bluuebunny/crossref_metadata_2025_split huggingface dataset:
The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase‐positive non‐small cell lung cancer
Authors: Heo Ja Yoon , Park Changhee , Keam Bhumsuk , Ock Chan‐Young , Kim Miso , Kim Tae Min , Kim Dong‐Wan , Kim Se Hyun , Kim Yu Jung , Lee Jong Seok , Heo Dae Seog 
Published: September 2019

AbstractBackgroundDespite recent advances in treating non‐small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK‐positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK‐positive NSCLC.MethodsBetween 2011 and 2018, a total of 14 ALK‐positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD‐L1 expression, and treatment outcomes were analyzed. RNA expression level and cytolytic activity by ALK positivity were analyzed using The Cancer Genome Atlas (TCGA) and National Cancer Center Research Institute (NCCRI) data sets.ResultsA total of 13 patients (92.9%) received ALK inhibitors. Patients received a median of three (range 2–8) courses of therapy. The study included nine patients (64.3%) who were PD‐L1‐high (>50%) and four (28.6%) who were PD‐L1‐low (<50%). The objective response rate was 14.3% (2/14). The median progression‐free survival time was 2.18 months (95% confidence interval [CI] 1.13 months‐not reached [NR]). The median overall survival time was 5.67 months (95% CI 3.00 months‐NR). RNA expression levels of CD274 were similar between the ALK‐positive and negative groups in both TCGA and NCCRI datasets. RNA levels of CD8A in both TCGA and NCCRI data sets were nonsignificantly lower in the ALK‐positive group. Cytolytic activity scores including interferon‐γ‐related response were lower in the ALK‐positive group in the NCCRI but not TCGA dataset.ConclusionsDespite high PD‐L1‐positive rates, ICIs show limited efficacy in ALK‐positive NSCLC. Decreased interferon‐γ‐related response may underlie these findings.
Dementia and CSF‐biomarkers for Alzheimer's disease predict mortality after acute hip fracture
Authors: Dutkiewicz Robert , Zetterberg Henrik , Andreasson Ulf , Blennow Kaj , Nellgård Bengt 
Published: September 2019

BackgroundMortality is high after an acute hip fracture (AHF) surgery. Are cognitive impairment and/or altered levels of Alzheimer's Disease (AD)‐biomarkers in cerebrospinal fluid (CSF) predictors of mortality in AHF‐patients, as retrospective studies indicate?MethodsProspective single‐center study including 373 AHF‐patients, operated in spinal anesthesia. Cognitive status was evaluated by clinical dementia rating (CDR); CSF was analyzed for AD‐biomarker concentrations (total tau (T‐tau), phosphorylated tau (P‐tau), amyloid beta ratio (Aβ42/Aβ40). CDR and biomarker levels were related to mortality up to one‐year post‐surgery, using univariate logistic regression analysis.ResultsSurvival analyses showed that mortality was associated to the degree of dementia. In the entire patient cohort 30‐, 90‐, and 365‐day mortality rates were 7.2%, 15.5%, and 25.5%, respectively, but only 2.7%, 5.5%, and 12.6%, for cognitively intact vs 16.3%, 31.7%, and 42.3% for demented patients (OR = 2.2‐2.8 [CI = 1.6‐4.9]; P = .0001). High CSF T‐tau (OR = 1.19 [CI = 1.05‐1.33]; P = .004) and low Aβ42/Aβ40‐ratio (OR = 0.85 [CI = 0.74‐0.97]; P = .017) were associated with increased 90‐day mortality. Analysis of 4 subgroups (Cognitive impairment ± and Biomarkers ±) showed significant associations of dementia and CSF biomarker concentrations to mortality after an AHF. Even cognitively intact patients presenting with abnormal AD‐biomarkers showed an increased 90‐day mortality which, however, was statistically insignificant.ConclusionsCognitive impairment and altered CSF biomarker concentrations indicative of AD pathology can predict increased mortality in patients with an AHF, and so probably even before clinical dementia diagnosis by early biomarker analysis; a notion that may have substantial clinical implications by improving perioperative treatment and postoperative rehabilitation.
Incidental observation of pre‐eruptive intracoronal resorption after seven years
Authors: Currell SD , Cakar T 
Published: September 2019

AbstractPre‐eruptive intracoronal resorption (PIER) can be described by the presence of coronal radiolucency in a unerupted tooth. Upon eruption, the resorbed dentine might leave the occlusal layer of enamel unsupported and susceptible to fracture, potentially exposing the pulp chamber and root canals to the oral flora. With current case studies showing unfavourable endodontic and restorative consequences of PIER lesions when left untreated, this case report presents an unchanged lesion, 7 years following initial identification.
P40 polyester sheet plastination technique for brain and body slices: The vertical and horizontal flat chamber methods
Authors: Baptista Carlos A. C. , DeJong Kees , Latorre Rafael , Bittencourt Athelson S. 
Published: September 2019

AbstractThe P40 technique produces high‐quality brain and body slices and is the user‐friendliest of the polyester techniques. The P40 polyester technique follows the same classical steps for plastination. That is, preparation of the specimen, fixation (optional), dehydration by freeze substitution, forced impregnation and curing. Two methods used to prepare two different types of specimens, that is, brain slices and body slices are described. Each method has its own characteristics depending on the specimen type used. Brain slices were used to illustrate the vertical small chamber method while the body slices were used to illustrate the horizontal large chamber method. The brain slices obtained using P40 are of very good quality presenting good contrast between grey and white matter. The body slices are also of very good quality. The physical appearance of these slices makes them an exceptional instrument for diagnostic imaging and anatomical correlation. Body slices prepared with P40 retain the natural colour of the tissue and preserve the anatomical relationships.
Histological and ultrastructural studies on the coronary artery of adult domestic dog (Canis familiaris)
Authors: Kilany Maha S. , El Sayed Shafika A. , Salem Hoda F. , Beheiry Rasha R. 
Published: September 2019

AbstractThe objective of this work was to study the histological structure of the dog's coronary artery by light and transmission electron microscope (TEM). The coronary artery consisted of three tunics: tunica intima, tunica media and tunica adventitia. The tunica intima consisted of endothelium rested directly on internal elastic lamina without the subendothelial connective tissue layer. The tunica media were composed of smooth muscle fibres interspersed with few elastic and collagen fibres. The tunica adventitia consisted of collagen and elastic fibres intermingled with fibroblast cells; it had vasa vasorum and nervi vasorum. Some histomorphometric measurements were performed and compared statistically. The ultrastructural study showed that the endothelial cells were communicated through complex junctions and characterised by filiform cytoplasmic processes passed through the opening of the underlying internal elastic membrane. The smooth muscle fibres of tunica media communicated with each other through cytoplasmic processes. The tunica adventitia showed minute non‐myelinated nerve. This work revealed that the dog's coronary arteries are typical muscular arteries, which show little structural variations from that of other mammals.
Clinical predictors of small solitary hepatitis B virus‐related hepatocellular carcinoma microinvasion
Authors: Lu Wenping , Tang Haowen , Yang Zhanyu , Jiang Kai , Chen Yongliang , Lu Shichun 
Published: September 2019

AbstractBackgroundMicroinvasion serves as a reliable indicator of poor prognosis after hepatectomy or transplantation for hepatocellular carcinoma (HCC). However, microinvasion is difficult to detect with current imaging modalities and is usually diagnosed histopathologically. The aim of this study is to identify the preoperative clinical predictors of microinvasion of small solitary hepatitis B virus (HBV)‐related HCC.MethodsFrom January 2000 to December 2009, 110 patients with HBV‐related small primary solitary HCC (tumour diameter ≤3.0 cm) who underwent hepatectomy at Chinese PLA General Hospital were enrolled. The independent predictors of microinvasion, such as microvascular invasion and microscopic satellite nodules, were analysed. The prognosis of patients with microinvasion was compared with that of patients without microinvasion.ResultsOf the 110 patients, 31 (28.2%) exhibited microinvasion. Among them, 16 (51.6%) had microvascular invasion with microscopic satellite nodules, five (16.1%) had microscopic satellite nodules without microvascular invasion and 10 (32.3%) had microvascular invasion without microscopic satellite nodules. Two independent predictors of microinvasion were identified: serum alpha‐fetoprotein >20 ng/mL and a viral load of >104 copies/mL. Patients without microinvasion exhibited a significantly better prognostic outcome compared with those with microinvasion.ConclusionRegarding HBV‐related small HCC, patients presenting with alpha‐fetoprotein levels >20 ng/mL and a high viral load (HBV‐DNA >104 copies/mL) are at substantial risk for microinvasion.
Prostate‐specific membrane antigen‐positron emission tomography/computed tomography (PSMA‐PET/CT)‐guided stereotactic ablative body radiotherapy for oligometastatic prostate cancer: a single‐institution experience and review of the published literature
Authors: Ong Wee Loon , Koh Tze Lui , Lim Joon Daryl , Chao Michael , Farrugia Briana , Lau Eddie , Khoo Vincent , Lawrentschuk Nathan , Bolton Damien , Foroudi Farshad 
Published: September 2019

ObjectivesTo report the outcomes of stereotactic ablative body radiotherapy (SABR) in men with oligometastatic prostate cancer (PCa) diagnosed on prostate‐specific membrane antigen (PSMA)‐positron emission tomography/computed tomography (PET/CT), based on a single‐institution experience and the published literature.Patients and MethodsThis was a retrospective cohort study of the first 20 consecutive men with oligometastatic PCa, treated with SABR in a single institution, who had biochemical recurrence after previous curative treatment (surgery/radiotherapy), had no evidence of local recurrence, were not on palliative androgen deprivation therapy (ADT), and had PSMA‐PET/CT‐confirmed oligometastatic disease (≤3 lesions). These men were treated with SABR to a dose of 30 Gy in three fractions for bone metastases, and 35–40 Gy in five fractions for nodal metastases. The outcomes of interest were: PSA response; local progression‐free survival (LPFS); distant progression‐free survival (DPFS); and ADT‐free survival (ADTFS). A literature review was performed to identify published studies reporting on outcomes of PSMA‐PET/CT‐guided SABR.ResultsIn our institutional cohort, 12 men (60%) had a decline in PSA post‐SABR. One man had local progression 9.6 months post‐SABR, with 12‐month LPFS of 93%. Ten men had distant progression outside of their SABR treatment field, confirmed on PSMA‐PET/CT, with 12‐month DPFS of 62%, of whom four were treated with palliative ADT, two received prostate bed radiotherapy for prostate bed progression (confirmed on magnetic resonance imaging), and four received a further course of SABR (of whom one had further progression and was treated with palliative ADT). At last follow‐up, six men (one with local progression and five with distant progression) had received palliative ADT. The 12‐month ADTFS was 70%. Men with longer intervals between local curative treatment and SABR had better DPFS (P = 0.03) and ADTFS (P = 0.005). Four additional studies reporting on PSMA‐PET/CT‐guided SABR for oligometastatic PCa were identified and included in the review, giving a total of 346 patients. PSA decline was reported in 60–70% of men post‐SABR. The 2‐year LPFS, DPFS and ADTFS rates were 76–100%, 27–52%, and 58–62%, respectively.ConclusionOur results showed that PSMA‐PET/CT could have an important role in identifying men with true oligometastatic PCa who would benefit the most from metastases‐directed therapy with SABR.
Pharmacological targeting of β2‐adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease
Authors: O'Neill Eoin , Yssel Justin D. , McNamara Caoimhe , Harkin Andrew 
Published: September 2019

Background and PurposeChronic inflammation may play a role in the pathogenesis of Parkinson's disease (PD). Noradrenaline is an endogenous neurotransmitter with anti‐inflammatory properties. In the present investigation, we assessed the immunomodulatory and neuroprotective efficacy of pharmacologically targeting the CNS noradrenergic system in a rat model of PD.Experimental ApproachThe impact of treatment with the β2‐adrenoceptor agonists clenbuterol and formoterol was assessed in the intranigral LPS rat model of PD. The immunomodulatory potential of formoterol to influence the CNS response to systemic inflammation was also assessed.Key ResultsLPS‐induced deficits in motor function (akinesia and forelimb‐use asymmetry) and nigrostriatal dopamine loss were rescued by both agents. Treatment with the noradrenaline reuptake inhibitor atomoxetine reduced striatal dopamine loss and motor deficits following intranigral LPS injection. Co‐treatment with the β2‐adrenoceptor antagonist ICI 118,551 attenuated the protective effects of atomoxetine. Systemic LPS challenge exacerbated reactive microgliosis, IL‐1β production, dopamine cell loss in the substantia nigra, nerve terminal degeneration in the striatum, and associated motor impairments in animals that previously received intranigral LPS. This exacerbation was attenuated by formoterol treatment.Conclusion and ImplicationsThe results indicate that pharmacologically targeting β2‐adrenoceptors has the propensity to regulate the neuroinflammatory phenotype in vivo and may be a potential neuroprotective strategy where inflammation contributes to the progression of dopaminergic neurodegeneration. In accordance with this, clinical agents such as β2‐adrenoceptor agonists may prove useful as immunomodulatory agents in the treatment of neurodegenerative conditions associated with brain inflammation.
Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies
Authors: Najafi Arash , Caspar Sylvan M. , Meienberg Janine , Rohrbach Marianne , Steinmann Beat , Matyas Gabor 
Published: September 2019

AbstractGenome‐scale high‐throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by mutation databases, in silico tools, and population‐based reference datasets such as ExAC/gnomAD, while variants are classified using the ACMG/AMP guidelines. These methods, however, pose clinically relevant challenges. We queried the gnomAD dataset for (likely) pathogenic variants in genes causing autosomal‐dominant disorders. Furthermore, focusing on the fibrillinopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), we screened 500 genomes of our patients for co‐occurring variants in FBN1 and FBN2. In gnomAD, we detected 2653 (likely) pathogenic variants in 253 genes associated with autosomal‐dominant disorders, enabling the estimation of variant‐filtering thresholds and disease predisposition/prevalence rates. In our database, we discovered two families with hitherto unreported co‐occurrence of FBN1/FBN2 variants causing phenotypes with mixed or modified MFS/CCA clinical features. We show that (likely) pathogenic gnomAD variants may be more frequent than expected and are challenging to classify according to the ACMG/AMP guidelines as well as that fibrillinopathies are likely underdiagnosed and may co‐occur. Consequently, selection of appropriate frequency cutoffs, recognition of digenic variants, and variant classification represent considerable challenges in variant interpretation. Neglecting these challenges may lead to incomplete or missed diagnoses.
Effect of platelet‐rich plasma on peri‐implant trabecular bone volume and architecture: A preclinical micro‐CT study in beagle dogs
Authors: Huang Yan , Li Zhaokai , Van Dessel Jeroen , Salmon Benjamin , Huang Bo , Lambrichts Ivo , Politis Constantinus , Jacobs Reinhilde 
Published: September 2019

AbstractObjectivesTo evaluate the peri‐implant trabecular bone volume and architecture changes with 6‐month follow‐up after local application of platelet‐rich plasma (PRP) and platelet‐poor plasma (PPP) using high‐resolution micro‐CT.Material and methodsSeventy‐two dental implants were placed into healed mandibular sites of 9 beagle dogs. Implants were randomly divided into 4 groups following a split‐mouth design: control I; control II; PPP; and PRP. Primary and secondary stabilities were assessed using resonance frequency analyses. At 1, 3, and 6 months after implant loading, trabecular structural parameters were evaluated at 0.5, 1, and 1.5 mm away from implants using micro‐CT (voxel = 20 μm).ResultsPrimary and secondary stabilities were equivalent in all conditions. PPP and PRP groups showed higher bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) but lower trabecular separation (Tb.Sp) and total porosity percentage (Po (tot)) at all 3 time points. A significant decrease in BV/TV and Tb.Th was found for the control groups after 3 months of healing, while this was not observed in both the PPP and PRP groups. However, no distinct difference was found between the PRP and PPP groups over time. Moreover, as the investigated distance from the implant surface increased, BV/TV and Po (tot) within the same group and time point stayed the same, yet Tb.Th and Tb.Sp continued to increase.ConclusionsPlatelet‐rich plasma and PPP with conventional implant placement lead to similar primary and secondary implant stability, but improved peri‐implant bone volume and structural integration. The present research does not seem to suggest a different bone remodeling pattern when using PRP or PPP.
Living toward the end
Authors: Sponheim Paul R. 
Published: September 2019

AbstractHuman beings look to the end as terminus, a passing away when the individual's life story will be complete. Against a cultural tendency to deny death, Christians—claiming a Creator God who does not die—can accept their finitude in principle and aspire to a “high definition” ending. That hope is threatened by the devastating reality of dementia. But Kierkegaard reminds us that the “positive third” of selfhood is not to be identified with mentality and Whitehead stresses that the reception of the inrushing world does not depend on conscious mentality. Against the prevalent culture of individualism, a person of faith can recognize the constitutive role of community past and present. She can find in her terminus a telos, a passing on of life to the others as she steps aside. Is there more? The Newer Testament proclaims a new creation in which life's ending is transformed by the sense of end as beginning, end as advent. This omega as alpha entails both continuity and discontinuity. As to discontinuity, the Christian envisions a life “beyond Eden,” where the perilous gift of freedom is transformed in an integrating knowledge of self, world, and God—fulfilling the calling given to all as created in God's image. This sense of end does not function as an “escape to a transcendent elsewhere,” but motivates and empowers the believer to care for the suffering victims of this volatile and violent age.
Aging and the cross: Explorations in Deep Incarnation
Authors: Simmons Ernest L. 
Published: September 2019

AbstractAging is theologically explored in both creation and the cross through the concept of Deep Incarnation. As a partial extension of Martin Luther's thought, Deep Incarnation affirms God to be intimately involved in the natural processes of all biological creation, including aging, bringing solace, companionship, and hope to the elderly. God conceived as being both in the creation and beyond it (panentheism) allows for divine grace to relate to all creatures from the cellular level on up, including through evolutionary development. Employing the concept of compound theodicy, evolutionary theodicy is also briefly explored.
Influence of digital hypothermia on lamellar events related to IL‐6/gp130 signalling in equine sepsis‐related laminitis
Authors: Dern K. , Burns T. A. , Watts M. R. , van Eps A. W. , Belknap J. K. 
Published: September 2019

SummaryBackgroundInterleukin‐6 (IL‐6) is consistently increased in the digital lamellae in different studies of sepsis‐related laminitis (SRL). IL‐6 signalling through the gp130 receptor activates similar signalling (i.e. mTORC1‐related signalling) previously reported to be activated in models of endocrinopathic laminitis.ObjectivesTo assess the activation state of signalling proteins downstream of IL‐6/gp130 receptor complex activation in an experimental model of SRL.Study designRandomised experimental study.MethodsLamellar phospho‐(P) protein concentrations downstream of the IL‐6/gp130 receptors were assessed in the oligofructose (OF) model of SRL. Fifteen Standardbred horses were administered water (CON, n = 8) or oligofructose (OF, n = 7) via a nasogastric tube. At 12 h post‐OF/water administration, one randomly assigned forelimb was exposed to continuous digital hypothermia (CDH) by placement in ice water (ICE, maintained at <7°C); the other forelimb was maintained at ambient temperature (AMB). Lamellar tissue samples were collected after 24 h of CDH from both ICE and AMB forelimbs and immediately snap‐frozen. Lamellar proteins of interest were assessed by immunoblotting and immunofluorescence.ResultsImmunoblotting revealed increase (P<0.05) in the phosphorylation states of Akt (Ser 473), RPS6 (Ser235/236), RPS6 (Ser240/244), STAT3 (Ser727) and STAT3 (Tyr705) in lamellar tissue from OF‐treated animals (AMB OF vs. AMB CON limbs); CDH resulted in decreased (P<0.05) lamellar concentrations of phosphorylated Akt, p70S6K, RPS6 (235/236), RPS6 (240/244) and STAT3 (S727) in OF‐treated animals (AMB OF vs. ICE OF). Immunofluorescence showed that activated/phosphorylated forms of RPS6 and STAT3 were primarily localised to lamellar epithelial cells.Main limitationsThe nature, sequence and timing of sub‐cellular events in this experimental model may differ from those that accompany naturally occurring sepsis.ConclusionsThere were increased lamellar concentrations of activated signalling proteins downstream of the IL‐6/Gp130 receptor complex in OF‐treated horses; CDH inhibited this activation for the majority of the proteins assessed. These results demonstrate similar lamellar signalling (e.g. mTORC1‐related signalling) and, therefore, possible therapeutic targets occurring in sepsis‐related laminitis as previously reported in models of endocrinopathic laminitis.