bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prescription of analgesia in emergency medicine (POEM) secondary analysis: an observational multicentre comparison of pain relief provided to adults and children with an isolated limb fracture and/or dislocation
Authors: Wilson Sarah , Quinlan Jane , Beer Sally , Darwent Melanie , Dainty Jack R. , Sheehan James Robert , Keating Liza 
Published: January 2021

BackgroundAcute pain is a common reason for emergency department (ED) attendance. Royal College of Emergency Medicine (RCEM) pain management audits have shown national variation and room for improvement. Previous evidence suggests that children receive less satisfactory pain management than adults.MethodsPrescription of analgesia in emergency medicine is a cross-sectional observational study of consecutive patients presenting to 12 National Health Service EDs with an isolated long bone fracture and/or dislocation, and was carried out between 2015 and 2017. Using the recommendations in the RCEM Best Practice Guidelines, pain management in ED was assessed for differences of age (adults vs children) and hospital type (children’s vs all patients).ResultsFrom the total 8346 patients, 38% were children (median age 8 years). There was better adherence to the RCEM guidance for children than adults (24% (766/3196) vs 11% (579/5123)) for the combined outcome of timely assessment, pain score and appropriate analgesia. In addition, children were significantly more likely than adults to receive analgesia appropriate to the pain score (of those with a recorded pain score 67% (1168/1744) vs 52% (1238/2361)). Children’s hospitals performed much better across all reported outcomes compared with general hospitals.ConclusionsIn contrast to previous studies, children with a limb fracture/dislocation are more likely than adults to have a pain score documented and to receive appropriate analgesia. Unexpectedly, children’s EDs performed better than general EDs in relation to timely and appropriate analgesia but the reasons for this are not apparent from the present study.
Medication adherence in community-dwelling older people exposed to chronic polypharmacy
Authors: Franchi Carlotta , Ardoino Ilaria , Ludergnani Monica , Cukay Gjiliola , Merlino Luca , Nobili Alessandro 
Published: January 2021

BackgroundTo evaluate medication adherence and associated factors of seven of the most common drug classes prescribed to community-dwelling older people.MethodsThis is a retrospective cohort study on medication adherence in community-dwelling older people (65–94 years old) on chronic polypharmacy and recorded from 2013 to 2015 in the administrative database of the Lombardy region (Northern Italy). Adherence was assessed for diabetic drugs, antithrombotic agents, drugs acting on the renin–angiotensin system, statins, bisphosphonates, antidepressants and drugs for obstructive airway diseases by calculating the medication possession ratio (MPR). Patients were then divided in fully (MPR ≥80%), partially (40%≤MPR<80%) and poorly adherent (10%<MPR<40%).ResultsAmong 140 537 patients included in the study, only 19.3% was fully adherent to all the therapies considered. Almost 40% of them were poorly adherent to at least one drug class, becoming 50% when patients exposed to four or more drug classes were considered. In adjusted regression model, being women (OR=1.14, 95% CI 1.13 to 1.16) and aged ≥80 years old (OR=1.22, 95% CI 1.20 to 1.24) were associated with an overall lower adherence. Instead, the participation to an experimental healthcare programme was associated with higher adherence (OR=0.92, 95% CI 0.87 to 0.96). Furthermore, being coprescribed with ≥10 drugs was associated with lower adherence to all the drug classes, with different effects (ORs from 0.42 to 0.73).ConclusionThis study overall shows a low medication adherence in community-dwelling older people on chronic polypharmacy, especially in women and oldest old. The implementation and promotion of healthcare programmes for these patients could help improve overall adherence to chronic drug therapies.
Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma
Authors: Pokorny Rebecca , McPherson Jordan P , Haaland Benjamin , Grossmann Kenneth F , Luckett Carolyn , Voorhies Benjamin Newell , Sageser Daniel S , Wallentine Jocelyn , Tolman Zachary , Hu-Lieskovan Siwen , Swami Umang 
Published: January 2021

BackgroundRandomized trials evaluating programmed cell death protein 1 (PD-1) inhibitors in metastatic melanoma either permitted treatment for 2 years (pembrolizumab) or more (nivolumab). The optimal duration of therapy is currently unknown due to limited data, and shorter therapies may be effective.MethodsData of patients with metastatic cutaneous melanoma treated with single-agent PD-1 inhibitors at Huntsman Cancer Institute from January 1, 2015, to December 31, 2018, was reviewed to identify a continuous series of patients who made the joint decision with their provider to electively discontinue therapy at 1 year (>6 months and <18 months) in the setting of ongoing treatment response or disease stability. Patients were excluded if they received PD-1 inhibitors with other systemic therapy, had prior exposure to PD-1 therapy, or discontinued treatment due to disease progression or immune-related adverse event. Best objective response (BOR) per RECIST V.1.1 at treatment discontinuation, progression-free survival (PFS), and retreatment characteristics was analyzed.ResultsOf 480 patients who received PD-1 inhibitors, 52 met the inclusion criteria. The median treatment duration from first to the last dose was 11.1 months (95% CI 10.5 to 11.4). BOR was complete response in 13 (25%), partial response in 28 (53.8%), and stable disease in 11 (21.2%) patients. After a median follow-up of 20.5 months (range 3–49.2) from treatment discontinuation, 39 (75%) patients remained without disease progression, while 13 (25%) had progression (median PFS 3.9 months; range 0.7–30.9). On multivariable analysis, younger age, history of brain metastasis, and higher lactate dehydrogenase at the time of anti-PD-1 discontinuation were associated with recurrence. Patients with recurrent melanoma were managed with localized treatment, anti-PD-1 therapies, and BRAF-MEK inhibitors. All patients except one were alive at data cutoff.ConclusionIn this large real-world, observational cohort study, the majority of patients with metastatic melanoma after 1 year of anti-PD-1 therapy remained without progression on long-term follow-up. The risk of disease progression even in patients with residual disease on imaging was low. After prospective validation, elective PD-1 discontinuation at 1 year may reduce financial and immunotherapy-related toxicity without sacrificing outcomes.
Revisiting the supersymmetric Pati–Salam models from intersecting D6-branes
Authors: Li Tianjun , Mansha Adeel , Sun Rui 
Published: January 2021

AbstractEmploying novel random and supervised scanning methods, we systematically revisit the construction of three-family $$N=1$$

N
=
1

supersymmetric Pati–Salam models in Type IIA orientifolds on $$\mathbf{T}^6/({\mathbb {Z}}_2\times {\mathbb {Z}}_2)$$

T

6

/

(

Z
2

×

Z
2

)

with intersecting D6-branes. Arising from the stacks of D6-branes with U(n) gauge symmetries, the Pati–Salam gauge symmetries $$SU(4)_C\times SU(2)_L \times SU(2)_R$$

S
U

(
4
)

C

×
S
U

(
2
)

L

×
S
U

(
2
)

R

can be broken down to the Standard Model via D-brane splitting as well as D- and F-flatness preserving Higgs mechanism. Also, the hidden sector contains USp(n) branes, which are parallel with the orientifold planes or their $${{\mathbb {Z}}_2}$$

Z
2

images. We find that the Type II T-duality in the previous study is not an equivalent relation in Pati–Salam model building if the model is not invariant under $$SU(2)_L$$

S
U

(
2
)

L

and $$SU(2)_R$$

S
U

(
2
)

R

exchange, and provides a way to obtain new models. We systematically construct the new models with three families, which usually do not have gauge coupling unification at the string scale. We for the first time construct the Pati–Salam models with at least one wrapping number whose absolute value reaching 5. In particular, for one large wrapping number equal to 5, we find that one kind of model carries more refined gauge couplings, and thus with more possibilities to have approximate gauge coupling unification.
Mesenchymal Stem Cell–Secreted Extracellular Vesicles Instruct Stepwise Dedifferentiation of Breast Cancer Cells into Dormancy at the Bone Marrow Perivascular Region
Authors: Sandiford Oleta A. , Donnelly Robert J. , El-Far Markos H. , Burgmeyer Lisa M. , Sinha Garima , Pamarthi Sri Harika , Sherman Lauren S. , Ferrer Alejandra I. , DeVore Dariana E. , Patel Shyam A. , Naaldijk Yahaira , Alonso Sara , Barak Pradeep , Bryan Margarette , Ponzio Nicholas M. , Narayanan Ramaswamy , Etchegaray Jean-Pierre , Kumar Rakesh , Rameshwar Pranela 
Published: January 2021

Abstract

In the bone marrow (BM), breast cancer cells (BCC) can survive in dormancy for decades as cancer stem cells (CSC), resurging as tertiary metastasis. The endosteal region where BCCs exist as CSCs poses a challenge to target them, mostly due to the coexistence of endogenous hematopoietic stem cells. This study addresses the early period of dormancy when BCCs enter BM at the perivascular region to begin the transition into CSCs, which we propose as the final step in dormancy. A two-step process comprises the Wnt-β-catenin pathway mediating BCC dedifferentiation into CSCs at the BM perivascular niche. At this site, BCCs responded to two types of mesenchymal stem cell (MSC)–released extracellular vesicles (EV) that may include exosomes. Early released EVs began the transition into cycling quiescence, DNA repair, and reorganization into distinct BCC subsets. After contact with breast cancer, the content of EVs changed (primed) to complete dedifferentiation into a more homogeneous population with CSC properties. BCC progenitors (Oct4alo), which are distant from CSCs in a hierarchical stratification, were sensitive to MSC EVs. Despite CSC function, Oct4alo BCCs expressed multipotent pathways similar to CSCs. Oct4alo BCCs dedifferentiated and colocalized with MSCs (murine and human BM) in vivo. Overall, these findings elucidate a mechanism of early dormancy at the BM perivascular region and provide evidence of epigenome reorganization as a potential new therapy for breast cancer.

Significance:
These findings describe how the initial process of dormancy and dedifferentiation of breast cancer cells at the bone marrow perivascular niche requires mesenchymal stem cell–derived exosomes, indicating a potential target for therapeutic intervention.
Gene Expression Pathways in Prostate Tissue Associated with Vigorous Physical Activity in Prostate Cancer
Authors: Pernar Claire H. , Parmigiani Giovanni , Giovannucci Edward L. , Rimm Eric B. , Tyekucheva Svitlana , Loda Massimo , Finn Stephen P. , Heiden Matthew G. Vander , Fiorentino Michelangelo , Ebot Ericka M. , Mucci Lorelei A. 
Published: January 2021

Abstract

Background:
Men engaged in high physical activity have lower risks of advanced and fatal prostate cancer. Mechanisms underlying this association are not well understood but may include systemic and tumor-specific effects. We investigated potential mechanisms linking physical activity and gene expression in prostate tissue from men with prostate cancer.

Methods:
We included a subset of 118 men in the Health Professionals Follow-up Study diagnosed with prostate cancer between 1986 and 2005 with whole-transcriptome gene expression profiling on tumor and adjacent normal prostate tissue and physical activity data. Long-term vigorous physical activity was self-reported as the average time spent engaged in various forms of recreational physical activity at baseline and biennially until prostate cancer diagnosis. Gene set enrichment analysis was performed among KEGG and Hallmark gene sets to identify pathways with differential expression based on vigorous physical activity.

Results:
In adjacent normal tissue, we identified 25 KEGG gene sets enriched (downregulated) in the highest compared with lowest quintile of vigorous physical activity at an FDR &lt;0.10, including a number of cancer- and immune-related pathways. Although no gene sets reached statistical significance in tumor tissue, top gene sets differentially expressed included TGF beta, apoptosis, and p53 signaling pathways.

Conclusions:
These findings suggest that physical activity may influence the tumor microenvironment. Future studies are needed to confirm these findings and further investigate potential mechanisms linking physical activity to lethal prostate cancer.

Impact:
Identification of gene expression alterations in the prostate associated with physical activity can improve our understanding of prostate cancer etiology.
Phase Ib Clinical Trial of IGV-001 for Patients with Newly Diagnosed Glioblastoma
Authors: Andrews David W. , Judy Kevin D. , Scott Charles B. , Garcia Samantha , Harshyne Larry A. , Kenyon Lawrence , Talekar Kiran , Flanders Adam , Atsina Kofi-Buaku , Kim Lyndon , Martinez Nina , Shi Wenyin , Werner-Wasik Maria , Liu Haisong , Prosniak Mikhail , Curtis Mark , Kean Rhonda , Ye Donald Y. , Bongiorno Emily , Sauma Sami , Exley Mark A. , Pigott Kara , Hooper D. Craig 
Published: January 2021

Abstract

Purpose:
Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma.

Patients and Methods:
This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4–6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies.

Results:
Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001–treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine–DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted.

Conclusions:
IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).
Transcription Strikes Back: Clinical Utility of Lung Adenocarcinoma Subtypes
Authors: Skoulidis Ferdinandos 
Published: January 2021

Abstract
Using transcriptional profiling, three robust subtypes of nonsquamous non–small cell lung cancer were defined, independently of initiating oncogenic driver events. Subtype-specific differential sensitivity to MEK1/2 inhibitors was reported and an interaction between the mucinous subtype, STK11/LKB1 genomic alterations, and inferior clinical outcomes with atezolizumab in the OAK clinical trial was identified.
See related article by Daemen et al., p. 1162
Combined PD-1/VEGFR Blockade: A New Era of Treatment for Hepatocellular Cancer
Authors: Pinato David J. , Fessas Petros , Cortellini Alessio , Rimassa Lorenza 
Published: January 2021

Abstract
Combination immunotherapy is an expanding therapeutic modality in hepatocellular carcinoma (HCC), a disease where single-agent immunotherapy has failed to lead to survival benefit. The RESCUE trial adds camrelizumab and apatinib to the therapeutic armamentarium of advanced HCC, raising questions around the optimal positioning of various combination regimens in liver cancer.
See related article by Xu et al., p. 1003
Predicting CAR-T cell Immunotherapy Success through ImmunoPET
Authors: Volpe Alessia , Nagle Veronica L. , Lewis Jason S. , Ponomarev Vladimir 
Published: January 2021

Abstract
Chimeric antigen receptor (CAR)-T cell therapy has generated unprecedented advances in the treatment of hematologic cancers, but readily translatable imaging approaches to visualize the in vivo dynamics of CAR-T cells are lacking. Noninvasive PET imaging is the ideal tool to monitor CAR-T cells.
See related article by Simonetta et al., p. 1058
Metabolic Regulator IAPP (Amylin) Is Required for BRAF and RAS Oncogene-Induced Senescence
Authors: Garnett Sam , de Bruyns Angeline , Provencher-Tom Veronique , Dutchak Kendall , Shu Ran , Dankort David 
Published: January 2021

Abstract

Cellular senescence is characterized by a prolonged and predominantly irreversible cell-cycle arrest state, which is linked to loss of tissue function and aging in mammals. Moreover, in response to aberrant oncogenic signals such as those from oncogenic RAS or BRAF, senescence functions as an intrinsic tumor suppressor mechanism restraining tumor progression. In addition to this durable proliferative block, senescent cells adopt altered morphologies, transcriptional profiles, and metabolism, while often possessing unusual heterochromatin formation termed senescence-associated heterochromatic foci. To uncover genes that are required to permit proliferation in the face of sustained oncogene signaling, we conducted an shRNA-based genetic screen in primary cells expressing inducible BRAF. Here we show that depletion of a known glycolysis regulator, islet amylin polypeptide (IAPP also known as amylin), prevents RAS and BRAF oncogene-induced senescence (OIS) in human cells. Importantly, depletion of IAPP resulted in changes of the cells' metabolome and this metabolic reprogramming was associated with widespread alterations in chromatin modifications compared with senescent cells. Conversely, exogenous treatment of IAPP-depleted cells with amylin restored OIS. Together, our results demonstrate that the metabolic regulator IAPP is important regulator of OIS. Moreover, they suggest that IAPP analog treatment or activation of IAPP signaling in RAS/BRAF mutant tumors may have therapeutic potential through senescence induction.

Implications:
These findings demonstrate that IAPP is a novel metabolic regulator of oncogene-induced senescence and use of IAPP analogs may be therapeutically effective to restore growth arrest to BRAF and/or RAS mutant cancers.
Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence
Authors: Duy Cihangir , Li Meng , Teater Matt , Meydan Cem , Garrett-Bakelman Francine E. , Lee Tak C. , Chin Christopher R. , Durmaz Ceyda , Kawabata Kimihito C. , Dhimolea Eugen , Mitsiades Constantine S. , Doehner Hartmut , D'Andrea Richard J. , Becker Michael W. , Paietta Elisabeth M. , Mason Christopher E. , Carroll Martin , Melnick Ari M. 
Published: January 2021

Abstract

Patients with acute myeloid leukemia (AML) frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary AML cells enter a senescence-like phenotype following chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA sequencing suggested depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations with distinct senescence-like cells. This senescence effect was transient and conferred superior colony-forming and engraftment potential. Entry into this senescence-like phenotype was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors. Altogether, we propose that AML relapse is facilitated by a senescence-like resilience phenotype that occurs regardless of their stem cell status. Upon recovery, these post-senescence AML cells give rise to relapsed AMLs with increased stem cell potential.

Significance:
Despite entering complete remission after chemotherapy, relapse occurs in many patients with AML. Thus, there is an urgent need to understand the relapse mechanism in AML and the development of targeted treatments to improve outcome. Here, we identified a senescence-like resilience phenotype through which AML cells can survive and repopulate leukemia.
This article is highlighted in the In This Issue feature, p. 1307
Predictors for Rapid Progression of Coronary Calcification: An Optical Coherence Tomography Study
Authors: Nakajima Akihiro , Araki Makoto , Kurihara Osamu , Minami Yoshiyasu , Soeda Tsunenari , Yonetsu Taishi , Higuma Takumi , Kakuta Tsunekazu , McNulty Iris , Lee Hang , Malhotra Rajeev , Nakamura Sunao , Jang Ik‐Kyung 
Published: January 2021

Background
The role of coronary calcification in cardiovascular events and plaque stabilization is still being debated, and factors involved in the progression of coronary calcification are not fully understood. This study aimed to identify the predictors for rapid progression of coronary calcification.

Methods and Results

Patients with serial optical coherence tomography imaging at baseline and at 6 months were selected. Changes in the calcification index and predictors for progression of calcification were studied. Calcification index was defined as the product of the mean calcification arc and calcification length. Rapid progression of calcification was defined as an increase in the calcification index above the median value. Among 187 patients who had serial optical coherence tomography imaging, 235 calcified plaques were identified in 105 patients (56.1%) at baseline. After 6 months, the calcification index increased in 95.3% of calcified plaques from 132.0 to 178.2 (
P
<0.001). In multivariable analysis, diabetes mellitus (odds ratio [OR], 3.911;
P
<0.001), chronic kidney disease (OR, 2.432;
P
=0.037), lipid‐rich plaque (OR, 2.698;
P
=0.034), and macrophages (OR, 6.782;
P
<0.001) were found to be independent predictors for rapid progression of coronary calcification. Interestingly, rapid progression of calcification was associated with a significant reduction of inflammatory features (thin‐cap fibroatheroma; from 21.2% to 11.9%,
P
=0.003; macrophages; from 74.6% to 61.0%,
P
=0.001).

Conclusions
Diabetes mellitus, chronic kidney disease, lipid‐rich plaque, and macrophages were independent predictors for rapid progression of coronary calcification. Baseline vascular inflammation and subsequent stabilization may be related to rapid progression of calcification.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01110538.