bluuebunny/crossref_metadata_2025_split huggingface dataset:
Theory of Pitch and Curvature Corrections for the Helical Spring—II (Torsion)
Authors: Ancker C. J. , Goodier J. N. 
Published: June 2021

Abstract
The helical spring of round cross section loaded in axial tension is solved. Both pitch and curvature are considered. All deformations and stresses are obtained by a “thin-slice” method which reduces the variables from three to two. The method is described in a previous paper. The form of the solution is deduced from considerations of symmetry. This knowledge, applied to the equations of the boundary-value problem, produces algebraic equations which are then solved.
Response of a Simply Supported Timoshenko Beam to a Purely Random Gaussian Process
Authors: Samuels J. C. , Eringen A. C. 
Published: June 2021

Abstract
The generalized Fourier analysis is applied to the damped Timoshenko beam equation to calculate the mean-square values of displacements and bending stress, resulting from purely random loading. Compared with the calculations, based on the classical beam theory, it was found that the displacement correlations of both theories were in excellent agreement. Moreover, the mean square of the bending stress, contrary to the results of the classical beam theory, was found to be convergent. Computations carried out with a digital computer are plotted for both theories.
The Wedge Under a Concentrated Couple: A Paradox in the Two-Dimensional Theory of Elasticity
Authors: Sternberg Eli , Koiter W. T. 
Published: June 2021

Abstract
The classical two-dimensional solution for the stress distribution in an elastic wedge which is subjected to a concentrated couple at the vertex, breaks down when the opening angle 2α of the wedge satisfies the equation tan 2α = 2α, i.e., when 2α is approximately 257 deg. As the foregoing critical opening angle 2α* is approached, all of the nonvanishing components of stress become infinite throughout the field, while the solution displays no obvious pathological characteristics for other values of the wedge angle. It is the purpose of the present paper to account for this peculiar singular behavior and to show that the solution under examination has physical significance only for wedge angles below the critical angle; for opening angles in the range 2α* ≤ 2α &lt; 2π, the notion of a “concentrated couple” at the vertex of an elastic wedge, is found to be inherently deficient in meaning. The present investigation, as a by-product, augments the supply of counterexamples to the traditional version of Saint Venant’s principle.
Relief of Thermal Stresses Through Creep
Authors: Poritsky H. , Fend F. A. 
Published: June 2021

Abstract
Equations are developed for analyzing the effects of thermal creep on stress distributions. In formulating these elastoplastic equations, the tensile test stress-strain creep data are extended to compound stresses by means of the Mises-Hencky hypothesis. The various equations are manipulated to yield a numerical procedure by means of which the stress and strain components are computed successively at the end of various time intervals. In these calculations it is assumed that the initial creep rates remain constant during each time interval. The resulting equations are applied to the axially symmetric problem of relief of thermal stresses in an infinitely long cylinder which is quickly heated to a parabolic temperature, and maintained at that temperature. End effects are neglected. The calculation is reduced to repeated solutions of a certain second-order ordinary differential equation. Curves are plotted showing the gradual relief of the stresses caused by the creep. The methods developed are illustrative of a procedure which may be followed for other stress-creep problems.
Laminar Flow in a Uniformly Porous Channel
Authors: White F. M. , Barfield B. F. , Goglia M. J. 
Published: June 2021

Abstract
The problem of laminar channel flow has been investigated for the case of uniform fluid suction or injection through the channel walls. The solution can be divided into three steps: (a) A judicious choice of stream function reduces the Navier-Stokes equations to an ordinary, fourth-order, nonlinear differential equation, which contains a free parameter R, the Reynolds number based upon fluid velocity through the wall. (b) Since general analysis of this equation is intractable, the parameter R is eliminated by a suitable transformation. (c) The transformed, nonparametric equation yields to a series solution, valid and absolutely convergent for all R. From this general solution, expressions are developed for velocity components, pressure distribution, and wall-friction coefficient.
Vibration Fatigue Assessment of Additive Manufactured Nickel Alloy With Inherent Damping
Authors: Scott-Emuakpor Onome , Sheridan Luke , Runyon Brian , George Tommy 
Published: June 2021

Abstract
The fatigue life behavior and internal surface conditions of inherently damped additive manufactured (AM) specimens subjected to vibration bending are under investigation. This study supports research that demonstrated 95% vibration suppression due to damping capability of AM components with 1–3% internal volume of unfused powder; however, the viability of fatigue performance is unknown. The following effort explores whether internal wall damage caused by unfused powder particle motion debits fatigue life. Comparisons between the fatigue behaviors of unfused powder pocket and fully fused nickel based alloy 718 specimens confirms a long suspected powder interaction phenomena critical to damping performance.
Mafic-ultramafic intrusion formed by multi-stage evolution of hydrous basaltic melts
Authors: Li Qi-Wei , Zhao Jun-Hong , Zhou Mei-Fu , Gao Jian-Feng 
Published: June 2021

AbstractThe magmatic processes beneath the active continental margins are very complicated and affect structures and compositions of the arc roots. Neoproterozoic igneous rocks are widely distributed around the margins of the Tarim Block in NW China. The Xingdier mafic-ultramafic intrusion is a composite body, located at the northern margin of the Tarim Block, and consists of gabbro, pyroxenite, and peridotite units. The gabbro unit has a secondary ion mass spectrometry zircon U-Pb age of 727 ± 5 Ma. Rocks from the Xingdier intrusion have a large range of MgO (12.9–32.8 wt%) and SiO2 (43.0–57.9 wt%), and low K2O + Na2O (0.11–2.25 wt%) contents. They have right inclined chondrite-normalized rare earth element patterns with (La/Yb)N ratios of 2.2–8.6. Their primitive mantle normalized trace element patterns show arc-affinity geochemical features characterized by enrichment in Rb, Ba, Th, U, and Pb and depletion in Nb, Ta, and Ti. They have variable initial 87Sr/86Sr ratios (0.7063–0.7093), εNd(t) values (−2.9 to −7.8), 206Pb/204Pb (17.08–17.80), 207Pb/204Pb (15.42–15.49), and 208Pb/204Pb ratios (37.48–38.05), forming an evolution trend from the peridotite unit to the gabbro and pyroxenite units. Clinopyroxene in the three units is chemically similar to those formed in hydrous magmas. The spinel inclusions in olivine from the peridotite unit show unmixing texture and have high Al contents and oxygen fugacity of ~FMQ+1. Therefore, the parental magma was probably derived from a lithospheric mantle enriched by slab-derived fluids. Rocks from the gabbro and peridotite units are proposed to have been derived from olivine-normative melts, whereas rocks from the pyroxenite unit are cumulates from the quartz-normative melts. Such contrasting parental magmas resulted from variable degrees of crustal contamination and fractional crystallization in the arc root.
Prevalence of monogenic disease in paediatric patients with a predominant respiratory phenotype
Authors: Dai Dan , Mei Mei , Hu Liyuan , Cao Yun , Wang Xiaochuan , Wang Libo , Lu Yulan , Yang Lin , Dong Xinran , Wang Huijun , Wu Bingbing , Qian Liling 
Published: June 2021

ObjectiveThis study aimed to investigate the prevalence and clinical characteristics of monogenic disease in paediatric patients with a predominant respiratory phenotype.MethodsExome sequencing was performed in a cohort of 971 children with a predominant respiratory phenotype and suspected genetic aetiology. A total of 140 positive cases were divided into subgroups based on recruitment age and the primary biological system(s) involved.ResultsThere were 140 (14.4%) patients with a positive molecular diagnosis, and their primary clinical manifestations were respiratory distress (12.9%, 18 of 140), respiratory failure (12.9%, 18 of 140) and recurrent/persistent lower respiratory infections (66.4%, 93 of 140). Primary immunodeficiency (49.3%), multisystem malformations/syndromes (17.9%), and genetic lung disease (16.4%) were the three most common genetic causes in the cohort, and they varied among the age subgroups. A total of 72 (51.4%) patients had changes in medical management strategies after genetic diagnosis, and the rate in those with genetic lung disease (82.6%, 19 of 23) was far higher than that in patients with genetic disease with lung involvement (45.3%, 53 of 117) (p=0.001).ConclusionOur findings demonstrate that exome sequencing is a valuable diagnostic tool for monogenic diseases in children with a predominant respiratory phenotype, and the genetic spectrum varies with age. Taken together, genetic diagnoses provide invaluable clinical and prognostic information that may also facilitate the development of precision medicine for paediatric patients.
Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts
Authors: Quintarelli Concetta , Guercio Marika , Manni Simona , Boffa Iolanda , Sinibaldi Matilde , Di Cecca Stefano , Caruso Simona , Abbaszadeh Zeinab , Camera Antonio , Cembrola Biancamaria , Ciccone Roselia , Orfao Alberto , Martin-Martin Lourdes , Gutierrez-Herrero Sara , Herrero-Garcia Maria , Cazzaniga Gianni , Nunes Vittorio , Songia Simona , Marcatili Paolo , Marin Frederikke I , Ruella Marco , Bertaina Valentina , Vinti Luciana , Del Bufalo Francesca , Algeri Mattia , Merli Pietro , De Angelis Biagio , Locatelli Franco 
Published: June 2021

Chimeric antigen receptor T-cells (CAR T-cells) for the treatment of relapsing/refractory B-cell precursor acute lymphoblastic leukemia have led to exciting clinical results. However, CAR T-cell approaches revealed a potential risk of CD19-/CAR+ leukemic relapse due to inadvertent transduction of leukemia cells.BackgroundMethodsWe evaluated the impact of a high percentage of leukemia blast contamination in patient-derived starting material (SM) on CAR T-cell drug product (DP) manufacturing. In vitro as well as in vivo models were employed to identify characteristics of the construct associated with better profile of safety in case of inadvertent B-cell leukemia transduction during CAR T-cell manufacturing.ResultsThe presence of large amounts of CD19+ cells in SM did not affect the transduction level of DPs, as well as the CAR T-cell rate of expansion at the end of standard production of 14 days. DPs were deeply characterized by flow cytometry and molecular biology for Ig-rearrangements, showing that the level of B-cell contamination in DPs did not correlate with the percentage of CD19+ cells in SM, in the studied patient cohort. Moreover, we investigated whether CAR design may affect the control of CAR+ leukemia cells. We provided evidences that CAR.CD19 short linker (SL) prevents complete epitope masking in CD19+CAR+ leukemia cells and we demonstrated in vitro and in vivo that CD19 +CAR(SL)+leukemic cells are killed by CAR.CD19 T-cells.ConclusionsTaken together, these data suggest that a VL-VH SL may result in a safe CAR-T product, even when manufacturing starts from biological materials characterized by heavy contamination of leukemia blasts.
Non-invasive measurement of PD-L1 status and prediction of immunotherapy response using deep learning of PET/CT images
Authors: Mu Wei , Jiang Lei , Shi Yu , Tunali Ilke , Gray Jhanelle E , Katsoulakis Evangelia , Tian Jie , Gillies Robert J , Schabath Matthew B 
Published: June 2021

BackgroundCurrently, only a fraction of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) experience a durable clinical benefit (DCB). According to NCCN guidelines, Programmed death-ligand 1 (PD-L1) expression status determined by immunohistochemistry (IHC) of biopsies is the only clinically approved companion biomarker to trigger the use of ICI therapy. Based on prior work showing a relationship between quantitative imaging and gene expression, we hypothesize that quantitative imaging (radiomics) can provide an alternative surrogate for PD-L1 expression status in clinical decision support.Methods18F-FDG-PET/CT images and clinical data were curated from 697 patients with NSCLC from three institutions and these were analyzed using a small-residual-convolutional-network (SResCNN) to develop a deeply learned score (DLS) to predict the PD-L1 expression status. This developed model was further used to predict DCB, progression-free survival (PFS), and overall survival (OS) in two retrospective and one prospective test cohorts of ICI-treated patients with advanced stage NSCLC.ResultsThe PD-L1 DLS significantly discriminated between PD-L1 positive and negative patients (area under receiver operating characteristics curve ≥0.82 in the training, validation, and two external test cohorts). Importantly, the DLS was indistinguishable from IHC-derived PD-L1 status in predicting PFS and OS, suggesting the utility of DLS as a surrogate for IHC. A score generated by combining the DLS with clinical characteristics was able to accurately (C-indexes of 0.70–0.87) predict DCB, PFS, and OS in retrospective training, prospective testing and external validation cohorts.ConclusionHence, we propose DLS as a surrogate or substitute for IHC-determined PD-L1 measurement to guide individual pretherapy decisions pending in larger prospective trials.
Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment
Authors: Aoyama Shota , Nakagawa Ryosuke , Nemoto Satoshi , Perez-Villarroel Patricio , Mulé James J , Mailloux Adam William 
Published: June 2021

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+T cell populations, increased CD4+and CD8+TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+tumors.
Whole-genome analysis as a diagnostic tool for patients referred for diagnosis of Silver-Russell syndrome: a real-world study
Authors: Alhendi Ahmed S N , Lim Derek , McKee Shane , McEntagart Meriel , Tatton-Brown Katriona , Temple I Karen , Davies Justin H , Mackay Deborah J G 
Published: June 2021

BackgroundSilver-Russell syndrome (SRS) is an imprinting disorder characterised by prenatal and postnatal growth restriction, but its clinical features are non-specific and its differential diagnosis is broad. Known molecular causes of SRS include imprinting disturbance, single nucleotide variant (SNV), CNV or UPD affecting several genes; however, up to 40% of individuals with a clinical diagnosis of SRS currently receive no positive molecular diagnosis.MethodsTo determine whether whole-genome sequencing (WGS) could uncover pathogenic variants missed by current molecular testing, we analysed data of 72 participants recruited to the 100,000 Genomes Project within the clinical category of SRS.ResultsIn 20 participants (27% of the cohort) we identified genetic variants plausibly accounting for SRS. Coding SNVs were identified in genes including CDKN1C, IGF2, IGF1R and ORC1. Maternal-effect variants were found in mothers of five participants, including two participants with imprinting disturbance and one with multilocus imprinting disorder. Two regions of homozygosity were suggestive of UPD involving imprinted regions implicated in SRS and Temple syndrome, and three plausibly pathogenic CNVs were found, including a paternal deletion of PLAGL1. In 48 participants with no plausible pathogenic variant, unbiased analysis of SNVs detected a potential association with STX4.ConclusionWGS analysis can detect UPD, CNV and SNV and is potentially a valuable addition to diagnosis of SRS and related growth-restricting disorders.
Design and characterization of a copper microchannel heat sink for SiP cooling
Authors: Miao Min , Zhang Hao , Yu Hejie , Cao Lili 
Published: June 2021

With the increasing flourishing of miniaturized, multifunctional, and heterogeneously integrated system in package (SiP), heating problem is becoming more and more serious. In this paper, to meet the heat dissipation needs of the chips thus assembled and to achieve effective thermal management, linear, serpent and spiral shaped microchannel heat sinks were designed and fabricated into copper substrate by electrical discharge machining (EDM) and precision machining technology, acting both as the cooler and mounting base for passive and active SiP interposers. A test platform was set up to characterize the heat dissipation performance of the copper-based microchannel heat sink. The experimental and simulation results show that heat dissipation rate increases with the increasing heat flux density in the range 5–30 W/cm2 for the three microchannel designs, and the peak temperature can all be kept below 340 K (67[Formula: see text]C) even for the highest heat flux. The three designs are compared from the perspective of peak temperature, temperature distribution uniformity and pressure drop. In all, the solution proposed hereby provides a new and optimal option for in-situ cooling for densely integrated electronic hardware.
Phase I Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844)
Authors: Roussos Torres Evanthia T. , Rafie Christine , Wang Chenguang , Lim David , Brufsky Adam , LoRusso Patricia , Eder Joseph Paul , Chung Vincent , Downs Melinda , Geare Molly , Piekarz Richard , Streicher Howard , Anforth Leslie , Rudek Michelle A. , Zhu Qingfeng , Besharati Sepideh , Cimino-Mathews Ashley , Anders Robert A. , Stearns Vered , Jaffee Elizabeth M. , Connolly Roisin M. 
Published: June 2021

Abstract

Purpose:
Epigenetic modulators improve immune checkpoint inhibitor (ICI) efficacy and increase CD8+ effector:FoxP3+ regulatory T cell ratios in preclinical models. We conducted a multicenter phase I clinical trial combining the histone deacetylase inhibitor entinostat with nivolumab ± ipilimumab in advanced solid tumors.

Patients and Methods:
Patients received an entinostat run-in (5 mg, weekly × 2) prior to the addition of ICIs. Dose escalation followed a modified 3+3 design [dose level (DL)1/2: entinostat + nivolumab; DL 3/4: entinostat + nivolumab + ipilimumab]. Blood and tissue samples were collected at baseline, after entinostat run-in, and after 8 weeks of combination therapy. Primary endpoints included safety and tolerability, and the recommended phase II dose (RP2D). Secondary endpoints included antitumor activity and change in tumor CD8/FoxP3 ratio pre- and post-therapy.

Results:
Thirty-three patients were treated across four dose levels. Treatment-related adverse events (AE) included fatigue (65%), nausea (41%), anemia (38%), diarrhea (26%), and anorexia (26%). Grade 3/4 AEs included fatigue (n = 7, 21%), anemia (n = 9, 27%), and neutropenia (n = 4, 12%). The RP2D was 3 mg entinostat weekly, 3 mg/kg every 2 weeks nivolumab, and 1 mg/kg every 6 weeks ipilimumab (max four doses). The objective response rate by RECIST 1.1 was 16%, including a complete response in triple-negative breast cancer. A statistically significant increase in CD8/FoxP3 ratio was seen following the addition of ICIs to entinostat, but not post-entinostat alone.

Conclusions:
The combination of entinostat with nivolumab ± ipilimumab was safe and tolerable with expected rates of immune-related AEs. Preliminary evidence of both clinical efficacy and immune modulation supports further investigation.
Irrigated Needle Ablation Compared With Other Advanced Ablation Techniques for Failed Endocardial Ventricular Arrhythmia Ablation
Authors: Narui Ryohsuke , Tanigawa Shinichi , Nakajima Ikutaro , Tokutake Kenichi , Nakamura Tomofumi , Richardson Travis , Salloum Joseph , Sapp John , Kanagasundram Arvindh , Tedrow Usha , Stevenson William 
Published: June 2021

Background:
Options when endocardial ventricular arrhythmia ablation fails include epicardial, simultaneous 2-site unipolar radiofrequency (SURF), and transcoronary ethanol ablation. Recently, investigational needle ablation has also been used, but how it compares to other advanced methods is not clear. This study sought to compare outcomes and complications for needle ablation versus other advanced ablation techniques in patients with structural heart disease, ventricular arrhythmia, and failed endocardial ablation.

Methods:
We retrospectively reviewed 136 procedures in 119 consecutive patients with structural heart disease (excluding arrhythmogenic right ventricular cardiomyopathy) who failed endocardial ablation and underwent ablation with either an investigational needle catheter (27 gauge, single end hole) or with other advanced techniques including epicardial, SURF or transcoronary ethanol ablation.

Results:

Of 136 procedures, needle ablation was performed in 58 procedures. In the remaining 78 procedures, 65 were epicardial ablation, including 10 with SURF ablation from endocardial and epicardial sites, 7 with SURF from both sides of the septum, one SURF and transcoronary ethanol ablation, and 5 transcoronary ethanol ablation procedures. Acute outcomes, 6-month ventricular arrhythmia recurrence, and mortality rates were not different between the 2 groups (49% versus 55%,
P
=0.54, 45% versus 46%,
P
=1.00, and 4% versus 3%,
P
=1.00, respectively). There were 22 major complications observed in 22 procedures with pericardial bleeding occurring less frequently with needle ablation (1.7% versus 12.8%,
P
=0.02).

Conclusions:
Ablation with an irrigated needle catheter compares favorably to other advanced ablation techniques.