bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities
Authors: Christodoulou Ilias , Ho Won Jin , Marple Andrew , Ravich Jonas W , Tam Ada , Rahnama Ruyan , Fearnow Adam , Rietberg Cambrynne , Yanik Sean , Solomou Elena E , Varadhan Ravi , Koldobskiy Michael A , Bonifant Challice L 
Published: December 2021

BackgroundThe prognosis of patients with recurrent/refractory acute myelogenous leukemia (AML) remains poor and cell-based immunotherapies hold promise to improve outcomes. Natural Killer (NK) cells can elicit an antileukemic response via a repertoire of activating receptors that bind AML surface ligands. NK-cell adoptive transfer is safe but thus far has shown limited anti-AML efficacy. Here, we aimed to overcome this limitation by engineering NK cells to express chimeric antigen receptors (CARs) to boost their anti-AML activity and interleukin (IL)-15 to enhance their persistence.MethodsWe characterized in detail NK-cell populations expressing a panel of AML (CD123)-specific CARs and/or IL-15 in vitro and in AML xenograft models.ResultsCARs with 2B4.ζ or 4-1BB.ζ signaling domains demonstrated greater cell surface expression and endowed NK cells with improved anti-AML activity in vitro. Initial in vivo testing revealed that only 2B4.ζ Chimeric Antigen Receptor (CAR)-NK cells had improved anti-AML activity in comparison to untransduced (UTD) and 4-1BB.ζ CAR-NK cells. However, the benefit was transient due to limited CAR-NK-cell persistence. Transgenic expression of secretory interleukin (sIL)-15 in 2B4.ζ CAR and UTD NK cells improved their effector function in the setting of chronic antigen simulation in vitro. Multiparameter flow analysis after chronic antigen exposure identified the expansion of unique NK-cell subsets. 2B4.ζ/sIL-15 CAR and sIL-15 NK cells maintained an overall activated NK-cell phenotype. This was confirmed by transcriptomic analysis, which revealed a highly proliferative and activated signature in these NK-cell groups. In vivo, 2B4.ζ/sIL-15 CAR-NK cells had potent anti-AML activity in one model, while 2B4.ζ/sIL-15 CAR and sIL-15 NK cells induced lethal toxicity in a second model.ConclusionTransgenic expression of CD123-CARs and sIL-15 enabled NK cells to function in the setting of chronic antigen exposure but was associated with systemic toxicities. Thus, our study provides the impetus to explore inducible and controllable expression systems to provide cytokine signals to AML-specific CAR-NK cells before embarking on early-phase clinical testing.
HDAC2 Facilitates Pancreatic Cancer Metastasis
Authors: Krauß Lukas , Urban Bettina C. , Hastreiter Sieglinde , Schneider Carolin , Wenzel Patrick , Hassan Zonera , Wirth Matthias , Lankes Katharina , Terrasi Andrea , Klement Christine , Cernilogar Filippo M. , Öllinger Rupert , de Andrade Krätzig Niklas , Engleitner Thomas , Schmid Roland M. , Steiger Katja , Rad Roland , Krämer Oliver H. , Reichert Maximilian , Schotta Gunnar , Saur Dieter , Schneider Günter 
Published: December 2021

Abstract

The mortality of patients with pancreatic ductal adenocarcinoma (PDAC) is strongly associated with metastasis, a multistep process that is incompletely understood in this disease. Although genetic drivers of PDAC metastasis have not been defined, transcriptional and epigenetic rewiring can contribute to the metastatic process. The epigenetic eraser histone deacetylase 2 (HDAC2) has been connected to less differentiated PDAC, but the function of HDAC2 in PDAC has not been comprehensively evaluated. Using genetically defined models, we show that HDAC2 is a cellular fitness factor that controls cell cycle in vitro and metastasis in vivo, particularly in undifferentiated, mesenchymal PDAC cells. Unbiased expression profiling detected a core set of HDAC2-regulated genes. HDAC2 controlled expression of several prosurvival receptor tyrosine kinases connected to mesenchymal PDAC, including PDGFRα, PDGFRβ, and EGFR. The HDAC2-maintained program disabled the tumor-suppressive arm of the TGFβ pathway, explaining impaired metastasis formation of HDAC2-deficient PDAC. These data identify HDAC2 as a tractable player in the PDAC metastatic cascade. The complexity of the function of epigenetic regulators like HDAC2 implicates that an increased understanding of these proteins is needed for implementation of effective epigenetic therapies.

Significance:
HDAC2 has a context-specific role in undifferentiated PDAC and the capacity to disseminate systemically, implicating HDAC2 as targetable protein to prevent metastasis.
Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma
Authors: Sen Arko , Prager Briana C. , Zhong Cuiqing , Park Donglim , Zhu Zhe , Gimple Ryan C. , Wu Qiulian , Bernatchez Jean A. , Beck Sungjun , Clark Alex E. , Siqueira-Neto Jair L. , Rich Jeremy N. , McVicker Graham 
Published: December 2021

Abstract

Glioblastoma is the most prevalent primary malignant brain tumor in adults and is characterized by poor prognosis and universal tumor recurrence. Effective glioblastoma treatments are lacking, in part due to somatic mutations and epigenetic reprogramming that alter gene expression and confer drug resistance. To investigate recurrently dysregulated genes in glioblastoma, we interrogated allele-specific expression (ASE), the difference in expression between two alleles of a gene, in glioblastoma stem cells (GSC) derived from 43 patients. A total of 118 genes were found with recurrent ASE preferentially in GSCs compared with normal tissues. These genes were enriched for apoptotic regulators, including schlafen family member 11 (SLFN11). Loss of SLFN11 gene expression was associated with aberrant promoter methylation and conferred resistance to chemotherapy and PARP inhibition. Conversely, low SLFN11 expression rendered GSCs susceptible to the oncolytic flavivirus Zika. This discovery effort based upon ASE revealed novel points of vulnerability in GSCs, suggesting a potential alternative treatment strategy for chemotherapy-resistant glioblastoma.

Significance:
Assessing allele-specific expression reveals genes with recurrent cis-regulatory changes that are enriched in glioblastoma stem cells, including SLFN11, which modulates chemotherapy resistance and susceptibility to the oncolytic Zika virus.
FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC
Authors: Nakajima Erica C. , Drezner Nicole , Li Xiaoxue , Mishra-Kalyani Pallavi S. , Liu Yajun , Zhao Hong , Bi Youwei , Liu Jiang , Rahman Atiqur , Wearne Emily , Ojofeitimi Idara , Hotaki Lauren Tesh , Spillman Dianne , Pazdur Richard , Beaver Julia A. , Singh Harpreet 
Published: December 2021

Abstract
On May 28, 2021, the FDA granted accelerated approval to sotorasib (Lumakras, Amgen) for the treatment of adults with advanced non–small cell lung cancer (NSCLC) with a Kirsten rat sarcoma proto-oncogene (KRAS) G12C mutation who have received at least one prior systemic therapy. The approval was based on CodeBreaK 100 (Study 20170543), a dose-escalation and dose-expansion trial in patients with an advanced, KRAS G12C-mutated, solid tumor. The overall response rate (ORR) observed in patients with KRAS G12C-mutated NSCLC treated with sotorasib (n = 124) was 36% [95% confidence interval (CI), 28–45]. The median duration of response was 10.0 months (95% CI, 6.9–not estimable). The most common adverse reactions (≥20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. This is the first approval of a targeted therapy for KRAS G12C-mutated NSCLC. Because of pharmacokinetic data and ORRs of patient cohorts who took sotorasib at lower doses in the dose-escalation portion of CodeBreaK 100, a dose comparison study is being conducted as a post-marketing requirement.
Chromatophony: A Potential Application of Living Images in the Pixel Era
Authors: Yokokawa Juppo , Masuda Nobuhiro , Jo Kazuhiro 
Published: December 2021

Abstract
Squids can rapidly change their body color using chromatophores that are controlled by electrical signals transmitted through nerves. The authors transform a squid’s skin into an audio visualizer called Chromatophony. This is accomplished by sending an electric tone signal composed as music to the skin. Although Chromatophony’s appearance is similar to that of computer-generated images, it is based on a natural phenomenon with a colorful mosaic display. By comparing chromatophores with pixels, the authors propose Living Images to expand the potential of visual expression from the perspective of bioart theory.
An Intraseasonal Mode Linking Wintertime Surface Air Temperature over Arctic and Eurasian Continent
Authors: Xiu Junyi , Jiang Xianan , Zhang Renhe , Guan Weina , Chen Gang 
Published: December 2021

AbstractKey processes associated with the leading intraseasonal variability mode of wintertime surface air temperature (SAT) over Eurasia and the Arctic region are investigated in this study. Characterized by a dipole distribution in SAT anomalies centered over north Eurasia and the Arctic, respectively, and coherent temperature anomalies vertically extending from the surface to 300 hPa, this leading intraseasonal SAT mode and associated circulation have pronounced influences on global surface temperature anomalies including the East Asian winter monsoon region. By taking advantage of realistic simulations of the intraseasonal SAT mode in a global climate model, it is illustrated that temperature anomalies in the troposphere associated with the leading SAT mode are mainly due to dynamic processes, especially via the horizontal advection of winter mean temperature by intraseasonal circulation. While the cloud–radiative feedback is not critical in sustaining the temperature variability in the troposphere, it is found to play a crucial role in coupling temperature anomalies at the surface and in the free atmosphere through anomalous surface downward longwave radiation. The variability in clouds associated with the intraseasonal SAT mode is closely linked to moisture anomalies generated by similar advective processes as for temperature anomalies. Model experiments suggest that this leading intraseasonal SAT mode can be sustained by internal atmospheric processes in the troposphere over the mid- to high latitudes by excluding forcings from Arctic sea ice variability, tropical convective variability, and the stratospheric processes.
Effect of 3D‐Printed Models on Cadaveric Dissection in Temporal Bone Training
Authors: Frithioff Andreas , Frendø Martin , Weiss Kenneth , Foghsgaard Søren , Pedersen David Bue , Sørensen Mads Sølvsten , Wuyts Andersen Steven Arild 
Published: December 2021

ObjectiveMastoidectomy is a cornerstone in the surgical management of middle and inner ear diseases. Unfortunately, training is challenged by insufficient access to human cadavers. Three‐dimensional (3D) printing of temporal bones could alleviate this problem, but evidence on their educational effectiveness is lacking. It is largely unknown whether training on 3D‐printed temporal bones improves mastoidectomy performance, including on cadavers, and how this training compares with virtual reality (VR) simulation. To address this knowledge gap, this study investigated whether training on 3D‐printed temporal bones improves cadaveric dissection performance, and it compared this training with the already‐established VR simulation.Study DesignProspective cohort study of an educational intervention.SettingTertiary university hospital, cadaver dissection laboratory, and simulation center in Copenhagen, Denmark.MethodsEighteen otorhinolaryngology residents (intervention) attending the national temporal bone dissection course received 3 hours of mastoidectomy training on 3D‐printed temporal bones. Posttraining cadaver mastoidectomy performances were rated by 3 experts using a validated assessment tool and compared with those of 66 previous course participants (control) who had received time‐equivalent VR training prior to dissection.ResultsThe intervention cohort outperformed the controls during cadaver dissection by 29% (P <. 001); their performances were largely similar across training modalities but remained at a modest level (~50% of the maximum score).ConclusionMastoidectomy skills improved from training on 3D‐printed temporal bone and seemingly more so than on time‐equivalent VR simulation. Importantly, these skills transferred to cadaveric dissection. Training on 3D‐printed temporal bones can effectively supplement cadaver training when learning mastoidectomy.
Evaluation of Patient‐Reported Delays and Affordability‐Related Barriers to Care in Head and Neck Cancer
Authors: Lenze Nicholas R. , Bensen Jeannette T. , Farnan Laura , Sheth Siddharth , Zevallos Jose P. , Yarbrough Wendell G. , Zanation Adam M. 
Published: December 2021

ObjectiveTo examine the prevalence and predictors of patient‐reported barriers to care among survivors of head and neck squamous cell carcinoma and the association with health‐related quality of life (HRQOL) outcomes.Study DesignRetrospective cohort study.SettingOutpatient oncology clinic at an academic tertiary care center.MethodsData were obtained from the UNC Health Registry/Cancer Survivorship Cohort. Barriers to care included self‐reported delays in care and inability to obtain needed care due to cost. HRQOL was measured with validated questionnaires: general (PROMIS) and cancer specific (FACT‐GP).ResultsThe sample included 202 patients with head and neck squamous cell carcinoma with a mean age of 59.6 years (SD, 10.0). Eighty‐two percent were male and 87% were White. Sixty‐two patients (31%) reported at least 1 barrier to care. Significant predictors of a barrier to care in unadjusted analysis included age ≤60 years (P =. 007), female sex (P =. 020), being unmarried (P =. 016), being uninsured (P =. 047), and Medicaid insurance (P =. 022). Patients reporting barriers to care had significantly worse physical and mental HRQOL on the PROMIS questionnaires (P <. 001 and P =. 002, respectively) and lower cancer‐specific HRQOL on the FACT‐GP questionnaire (P <. 001), which persisted across physical, social, emotional, and functional domains. There was no difference in 5‐year OS (75.3% vs 84.1%, P =. 177) or 5‐year CSS (81.6% vs 85.4%, P =. 542) in patients with and without barriers to care.ConclusionDelay‐ and affordability‐related barriers are common among survivors of head and neck cancer and appear to be associated with significantly worse HRQOL outcomes. Certain sociodemographic groups appear to be more at risk of patient‐reported barriers to care.
N95 vs Half‐face Respirator Wear in Surgical Trainees: Physiologic and Psychological Effects of Prolonged Use
Authors: Cohen Erin R. , Peña Stefanie , Misztal Carly , Iglesias Thomas , Alejandro Mantero , Dinh Christine T. , Holt Gregory , Thomas Giovana R. 
Published: December 2021

ObjectivesAs specialists of the upper airway, otolaryngologists are at high risk for COVID‐19 transmission. N95 and half‐face respirator (HFR) masks are commonly worn, each with advantages in functionality and comfort. In this study, physiologic and psychological parameters of prolonged N95 vs HFR wear were compared.Study DesignProspective crossover cohort study.SettingSingle academic tertiary care hospital.MethodsA prospective crossover cohort study was performed. Healthy otolaryngology trainees and medical students (N = 23) participated and wore N95 and HFR masks continuously for 3 hours each on separate days. Various measures were analyzed: vitals, spirometry variables, scores on the State‐Trait Anxiety Inventory and HIT‐6 (Headache Impact Test–6), distress, and “difficulty being understood.”ResultsThe average age was 26.3 years (SD, 3.42). There were no significant differences in vital signs and spirometry variables between N95 and HFR wear. N95 wear was associated with decreases in oxygen saturation of approximately 1.09% more than with HFRs (95% CI, 0.105‐2.077). State‐Trait Anxiety Inventory scores increased more with HFR wear when compared with mean changes with N95 wear (95% CI, 1.350‐8.741). There were no significant differences in HIT‐6 scores or distress levels between masks. The proportions of participants reporting difficulty being understood was significantly higher with HFRs.ConclusionsOxygen saturation decreases with prolonged N95 wear, but anxiety and difficulty being understood are greater with HFR wear. Although HFRs have less resistance to gas exchange, N95 respirators may produce less anxiety and distress in clinical situations. Further studies are warranted to evaluate the clinical significance of these differences.Level of Evidence2.
Dendoraite-(NH4), a new phosphate–oxalate mineral related to thebaite-(NH4) from the Rowley mine, Arizona, USA
Authors: Kampf Anthony R. , Cooper Mark A. , Celestian Aaron J. , Ma Chi , Marty Joe 
Published: December 2021

AbstractDendoraite-(NH4), (NH4)2NaAl(C2O4)(PO3OH)2(H2O)2, is a new mineral species from the Rowley mine, Maricopa County, Arizona, USA. It occurs in an unusual bat-guano-related, post-mining assemblage of phases that include a variety of vanadates, phosphates, oxalates and chlorides, some containing NH4+. Other secondary minerals found in association with dendoraite-(NH4) are antipinite, fluorite, mimetite, mottramite, relianceite-(K), rowleyite, salammoniac, struvite, vanadinite, willemite, wulfenite and at least one other new mineral. Crystals of dendoraite-(NH4) are colourless blades up to ~0.1 mm in length. The streak is white and lustre is vitreous, Mohs hardness is 2½, tenacity is brittle and fracture is splintery. The calculated density is 2.122 g⋅cm–3. Dendoraite-(NH4) is optically biaxial (–) with α = 1.490(5), β = 1.540(5) and γ = 1.541(5) (white light); 2Vcalc = 15.7°; and orientation X = b. Electron microprobe analysis gave the empirical formula [(NH4)1.48K0.52]Σ2.00Na0.96(Al0.96Fe3+0.03)Σ0.99(C2O4)[PO2.97(OH)1.03]2(H2O)2, with the C, N and H contents constrained by the crystal structure. Dendoraite-(NH4) is monoclinic, P21/n, with a = 10.695(6), b = 6.285(4), c = 19.227(12) Å, β = 90.933(10)°, V = 1292(2) Å3, and Z = 4. The structural unit in the crystal structure of dendoraite-(NH4) (R1 = 0.0467 for 1322 Io > 2σI reflections) is a double-strand chain of corner-sharing AlO6 octahedra and PO3OH tetrahedra decorated by additional PO3OH tetrahedra and C2O4 groups. Topologically, this is the same chain found in the structure of thebaite-(NH4). The decorated chains connect to one another through links to NaO7(H2O) polyhedra to form a [Na(H2O)Al(C2O4)(PO3OH)2]2– sheet, which connect to one another through bonds to (NH4)/K and through hydrogen bonds.
Relianceite-(K), a new phosphate–oxalate mineral related to davidbrownite-(NH4) from the Rowley mine, Arizona, USA
Authors: Kampf Anthony R. , Cooper Mark A. , Celestian Aaron J. , Ma Chi , Marty Joe 
Published: December 2021

AbstractRelianceite-(K), K4Mg(V4+O)2(C2O4)(PO3OH)4(H2O)10, is a new mineral species from the Rowley mine, Maricopa County, Arizona, USA. It occurs in an unusual bat-guano-related, post-mining assemblage of phases. Other secondary minerals associated with relianceite-(K) are antipinite, dendoraite-(NH4), fluorite, mimetite, mottramite, rowleyite, salammoniac, struvite, vanadinite, willemite, wulfenite and at least one other new mineral. Crystals of relianceite-(K) are sky blue prisms up to ~0.1 mm in length. The streak is very pale blue and lustre is vitreous, Mohs hardness is 2½, tenacity is brittle and fracture is splintery. The calculated density is 2.111 g⋅cm–3. Relianceite-(K) is optically biaxial (+) with α = 1.528(2), β = 1.529(2), γ = 1.562(2) (white light); 2Vmeas = 22(1)°; orientation Z = b; pleochroism: X = colourless, Y = pale blue, Z = pale blue; X < Y ≈ Z. Electron microprobe analysis gave the empirical formula [K2.21(NH4)1.79]Σ4.00Mg0.96(V4+0.95O)2(C2O4)[P1.03O3.03(OH)0.97]4(H2O)10, with the C, N and H contents constrained by the crystal structure. Raman spectroscopy confirmed the presence of NH4 and C2O4. Relianceite-(K) is monoclinic, Pc, with a = 12.404 (7) Å, b = 9.014 (6), c = 13.260 (8) Å, β = 100.803(10)°, V = 1456 (2) Å3 and Z = 2. The structural unit in the crystal structure of relianceite-(K) (R1 = 0.0540 for 3751 Io > 2σI reflections) is a (V4+O)2(C2O4)(PO3OH)4 chain in which VO6 octahedra are bridged by an oxalate group to form [V2C2O12] dimers, PO3OH tetrahedra form a double bridge between the VO6 octahedra of the dimers, and additional PO3OH tetrahedra decorate the chain. Topologically, this is the same chain found in the structure of davidbrownite-(NH4). The MgO(H2O)5 octahedron can be considered a distant decoration on the chain. The chains are linked to each other through an extensive system of K/NH4–O bonds and hydrogen bonds.
Increase in ACC GABA+ levels correlate with decrease in migraine frequency, intensity and disability over time
Authors: Peek Aimie L. , Leaver Andrew M. , Foster Sheryl , Puts Nicolaas A. , Oeltzschner Georg , Henderson Luke , Galloway Graham , Ng Karl , Refshauge Kathryn , Rebbeck Trudy 
Published: December 2021

Abstract
Background
An imbalance between inhibitory and excitatory neurometabolites has been implicated in chronic pain. Prior work identified elevated levels of Gamma-aminobutyric acid + macromolecules (“GABA+”) using magnetic resonance spectroscopy (MRS) in people with migraine. What is not understood is whether this increase in GABA+ is a cause, or consequence of living with, chronic migraine. Therefore, to further elucidate the nature of the elevated GABA+ levels reported in migraine, this study aimed to observe how GABA+ levels change in response to changes in the clinical characteristics of migraine over time.

Methods
We observed people with chronic migraine (ICHD-3) over 3-months as their treatment was escalated in line with the Australian Pharmaceutical Benefits Scheme (PBS). Participants underwent an MRS scan and completed questionnaires regarding migraine frequency, intensity (HIT-6) and disability (WHODAS) at baseline and following the routine 3 months treatment escalation to provide the potential for some participants to recover. We were therefore able to monitor changes in brain neurochemistry as clinical characteristics potentially changed over time.

Results
The results, from 18 participants who completed both baseline and follow-up measures, demonstrated that improvements in migraine frequency, intensity and disability were associated with an increase in GABA+ levels in the anterior cingulate cortex (ACC); migraine frequency (r = − 0.51, p = 0.03), intensity (r = − 0.51, p = 0.03) and disability (r = − 0.53, p = 0.02). However, this was not seen in the posterior cingulate gyrus (PCG). An incidental observation found those who happened to have their treatment escalated with CGRP-monoclonal antibodies (CGRP-mAbs) (n = 10) had a greater increase in ACC GABA+ levels (mean difference 0.54 IU IQR [0.02 to 1.05], p = 0.05) and reduction in migraine frequency (mean difference 10.3 IQR [2.52 to 18.07], p = 0.01) compared to those who did not (n = 8).

Conclusion
The correlation between an increase in ACC GABA+ levels with improvement in clinical characteristics of migraine, suggest previously reported elevated GABA+ levels may not be a cause of migraine, but a protective mechanism attempting to suppress further migraine attacks.