases in median overall survival for BRAF V600 mutation-positive melanoma patients and are in wide clinical use. BRAF inhibitors have also been used in an ad hoc fashion in BRAF V600 mutation-positive glioma in a number of glioma subtypes with varying prognoses.

Methods

An electronic search was performed on MEDLINE and Embase on February 1, 2019 to identify studies of any design that reported the outcome of patients with BRAF V600 mutation-positive glioma treated with BRAF inhibitors. Data was collected for demographic information, tumour information (type and grading), BRAF mutation type, prior treatment regimens, type of BRAF inhibitor, dose and duration of treatment, best objective response, progression free survival (PFS), overall survival (OS), glioma specific symptomatic relief and adverse events.

Preliminary Results

Seventy-nine case reports, case series and single arm cohort studies with a total of 286 patients were included. Duration of treatment was available for 197 patients and varied from 0.1 to 54 months, with 104 patients still undergoing treatment at the time of publication. Progression occurred in 158 patients (including both low-grade and high-grade glioma) at between 0.805 and 36 months following the start of treatment. 34 people died, at between 0.329 and 40.1 months following the start of treatment.

Conclusions

Our systematic review shows varying clinical effectiveness of BRAF inhibitors in BRAF V600 mutation-positive glioma depending on low-grade or high-grade glioma. This evidence may inform future trials of BRAF inhibitors for glioma patients.
Management and outcomes of meningiomas secondary to childhood and adolescent radiation treatment
Authors: Gillespie Conor , Islim Abdurrahman , Kumar Siddhant , Rathi Nitika , Gilkes Catherine , Chavredakis Emmanuel , Lawson David , Mills Samantha , Brodbelt Andrew , Jenkinson Michael
Published: October 2019

Background

With the increased rate of childhood cancer survivors, a marked rise in the incidence of secondary intracranial meningiomas has been established.

Objective

Determine the outcomes of patients diagnosed with radiation-induced meningiomas (RIM).

Methods

Single-centre retrospective cohort study of patients with new or recurrent RIM (2007–2018).

Results

47 patients were identified (21 females). Mean age at radiation was 15 years (SD=14) and the most common indications were leukaemia (n=8) and childhood brain tumours (n=35; medulloblastoma and pilocytic astrocytoma (n=7 each)). 93 de-novo meningiomas were identified. The median latency period between radiation and diagnosis was 28.5 years (IQR 22–37). 61% were asymptomatic whilst the remainder manifested headache (20%), focal neurological deficit (12%) and epilepsy (5%). 32 operated de-novo RIM revealed WHO grade I (n=19; 59%), WHO grade II (n=11; 34%) and 2 intraosseous meningiomas (n=2; 6%). After a median of 5 years (IQR 3–10), 9 (28%) operated RIM recurred/progressed. At recurrence, 5 were operated (3 WHO grade I, 2 WHO grade II and 1 WHO grade III), 2 patients were palliated and 2 remain under active observation. By the end of the study period, 20 patients were harbouring multiple meningiomas and 8 patients were deceased.

Conclusion

Radiation-induced meningioma should be monitored until symptomatic. Operated RIMs have a high recurrence rate. Further radiotherapy is not effective. Further clinical and genetic analyses as part of an international multi-centre collaboration are planned.
A Bioinformatics Approach to Establishing Novel Transforming Growth Factor-Beta Target Genes in Glioblastoma.
Authors: Willison Alice , Taylor Richard , Hossain-Ibrahim Kismet , Inman Gareth
Published: October 2019

Introduction

TGFβ inhibition is becoming an increasingly exciting prospect for the treatment of glioblastoma (GBM) as more about its efficacy is understood. However, there is little demonstrated improvement in patient outcomes from clinical trials using small molecule inhibitors of the TGFβ receptors. Clearly, the potential of TGFβ therapy has not yet been realised. We scrutinised the TGFβ canonical genes at a cytogenetic, genetic and gene expression level for novel therapeutic targets.

Materials and Methods

10 canonical TGFβ genes were analysed. Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature and graphics generated using the Cytogenetic Data Analysis System. Analysis and generation of graphics were carried out using The Cancer Genome Atlas (TCGA) Provisional Glioblastoma set of 290 whole-exome-sequenced tumours via cBioPortal. mRNA expression data were extracted from The Cancer Genome Atlas (TCGA) via cBioPortal. Kaplan-Meier graphs were generated using GraphPad Prism®, for which pairwise log rank comparisons were conducted to determine a difference in both overall survival (OS) and disease-free, progression-free (DFPF) survival.

Results

At cytogenetic and genetic levels, TGFβ genes are not markedly altered in GBM. However, mRNA expression of TGFβ2 is enhanced in GBM compared to other cancers. In addition, we correlated upregulation of both SMAD7 and SARA with improved OS and upregulation of SARA with improved DFPF survival.

Conclusions

TGFβ2 upregulation may be associated with GBM tumourigenesis and SMAD7 and SARA upregulation may be associated with improved survival. We demonstrate that three canonical genes have therapeutic potential, but their conflicting roles must be further understood before TGFβ-modulating therapies are successful.
Mass production of 2D materials by intermediate-assisted grinding exfoliation
Authors: Zhang Chi , Tan Junyang , Pan Yikun , Cai Xingke , Zou Xiaolong , Cheng Hui-Ming , Liu Bilu
Published: October 2019

The scalable and high-efficiency production of 2D materials is a prerequisite to their commercial use. Currently, only graphene and graphene oxide can be produced on a ton scale, and the inability to produce other 2D materials on such a large scale hinders their technological applications. Here we report a grinding exfoliation method that uses micro-particles as force intermediates to resolve applied compressive forces into a multitude of small shear forces, inducing the highly efficient exfoliation of layer materials. The method, referred to as intermediate-assisted grinding exfoliation (iMAGE), can be used for the large-scale production of many 2D materials. As an example, we have exfoliated bulk h-BN into 2D h-BN with large flake sizes, high quality and structural integrity, with a high exfoliation yield of 67%, a high production rate of 0.3 g h−1 and a low energy consumption of 3.01 × 106 J g−1. The production rate and energy consumption are one to two orders of magnitude better than previous results. Besides h-BN, this iMAGE technology has been used to exfoliate various layer materials such as graphite, black phosphorus, transition metal dichalcogenides, and metal oxides, proving its universality. Molybdenite concentrate, a natural low-cost and abundant mineral, was used as a demo for the large-scale exfoliation production of 2D MoS2 flakes. Our work indicates the huge potential of the iMAGE method to produce large amounts of various 2D materials, which paves the way for their commercial application.
Risk Factors for BI/NAP1/027 Clostridioides difficile Infections and Clinical Outcomes Compared With Non-NAP1 Strains
Authors: Mani Nandita S , Lynch John B , Fang Ferric C , Chan Jeannie D
Published: October 2019

We aim to describe the characteristics, risk factors, and clinical outcomes associated with NAP1 strain Clostridioides difficile infection (CDI) in this single-center, retrospective, case–control (1:1) study. We found that the NAP1 strain accounted for 19.7% of CDI, and risk factors for acquisition included residence in skilled nursing facilities, previous CDI, and proton pump inhibitor use.
Mini-Open Lateral Corpectomy for Thoracolumbar Junction Lesions
Authors: Huangxs Shengbin , Christiansen Peter A , Tan Haitao , Smith Justin S , Shaffrey Mark E , Uribe Juan S , Shaffrey Christopher I , Yen Chun-Po
Published: October 2019

BACKGROUND

Neoplastic, traumatic, infectious, and degenerative pathologies affecting the thoracolumbar junction pose a unique challenge to spine surgeons. Posterior or anterior approaches have traditionally been utilized to treat these lesions. Although minimally invasive surgeries through a lateral approach to the thoracic or lumbar spine have gained popularity, lateral access to the thoracolumbar junction remains technically challenging due to the overlying diaphragm positioned at the interface of the peritoneum and pleura.

OBJECTIVE

To describe a mini-open lateral retropleural retroperitoneal approach for pathologies with spinal cord/cauda equina compression at the thoracolumbar junction.

METHODS

A mini-open lateral corpectomy is described in detail in a patient with an L1 metastatic tumor.

RESULTS

Satisfactory decompression and spinal column reconstruction were achieved. The patient obtained neural function recovery following the procedure with no intra- or postoperative complications.

CONCLUSION

The morbidities associated with traditional posterior or anterior approaches to thoracolumbar junction pathologies have led to a growing interest in minimally invasive alternatives. The mini-open lateral approach allows for a safe and efficacious corpectomy and reconstruction for thoracolumbar junction pathologies. Thorough understanding of the anatomy, particularly of the diaphragm, is critical. This approach will have expanded roles in the management of patients with thoracolumbar neoplasms, fractures, infections, deformities, or degenerative diseases.
Tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex
Authors: Koo Chek Ziu , Harrison Neale , Noy Peter J. , Szyroka Justyna , Matthews Alexandra L. , Hsia Hung-En , Mueller Stephan A. , Tüshaus Johanna , Goulding Joelle , Willis Katie , Apicella Clara , Cragoe Bethany , Davis Edward , Keles Murat , Malinova Antonia , McFarlane Thomas A. , Morrison Philip R. , Sykes Michael C. , Ahmed Haroon , Di Maio Alessandro , Seipold Lisa , Saftig Paul , Cull Eleanor , Rubinstein Eric , Poulter Natalie S. , Briddon Stephen J. , Holliday Nicholas D. , Lichtenthaler Stefan F. , Tomlinson Michael G.
Published: October 2019

A disintegrin and metalloprotease 10 (ADAM10) is essential for embryonic development and impacts on diseases such as cancer, Alzheimer’s and inflammatory diseases. ADAM10 is a ‘molecular scissor’ that proteolytically cleaves the extracellular region from over 100 substrates, including Notch, amyloid precursor protein, cadherins, growth factors and chemokines. ADAM10 was recently proposed to function as six distinct scissors with different substrates, depending on its association with one of six regulatory tetraspanins, termed TspanC8s. However, it remains unclear to what degree ADAM10 function is critically dependent on a TspanC8 partner. To address this, we generated the first monoclonal antibodies to Tspan15 as a model TspanC8. These were used to show that ADAM10 is the principal Tspan15-interacting protein, that Tspan15 expression requires ADAM10 in cell lines and primary cells, and that a synthetic ADAM10/Tspan15 fusion protein is a functional scissor. Together these findings suggest that ADAM10 exists as an intimate ADAM10/TspanC8 scissor complex.
Mechanisms of Synchrony in Heterogeneous Inhibitory Interneuronal Networks for Type 1 versus Type 2 Excitability
Authors: Tikidji-Hamburyan Ruben A. , Canavier Carmen C.
Published: October 2019

PV+ fast spiking basket interneurons are often implicated in gamma rhythms. Here we focus on mechanisms present in purely inhibitory networks. Neurons with type 1 excitability can fire arbitrarily slowly, whereas those with type 2 excitability cannot fire below a minimum frequency. We systematically examine how excitability type affects synchronization of individual spikes to a population rhythm in the presence of heterogeneity and noise, using model neurons of each type with matched F/I curve, input resistance, time constant and action potential shape. Population synchrony in noisy heterogeneous networks is maintained because neurons either fire within a tight time window or skip that cycle. Type 2 neurons with hyperpolarizing inhibition skip cycles due to their intrinsic dynamics; we show here the cycle skipping mechanism for type 1 neurons or type 2 neurons with shunting inhibition is synaptic and not intrinsic. Type 2 neurons are more resistant than type 1 to partial and complete suppression in networks with hyperpolarizing inhibition that exhibit network gamma. Moreover, type 2 neurons are recruited more rapidly and more completely into theta-nested gamma. In contrast, type 1 networks perform better with shunting inhibition on both counts, because the nonlinear dynamics in that case favor suppression of type 2 compared to type 1 neurons. Conductances that control excitability type may provide a therapeutic target to improve spatial and working memory and other tasks that rely on gamma synchrony or phase amplitude coupling.

Author Summary

The collective, synchronized activity of neurons produces brain rhythms. These rhythms are thought to subserve cognitive functions such as attention and memory encoding and retrieval. Faster rhythms are nested in slower rhythms as a putative way of chunking information. A subset of neurons called fast spiking basket cells tend to inhibit other neurons from firing. These neurons play an important role in oscillations, and in the coupling of faster oscillations to slower ones. In some brain regions these neurons can fire arbitrarily slowly (type 1 dynamics) whereas in others they cannot fire below a minimum cutoff frequency (type 2 dynamics). Mathematically, these distinct origins of rhythmic firing are signatures of very different dynamics. Here, we show that these distinct excitability types affect the ability of networks of these neurons to synchronize their fast oscillatory activity, as well as the ability of slower oscillations to modulate these fast oscillations. The exact nature of the inhibitory coupling, which may vary between brain regions, determines which type synchronizes better and is modulated better.
The C. elegans homolog of the Evi1 proto-oncogene, egl-43, coordinates G1 cell cycle arrest with pro-invasive gene expression during anchor cell invasion
Authors: Deng Ting , Daube Michael , Hajnal Alex , Lattmann Evelyn
Published: October 2019

Cell invasion allows cells to migrate across compartment boundaries formed by basement membranes. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells.

Anchor cell (AC) invasion in C. elegans is an excellent in vivo model to study the regulation of cell invasion during development. Here, we have examined the function of egl-43, the homolog of the human Evi1 proto-oncogene (also called MECOM), in the invading AC. egl-43 plays a dual role in this process, firstly by imposing a G1 cell cycle arrest to prevent AC proliferation, and secondly, by activating pro-invasive gene expression. We have identified the AP-1 transcription factor fos-1 and the Notch homolog lin-12 as critical egl-43 targets. A positive feedback loop between fos-1 and egl-43 induces pro-invasive gene expression in the AC, while repression of lin-12 Notch expression by egl-43 ensures the G1 cell cycle arrest necessary for invasion. Reducing lin-12 levels in egl-43 depleted animals restored the G1 arrest, while hyperactivation of lin-12 signaling in the differentiated AC was sufficient to induce proliferation.

Taken together, our data have identified egl-43 Evi1 as a critical factor coordinating cell invasion with cell cycle arrest.

Author summary

Cells invasion is a fundamental biological process that allows cells to cross compartment boundaries and migrate to new locations. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells.

We have investigated how a specialized cell in the Nematode C. elegans, the so-called anchor cell, can invade into an adjacent epithelium. Our work has identified an oncogenic transcription factor that controls the expression of specific target genes necessary for cell invasion, and at the same time inhibits the proliferation of the invading anchor cell.

These findings shed light on the mechanisms, by which cells decide whether to proliferate or invade.
Duplication and divergence of the retrovirus restriction geneFv1inMus carolimice allows protection from multiple retroviruses
Authors: Yap Melvyn W. , Young George R. , Varnaite Renata , Morand Serge , Stoye Jonathan P.
Published: October 2019

Viruses and their hosts are locked in an evolutionary race where resistance to infection is acquired by the hosts while viruses develop strategies to circumvent these host defenses. Forming one arm of the host defense armory are cell autonomous restriction factors like Fv1. Originally described as protecting laboratory mice from infection by murine leukemia virus (MLV), Fv1s from some wild mice have also been found to restrict non-MLV retroviruses, suggesting an important role in the protection against viruses in nature. To begin to understand how restriction factors evolve, we surveyed theFv1genes of wild mice trapped in Thailand and characterized their restriction activities against a panel of retroviruses. An extra copy of theFv1gene, named Fv7, was found on chromosome 6 of three closely related Asian species of mice (Mus caroli,M. cervicolorandM. cookii). The presence of flanking repeats suggested it arose by LINE-mediated retrotransposition. A high degree of natural variation was observed in bothFv1andFv7, including numerous single nucleotide polymorphisms resulting in altered amino acids, as well as insertions and deletions that changed the length of the reading frames. These genes exhibited a range of restriction phenotypes with activities directed against feline foamy virus (FFV), equine infectious anemia virus (EIAV) and MLV. It seems likely, at least in the case ofM. caroli, that the observed gene duplication confers protection against multiple viruses not possible with a single restriction factor. We suggest that EIAV-, FFV- and MLV-like viruses are endemic within these populations, driving the evolution of theFv1andFv7genes.

Author Summary

During the passage of time all vertebrates will be exposed to infection by a variety of different kinds of virus. To meet this threat, a variety of genes for natural resistance to viral infection have evolved. The prototype of such so-called restriction factors is encoded by the mouseFv1gene, which acts to block the life cycle of retroviruses at a stage between virus entry into the cell and integration of the viral genetic material into the nuclear DNA. We have studied the evolution of this gene in certain species of wild mice from South East Asia and describe an example where a duplication of theFv1gene has taken place. The two copies of the gene, initially identical, have evolved separately allowing the development of resistance to two rather different kinds of retroviruses, lentiviruses and spumaviruses. Independent selection for resistance to these two kinds of retrovirus suggests that such mice are repeatedly exposed to never-before-reported pathogenic retroviruses of these genera.
Novel biallelic variants in MSTO1 associated with mitochondrial myopathy
Authors: Schultz-Rogers Laura , Ferrer Alejandro , Dsouza Nikita R. , Zimmermann Michael T. , Smith Benn E. , Klee Eric W. , Dhamija Radhika
Published: October 2019

Mitochondrial disorders are caused by nuclear and mitochondrial pathogenic variants leading to defects in mitochondrial function and cellular respiration. Recently, the nuclear-encoded mitochondrial fusion gene MSTO1 (Misato 1) has been implicated in mitochondrial myopathy and ataxia. Here we report on a 30-yr-old man presenting with a maternally inherited NM_018116.3:c.651C>G, p.F217L missense variant as well as a paternally inherited arr[GRCh37] 1q22(155581773_155706887) × 1 deletion encompassing exons 7–14 of MSTO1. His phenotype included muscle weakness, hypotonia, early motor developmental delay, pectus excavatum, and scoliosis. Testing revealed elevated plasma creatine kinase, and electromyogram results were consistent with longstanding generalized myopathy. These phenotypic features overlap well with previously reported patients harboring biallelic MSTO1 variants. Additionally, our patient presents with dysphagia and restrictive lung disease, not previously reported for MSTO1-associated disorders. The majority of patients with disease-associated variants in MSTO1 present with biallelic variants suggesting autosomal recessive inheritance; however, one family has been reported with a single variant and presumed autosomal dominant inheritance. The pattern of inheritance we observed is consistent with the majority of previous reports suggesting an autosomal recessive disorder. We add to our knowledge of the syndrome caused by variants in MSTO1 and provide additional evidence supporting autosomal recessive inheritance. We also describe phenotypic features not reported in previous cases, although further research is needed to confirm they are associated with defects in MSTO1.
Climate teleconnections synchronizePicea glaucamasting and fire disturbance: Evidence for a fire‐related form of environmental prediction
Authors: Ascoli Davide , Hacket‐Pain Andrew , LaMontagne Jalene M. , Cardil Adrián , Conedera Marco , Maringer Janet , Motta Renzo , Pearse Ian S. , Vacchiano Giorgio
Published: October 2019

Synchronous pulses of seed masting and natural disturbance have positive feedbacks on the reproduction of masting species in disturbance‐prone ecosystems. We test the hypotheses that disturbances and proximate causes of masting are correlated, and that their large‐scale synchrony is driven by similar climate teleconnection patterns at both inter‐annual and decadal time scales.

Hypotheses were tested on white spruce (Picea glauca), a masting species which surprisingly persists in fire‐prone boreal forests while lacking clear fire adaptations. We built masting, drought and fire indices at regional (Alaska, Yukon, Alberta, Quebec) and sub‐continental scales (western North America) spanning the second half of the 20th century. Superposed Epoch Analysis tested the temporal associations between masting events, drought and burnt area at the regional scale. At the sub‐continental scale, Superposed Epoch Analysis tested whether El Niño‐Southern Oscillation (ENSO) and its coupled effects with the Atlantic Multidecadal Oscillation (AMO) in the positive phase (AMO+/ENSO+) synchronize drought, burnt area and masting. We additionally tested the consistency of our synchronization hypotheses on a decadal temporal scale to verify whether long‐term oscillations in AMO+/ENSO+ are coherent to decadal variation in drought, burnt area and masting.

Analyses demonstrated synchronicity between drought, fire and masting. In all regions the year before a mast event was drier and more fire‐prone than usual. During AMO+/ENSO+ events sub‐continental indices of drought and burnt area experienced significant departures from mean values. The same was observed for large‐scale masting in the subsequent year, confirming 1‐year lag between fire and masting. Sub‐continental indices of burnt area and masting showed in‐phase decadal fluctuations led by the AMO+/ENSO+. Results support the ‘Environmental prediction hypothesis’ for mast seeding.

Synthesis. We provide evidence of large‐scale synchronicity between seed masting inPicea glaucaand fire regimes in boreal forests of western North America at both inter‐annual and decadal time scales. We conclude that seed production in white spruce predicts changes in disturbance regimes by sharing the same large‐scale climate drivers with drought and fire. This gives new insides in a mechanism providing a fire‐sensitive species with higher than expected adaptability to changes in climate.
Downregulation of the inflammatory network in senescent fibroblasts and aging tissues of the long‐lived and cancer‐resistant subterranean wild rodent, Spalax
Authors: Odeh Amani , Dronina Maria , Domankevich Vered , Shams Imad , Manov Irena
Published: October 2019

The blind mole rat (Spalax) is a wild, long‐lived rodent that has evolved mechanisms to tolerate hypoxia and resist cancer. Previously, we demonstrated high DNA repair capacity and low DNA damage in Spalax fibroblasts following genotoxic stress compared with rats. Since the acquisition of senescence‐associated secretory phenotype (SASP) is a consequence of persistent DNA damage, we investigated whether cellular senescence in Spalax is accompanied by an inflammatory response. Spalax fibroblasts undergo replicative senescence (RS) and etoposide‐induced senescence (EIS), evidenced by an increased activity of senescence‐associated beta‐galactosidase (SA‐β‐Gal), growth arrest, and overexpression of p21, p16, and p53 mRNAs. Yet, unlike mouse and human fibroblasts, RS and EIS Spalax cells showed undetectable or decreased expression of the well‐known SASP factors: interleukin‐6 (IL6), IL8, IL1α, growth‐related oncogene alpha (GROα), SerpinB2, and intercellular adhesion molecule (ICAM‐1). Apparently, due to the efficient DNA repair in Spalax, senescent cells did not accumulate the DNA damage necessary for SASP activation. Conversely, Spalax can maintain DNA integrity during replicative or moderate genotoxic stress and limit pro‐inflammatory secretion. However, exposure to the conditioned medium of breast cancer cells MDA‐MB‐231 resulted in an increase in DNA damage, activation of the nuclear factor κB (NF‐κB) through nuclear translocation, and expression of inflammatory mediators in RS Spalax cells. Evaluation of SASP in aging Spalax brain and intestine confirmed downregulation of inflammatory‐related genes. These findings suggest a natural mechanism for alleviating the inflammatory response during cellular senescence and aging in Spalax, which can prevent age‐related chronic inflammation supporting healthy aging and longevity.
The efficacy of remote ischemic conditioning in preventing contrast‐induced nephropathy among patients undergoing coronary angiography or intervention: An updated systematic review and meta‐analysis
Authors: Zhan Biming , Zhu Bo , Hu Jianxin , Huang Qianghui , Bao Huihui , Huang Xiao , Cheng Xiaoshu
Published: October 2019

Background

Numerous trials have investigated the effect of remote ischemic conditioning (RIC) in preventing contrast‐induced nephropathy (CIN) in patients receiving contrast medium (CM). This meta analysis aims to validate the role of RIC in preventing CIN.

Methods

We searched the PubMed, EMBASE, and Web of Science databases for eligible randomized controlled trials (RCTs) published before April 27, 2019. Two investigators independently extracted basic characteristics from each study. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to examine the treatment effect.

Results

A total of 18 studies comprising 2,503 patients were included in our meta‐analysis. Compared with conventional therapy, RIC significantly reduced the risk of CIN (OR = 0.43, 95% CI: 0.33, 0.56, p < .05). Subgroup analyses showed that the protective effect of RIC was stronger in the low‐osmolar contrast media group (OR = 0.32; 95% CI: 0.23, 0.45, p < .05) and the nondiabetic group (OR = 0.39; 95% CI: 0.29, 0.53 p < .05). RIC also significantly reduced major adverse cardiovascular events within the first 6 months (OR = 0.39; p < .05), but the influence was not present after long‐term follow‐up.

Conclusions

Our meta‐analysis showed that RIC could effectively reduce CIN risk and decrease the short‐term incidence of relevant adverse events. Furthermore, the effects of CIN are more pronounced in nondiabetic patients and with the use of low‐osmolar contrast medium. This meta‐analysis of small trials suggests a possible protective effect of RIC on contrast‐induced nephropathy and favors the performance of a large randomized trial to further investigate this strategy.
Meta‐analysis of the differential effects of habitat fragmentation and degradation on plant genetic diversity
Authors: González Alejandra V. , Gómez‐Silva Valeria , Ramírez María José , Fontúrbel Francisco E.
Published: October 2019

Genetic diversity is a key factor for population survival and evolution. However, anthropogenic habitat disturbance can erode it, making populations more prone to extinction. Aiming to assess the global effects of habitat disturbance on plant genetic variation, we conducted a meta‐analysis based on 92 case studies obtained from published literature. We compared the effects of habitat fragmentation and degradation on plant allelic richness and gene diversity (equivalent to expected heterozygosity) and tested whether such changes are sensitive to different life‐forms, life spans, mating systems, and commonness. Anthropogenic disturbance had a negative effect on allelic richness, but not on gene diversity. Habitat fragmentation had a negative effect on genetic variation, whereas habitat degradation had no effect. When we examined the individual effects in fragmented habitats, allelic richness and gene diversity decreased, but this decrease was strongly dependent on certain plant traits. Specifically, common long‐lived trees and self‐incompatible species were more susceptible to allelic richness loss. Conversely, gene diversity decreased in common short‐lived species (herbs) with self‐compatible reproduction. In a wider geographical context, tropical plant communities were more sensitive to allelic richness loss, whereas temperate plant communities were more sensitive to gene diversity loss. Our synthesis showed complex responses to habitat disturbance among plant species. In many cases, the absence of effects could be the result of the time elapsed since the disturbance event or reproductive systems favoring self‐pollination, but attention must be paid to those plant species that are more susceptible to losing genetic diversity, and appropriate conservation should be actions taken.
The use of the orbitofrontal H‐sulcus as a reference frame for value signals
Authors: Troiani Vanessa , Patti Marisa A. , Adamson Kayleigh
Published: October 2019

Understanding the factors that drive organization and function of the brain is an enduring question in neuroscience. Using functional magnetic resonance imaging (fMRI), structure and function have been mapped in primary sensory cortices based on knowledge of the organizational principles that likely drive a given region (e.g., aspects of visual form in primary visual cortex and sound frequency in primary auditory cortex) and knowledge of underlying cytoarchitecture. The organizing principles of higher‐order brain areas that encode more complex signals, such as the orbitofrontal cortex (OFC), are less well understood. One fundamental component that underlies the many functions of the OFC is the ability to compute the reward or value of a given object. There is evidence of variability in the spatial location of responses to specific categories of objects (or value of said objects) within the OFC, and several reference frames have been proposed to explain this variability, including topographic spatial gradients that correspond to axes of primary versus secondary rewards and positive versus negative reinforcers. One potentially useful structural morphometric reference frame in the OFC is the “H‐sulcus,” a pattern formed by medial orbital, lateral orbital and transverse orbital sulci. In 48 human subjects, we use a structural morphometric tracing procedure to localize functional activation along the H‐sulcus for face and food stimuli. We report the novel finding that food‐selective responses are consistently found within the caudal portion of the medial orbital sulcus, but no consistency within the H‐sulcus for response to face stimuli. These results suggest that sulcogyral anatomy of the H‐sulcus may be an important morphological metric that contributes to the organizing principles of the OFC response to certain stimulus categories, including food.
Update on temporal lobe‐dependent information processing, in health and disease
Authors: Chauvière Laëtitia
Published: October 2019

The past decade has been characterized by a lot of remodeling in the field of learning and memory. Both of them, often associated with neuronal oscillations, an emergent property of brain networks, are governed by temporal lobe (TL) functional connectivity. An impairment of oscillatory mechanisms indeed often leads to TL‐dependent cognitive deficits. While the classical view assigned the TL a major role in spatial information processing, new theories rather confer to the TL a more general function in cognitive processes beyond space representation. The present review covers, both in humans and in animal models, (a) the updated role of the TL in cognitive processes, addressing current debates in the field and proposing a scenario on how TL structures cooperate in order to bind an integrated representation of afferent information, (b) the oscillatory mechanisms underlying these TL‐dependent cognitive functions (theta, gamma, sharp wave ripples) and (c) how TL‐dependent cognition is altered during temporal lobe epilepsy, proposing a scenario on how reorganized TL networks in TLE leads to rhythmopathies and cognitive deficits. Temporal lobe epilepsy (TLE) is a well‐studied neurological disease. Patients do not only suffer from epileptic seizures but also from cognitive and behavioral deficits between their seizures called comorbidities. TLE animal models are therefore used to understand how and when these comorbidities arise and what their underlying mechanisms are.