bluuebunny/crossref_metadata_2025_split huggingface dataset:
Camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer: a single-arm, open-label, phase II trial
Authors: Chen Xiaofeng , Wu Xiaofeng , Wu Hao , Gu Yanhong , Shao Yang , Shao Qianwen , Zhu Feipeng , Li Xiao , Qian Xiaofeng , Hu Jun , Zhao Fengjiao , Mao Weidong , Sun Jing , Wang Jian , Han Gaohua , Li Changxian , Xia Yongxiang , Seesaha Poshita Kumari , Zhu Dongqin , Li Huajun , Zhang Junling , Wang Guoqiang , Wang Xuehao , Li Xiangcheng , Shu Yongqian 
Published: November 2020

BackgroundImmune checkpoint inhibitors monotherapy has been studied in patients with advanced biliary tract cancer (BTC). The aim of this study was to assess the efficacy and safety of camrelizumab, plus gemcitabine and oxaliplatin (GEMOX) as first-line treatment in advanced BTC and explored the potential biomarkers associated with response.MethodsIn this single-arm, open-label, phase II study, we enrolled stage IV BTC patients. Participants received camrelizumab (3 mg/kg) plus gemcitabine (800 mg/m2) and oxaliplatin (85 mg/m2). Primary endpoints were 6-month progression-free survival (PFS) rate and safety. Secondary endpoints were objective response rate (ORR), PFS and overall survival (OS). Exploratory endpoints included association between response and tumor mutational burden (TMB), blood TMB, dynamic change of ctDNA and immune microenvironment.Results54 patients with advanced BTC were screened, of whom 38 eligible patients were enrolled. One patient withdrew informed consent before first dose treatment. Median follow-up was 11.8 months. The 6-month PFS rate was 50% (95% CI 33 to 65). Twenty (54%) out of 37 patients had an objective response. The median PFS was 6.1 months and median OS was 11.8 months. The most common treatment-related adverse events (TRAEs) were fatigue (27 (73%)) and fever (27 (73%)). The most frequent grade 3 or worse TRAEs were hypokalemia (7 (19%)) and fatigue (6 (16%)). The ORR was 80% in patients with programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≥1% versus 53.8% in PD-L1 TPS <1%. There was no association between response and TMB, blood TMB, immune proportion score or immune cells (p>0.05), except that PFS was associated with blood TMB. Patients with positive post-treatment ctDNA had shorter PFS (p=0.007; HR, 2.83; 95% CI 1.27 to 6.28).ConclusionCamrelizumab plus GEMOX showed a promising antitumor activity and acceptable safety profile as first-line treatment in advanced BTC patients. Potential biomarkers are needed to identify patients who might respond to camrelizumab plus GEMOX.Trial registration numberNCT03486678.
Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment
Authors: Wang Zhenghang , Zhao Xiaochen , Gao Chan , Gong Jifang , Wang Xicheng , Gao Jing , Li Zhongwu , Wang Jie , Yang Bo , Wang Lei , Zhang Bei , Zhou Yifan , Wang Dalei , Li Xiaofang , Bai Yuezong , Li Jian , Shen Lin 
Published: November 2020

BackgroundMicrosatellite instability (MSI) represents the first pan-cancer biomarker approved to guide immune checkpoint blockade (ICB) treatment. However its widespread testing, especially outside of gastrointestinal cancer, is hampered by tissue availability.MethodsAn algorithm for detecting MSI from peripheral blood was established and validated using clinical plasma samples. Its value for predicting ICB efficacy was evaluated among 60 patients with advanced gastrointestinal cancer. The landscape of MSI in blood was also explored among 5138 advanced solid tumors.ResultsThe algorithm included 100 microsatellite markers with high capture efficiency, sensitivity, and specificity. In comparison with orthogonal tissue PCR results, the method displayed a sensitivity of 82.5% (33/40) and a specificity of 96.2% (201/209), for an overall accuracy of 94.0% (234/249). When the clinical validation cohort was dichotomized by pretreatment blood MSI (bMSI), bMSI-high (bMSI-H) predicted both improved progression-free survival and overall survival than the blood microsatellite stable (bMSS) patients (HRs: 0.431 and 0.489, p=0.005 and 0.034, respectively). Four patients with bMSS were identified to have high blood tumor mutational burden (bTMB-H) and trended towards a better survival than the bMSS-bTMB-low (bTMB-L) subset (HR 0.026, 95% CI 0 to 2.635, p=0.011). These four patients with bMSS-bTMB-H plus the bMSI-H group collectively displayed significantly improved survival over the bMSS-bTMB-L patients (HR 0.317, 95% CI 0.157 to 0.640, p<0.001). Pan-cancer prevalence of bMSI-H was largely consistent with that shown for tissue except for much lower rates in endometrial and gastrointestinal cancers, and a remarkably higher prevalence in prostate cancer relative to other cancer types.ConclusionsWe have developed a reliable and robust next generation sequencing-based bMSI detection strategy which, in combination with a panel enabling concurrent profiling of bTMB from a single blood draw, may better inform ICB treatment.
Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma
Authors: Tripathi Abhishek , Lin Edwin , Xie Wanling , Flaifel Abdallah , Steinharter John A , Stern Gatof Emily N , Bouchard Gabrielle , Fleischer Justin H , Martinez-Chanza Nieves , Gray Connor , Mantia Charlene , Thompson Linda , Wei Xiao X , Giannakis Marios , McGregor Bradley A , Choueiri Toni K , Agarwal Neeraj , McDermott David F , Signoretti Sabina , Harshman Lauren C 
Published: November 2020

BackgroundCD73–adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5′-nucleotidase (NT5E), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)) and A2 adenosine receptor (A2AR;ADORA2A) transcript levels with markers of angiogenesis and antitumor immune response.MethodsPatients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73negative(CS=0), CD73lowor CD73high(< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and highNT5E,ENTPD1andADORA2Agene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared betweenNT5E,ENTPD1andADORA2Aexpression groups.ResultsAmong the 138 patients eligible for inclusion, ‘any’ CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73hightumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73negativegroup (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, highNT5Eexpression was associated with significantly worse 5-year OS (p=0.008).NT5EandENTPD1expression correlated with higher regulatory T cell (Treg) signature, whileADORA2Aexpression was associated with increased Treg and angiogenesis signatures.ConclusionsHigh CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73–adenosine pathway in RCC.
New non-invasive device to promote primary closure of the fascia and prevent loss of domain in the open abdomen: a pilot study
Authors: Rezende-Neto Joao Baptista , Camilotti Bruna Gewehr 
Published: November 2020

BackgroundPrimary closure of the fascia at the conclusion of a stage laparotomy can be a challenging task. Current techniques to medialize the fascial edges in open abdomens entail several trips to the operating room and could result in fascial damage. We conducted a pilot study to investigate a novel non-invasive device for gradual reapproximation of the abdominal wall fascia in the open abdomen.MethodsMechanically ventilated patients ≥16 years of age with the abdominal fascia deliberately left open after a midline laparotomy for trauma and acute care surgery were randomized into two groups. Control group patients underwent standard care with negative pressure therapy only. Device group patients were treated with negative pressure therapy in conjunction with the new device for fascial reapproximation. Exclusion criteria: pregnancy, traumatic hernias, pre-existing ventral hernias, burns, and body mass index ≥40 kg/m2. The primary outcome was successful fascial closure by direct suture of the fascia without mesh or component separation. Secondary outcomes were abdominal wall complications.ResultsThirty-eight patients were investigated, 20 in the device group and 18 in the control group. Primary closure of the fascia by direct suture without mesh or component separation was achieved in 17 patients (85%) in the device group and only 10 patients (55.6%) in the control group (p=0.0457). Device group patients were 53% more likely to experience primary fascial closure by direct suture than control group patients. Device group showed gradual reduction (p<0.005) in the size of the fascial defects; not seen in control group. There were no complications related to the device.ConclusionsThe new device applied externally on the abdominal wall promoted reapproximation of the fascia in the midline, preserved the integrity of the fascia, and improved primary fascial closure rate compared with negative pressure therapy system only.Level of evidenceI, randomized controlled trial.
Intraoperative vasopressor use during emergency surgery on injured meth users
Authors: Edwards Alexandra Marie , Johnson Eric Gregory , Bernard Andrew C. 
Published: November 2020

BackgroundMethamphetamine is a growing drug of abuse in America. Patients with recent methamphetamine use pose potential complications to general anesthesia due to changes in hemodynamics and arrhythmias. Limited data exists on the incidence of intraoperative complications on methamphetamine-intoxicated patients requiring urgent or emergent trauma surgery. This study aims to describe intraoperative complications observed in methamphetamine and amphetamine-intoxicated patients requiring emergent surgery.MethodsUsing the Trauma Registry at our ACS-verified level I trauma center, we completed a single-center, descriptive, retrospective cohort review between July 1, 2012 and June 30, 2016, of adult patients requiring emergent surgery with a positive urine-drug screen for methamphetamines or amphetamines. The objective was to evaluate vasopressor utilization during surgical operation.ResultsA total of 92 patients were identified with a positive UDS for amphetamine and/or methamphetamine who went to the operating room within 24 hours of admission. Thirty-two (34%) patients received one or more (≥1) doses of vasopressor, while 60 patients (66%) received no vasopressor. Changes in mean arterial pressure (MAP) were noted in 64%, while only 3% experienced an EKG change. A binomial logistic regression showed age, base deficit and change in MAP to be predictive of vasopressor use (p<0.002). No intraoperative cardiac events or anesthetic complications were seen.DiscussionHemodynamic instability in the amphetamine and methamphetamine-intoxicated population may be more directly related to degree of resuscitation required, than the presence of a positive UDS.Level of evidenceIV
Potassium and micronutrient fertilizer addition in a mock aquaponic system for drug-type Cannabis sativa L. cultivation
Authors: Yep Brandon , Zheng Youbin 
Published: November 2020

Cultivating drug-type Cannabis sativa L. with aquaponics could reduce mineral fertilizer use; however, its nutrient solution is often unbalanced and low in K+ and micronutrients. It is unknown if a K+ fertilizer, a micronutrient fertilizer, or both, would improve C. sativa production in aquaponic solution, as optimal K+ and micronutrient concentrations in the root zone for C. sativa during the flowering stage have not been investigated. To determine the effects of adding a K+ fertilizer and a micronutrient fertilizer to aquaponic solution for C. sativa production, we grew drug-type C. sativa in five aquaponic based solutions: aquaponic solution (control plants) (15 mg·L−1 K+); aquaponic solution with added micronutrients (Fe3+, Cu2+, Mn2+, B3+, Mo3+, and Zn2+); and aquaponic solution with added micronutrients and three K+ concentrations (75, 113, and 150 mg·L−1) during the flowering stage. To evaluate the impact of additional K+ and micronutrients on C. sativa production, we measured growth (vegetative parameters and weight), physiology (leaf gas exchange), leaf nutrition content, and yield (inflorescence weight). Adding the K+ fertilizer at 75 and 113 mg·L−1 with micronutrients to aquaponic solution increased harvest index (marketable inflorescence to shoot weight) by 16% and 22% compared with the control, respectively. Cannabis sativa dry apical inflorescence and total inflorescence yield also increased linearly with increasing K+ concentration. Alternatively, plants grown in the control (suboptimal K+ and micronutrient conditions) had no difference in growth or measured physiological parameters compared with plants with supplemented nutrients. Our study suggests that aquaponic solution mitigates low K+ concentrations from causing deficiency.
Rastall gravity extension of the standard $$\Lambda $$CDM model: theoretical features and observational constraints
Authors: Akarsu Özgür , Katırcı Nihan , Kumar Suresh , Nunes Rafael C. , Öztürk Burcu , Sharma Shivani 
Published: November 2020

AbstractWe present a detailed investigation of the Rastall gravity extension of the standard $$\Lambda $$
Λ
CDM model. We review the model for two simultaneous modifications of different nature in the Friedmann equation due to the Rastall gravity: the new contributions of the material (actual) sources (considered as effective source) and the altered evolution of the material sources. We discuss the role/behavior of these modifications with regard to some low redshift tensions, including the so-called $$H_0$$

H
0

tension, prevailing within the standard $$\Lambda $$
Λ
CDM. We constrain the model at the level of linear perturbations, and obtain the first constraints through a robust and accurate analysis using the latest full Planck cosmic microwave background (CMB) data, with and without including baryon acoustic oscillations (BAO) data. We find that the Rastall parameter $$\epsilon $$
ϵ
(null for general relativity) is consistent with zero at 68% CL (with a tendency towards positive values, $$-0.0001< \epsilon < 0.0007$$

-
0.0001
<
ϵ
<
0.0007

(CMB+BAO) at 68% CL), which in turn implies no significant statistical evidence for deviation from general relativity, and also a precision of $$\mathcal {O}(10^{-4})$$

O
(

10

-
4

)

for the coefficient $$-1/2$$

-
1
/
2

of the term $$g_{\mu \nu }R$$

g

μ
ν

R

in the Einstein field equations of general relativity (guaranteeing the local energy-momentum conservation). We explore the consequences led by the Rastall gravity on the cosmological parameters in the light of the observational analyses. It turns out that the effective source, with a present-day density parameter $$\Omega _\mathrm{X0}=-0.0010\pm 0.0013$$

Ω

X
0

=
-
0.0010
±
0.0013

(CMB+BAO, 68% CL), dynamically screens the usual vacuum energy at high redshifts, but this mechanism barely works due to the opposition by the altered evolution of cold dark matter. Consequently, two simultaneous modifications of different nature in the Friedmann equation by the Rastall gravity act against each other, and do not help to considerably relax the low redshift tensions, including the so-called $$H_0$$

H
0

tension. Our results may offer a guide for the research community that studies the Rastall gravity in various aspects of gravitation and cosmology.
Revisiting the production of $$J/\psi $$ pairs at the LHC
Authors: Prokhorov A. A. , Lipatov A. V. , Malyshev M. A. , Baranov S. P. 
Published: November 2020

AbstractWe consider the prompt double$$J/\psi $$J/ψproduction inppcollisions at the LHC in the framework of$$k_T$$kT-factorization QCD approach. Using the fragmentation mechanism, we evaluate the color octet contributions to the production cross sections taking into account the combinatorial effects of multiple gluon radiation in the initial state driven by the Ciafaloni–Catani–Fiorani–Marchesini evolution equation. We demonstrate the importance of these contributions in a certain kinematical region covered by the CMS and ATLAS measurements. On the other hand, the experimental data taken by the LHCb Collaboration at forward rapidities and moderate transverse momenta can be described well by$${{{\mathcal {O}}}}(\alpha _s^4)$$O(αs4)color singlet terms and contributions from the double parton scattering mechanism. The extracted value of the effective cross section is compatible with many other estimations based on different final states.
Dynamical transition from a naked singularity to a black hole
Authors: Hioki Kenta , Harada Tomohiro 
Published: November 2020

We show that a Reissner–Nordström (RN) black hole can be formed by dropping a charged thin dust shell onto a RN naked singularity. This is in contrast to the fact that a RN naked singularity is prohibited from forming by dropping a charged thin dust shell onto a RN black hole. This implies the strong tendency of the RN singularity to be covered by a horizon in favor of cosmic censorship. We show that an extreme RN black hole can also be formed from a RN naked singularity by the same process in a finite advanced time. We also discuss the evolution of the charged thin dust shells and the causal structure of the resultant space–times. a a The statements expressed in this paper are those of the authors and do not represent the views of Sumitomo Mitsui Banking Corporation or its staff.
A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy
Authors: Liu Si-Qi , Grantham Alyssa , Landry Casey , Granda Brian , Chopra Rajiv , Chakravarthy Srinivas , Deutsch Sabine , Vogel Markus , Russo Katie , Seiss Katherine , Tschantz William R. , Rejtar Tomas , Ruddy David A. , Hu Tiancen , Aardalen Kimberly , Wagner Joel P. , Dranoff Glenn , D'Alessio Joseph A. 
Published: November 2020

AbstractCD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. IFNγ functioned by stimulating the expression of T-cell killing–related molecules in a cell type–specific manner. By assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Proper fucosylation of CD123 was required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T-cell–engaging CD3-bispecific antibody therapies.
Hybrid Convergent Procedure for the Treatment of Persistent and Long-Standing Persistent Atrial Fibrillation
Authors: DeLurgio David B. , Crossen Karl J. , Gill Jaswinder , Blauth Christopher , Oza Saumil R. , Magnano Anthony R. , Mostovych Mark A. , Halkos Michael E. , Tschopp David R. , Kerendi Faraz , Taigen Tyler L. , Shults Christian C. , Shah Manish H. , Rajendra Anil B. , Osorio Jose , Silver Jonathan S. , Hook Bruce G. , Gilligan David M. , Calkins Hugh 
Published: November 2020

Background:
The limited effectiveness of endocardial catheter ablation (CA) for persistent and long-standing persistent atrial fibrillation (AF) treatment led to the development of a minimally invasive epicardial/endocardial ablation approach (Hybrid Convergent) to achieve a more comprehensive lesion set with durable transmural lesions. The multicenter randomized controlled CONVERGE trial (Convergence of Epicardial and Endocardial Ablation for the Treatment of Symptomatic Persistent AF) evaluated the safety of Hybrid Convergent and compared its effectiveness to CA for persistent and long-standing persistent AF treatment.

Methods:
One-hundred fifty-three patients were randomized 2:1 to Hybrid Convergent versus CA. Primary effectiveness was freedom from AF/atrial flutter/atrial tachycardia absent new/increased dosage of previously failed/intolerant class I/III antiarrhythmic drugs through 12 months. Primary safety was major adverse events through 30 days. CONVERGE permitted left atrium size up to 6 cm and imposed no limits on AF duration, making it the only ablation trial to substantially include long-standing persistent–AF, that is, 42% patients with long-standing persistent–AF.

Results:

Of 149 evaluable patients at 12 months, primary effectiveness was achieved in 67.7% (67/99) patients with Hybrid Convergent and 50.0% (25/50) with CA (
P
=0.036) on/off previously failed antiarrhythmic drugs and in 53.5% (53/99) versus 32.0% (16/50;
P
=0.0128) respectively off antiarrhythmic drugs. At 18 months using 7-day Holter, 74.0% (53/72) Hybrid Convergent and 55% (23/42) CA patients experienced ≥90% AF burden reduction. A total of 2.9% (3/102) patients had primary safety events within 7 days, and 4.9% (5/102) between 8 and 30 days postprocedure. No deaths, cardiac perforations, or atrioesophageal fistulas occurred. All but one primary safety event resolved.

Conclusions:
The Hybrid Convergent procedure has superior effectiveness compared to the CA for the treatment of persistent and long-standing persistent atrial fibrillation.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01984346.