bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer
Authors: Monge Cecilia , Xie Changqing , Myojin Yuta , Coffman Kelley , Hrones Donna Mabry , Wang Sophie , Hernandez Jonathan M , Wood Bradford J , Levy Elliot B , Juburi Israa , Hewitt Stephen M , Kleiner David E , Steinberg Seth M , Figg William D , Redd Bernadette , Homan Philip , Cam Maggie , Ruf Benjamin , Duffy Austin G , Greten Tim F 
Published: February 2023

BackgroundOncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial.MethodsAdult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring.ResultsThirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+T cells on treatment.ConclusionPexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers.Trial registration numberNCT03206073.
Incidence and mortality from malignant mesothelioma 1982–2020 and relationship with asbestos exposure: the Australian Mesothelioma Registry
Authors: Walker-Bone Karen , Benke Geza , MacFarlane Ewan , Klebe S , Takahashi Ken , Brims Fraser , Sim Malcolm Ross , Driscoll Tim R 
Published: February 2023

ObjectivesMalignant mesothelioma is an uncommon cancer associated with asbestos exposure, predominantly occupational. Asbestos has been banned in Australia since 2003 but mesothelioma has a long latency and incident cases continue to present. The Australian Mesothelioma Registry was incepted to collect systematic data about incidence and mortality alongside asbestos exposure.MethodsBenefiting from the Australian national system of cancer notification, all incident cases of mesothelioma in all states and territories are fast-tracked and notified regularly. Notified patients are contacted asking for consent to collect exposure information, initially by postal questionnaire and subsequently by telephone interview. Age-standardised annual incidence rates and mortality rates were calculated. Asbestos exposure was categorised as occupational, non-occupational, neither or, both; and as low, or high, probability of exposure.ResultsMesothelioma incidence appears to have peaked. The age-standardised incidence rates have declined steadily since the early 2000s (peaking in males at 5.9/100 000 and in all-persons at 3.2/100 000), driven by rates in males, who comprise the majority of diagnosed cases. Rates in women have remained fairly stable since that time. Age-standardised mortality rates have followed similar trends. Mesothelioma remains the most common in those aged over 80 years. Nearly all (94%) cases were linked with asbestos exposure (78% occupational in men; 6.8% in women).ConclusionsWith effective control of occupational asbestos use, the decline in age-standardised incidence and death rates has occurred. Incidence rates among women, in whom occupational asbestos exposure is rarely detectable, remain unchanged, pointing to the role of household and /or environmental asbestos exposure.
Genicular nerve and fracture site chemical neurolysis for distal femoral fracture: a case report
Authors: Dhingra Prateek , McHardy Paul G , Jenkinson Richard , Meng Howard 
Published: February 2023

BackgroundDistal femur fractures account for approximately 3%–6% of all femoral fractures. Non-operative management may be an attractive option for the elderly with significant perioperative mortality risk. Adequate pain control is a major barrier to non-operative fracture management. Chemical neurolysis has been described for analgesic management of proximal hip fractures, however no description of interventional management of distal femur fracture exists in literature. We describe a case of phenol chemical neurolysis of genicular nerves in addition to injection at the site of fracture to provide effective analgesia for distal femur fracture.Case presentationA patient in their 90s with a witnessed mechanical fall sustained an intra-articular displaced fracture of the distal right femur shaft with extension into the distal femoral condyle. The patient elected to undergo non-surgical management given the high perioperative mortality risk. Acute pain service was involved and multimodal oral analgesics including opioids were insufficient in managing the patient’s pain. The addition of femoral nerve catheter local anesthetic infusion did not sufficiently improve analgesia. Phenol chemical neurolysis of the superolateral, superomedial, inferomedial genicular nerves and of the fracture site was offered and performed. Resting pain decreased from Numerical Rating Scale 5/10 to 0/10 on postprocedure day 1. This was sustained at the 2-month timepoint.ConclusionsWe report the successful use of phenol neurolysis of genicular nerves and the fracture site in an elderly patient with a conservatively managed distal femur fracture. These interventions resulted in improved analgesia and achieved prolonged duration of effect.
Vacuum material properties and Cherenkov radiation in logarithmic electrodynamics
Authors: Gaete Patricio , Helayël-Neto J. A. 
Published: February 2023

AbstractWe study some observational signatures of nonlinearities of the electromagnetic field. First to all we show the vital role played by nonlinearities in triggering a material behavior of the vacuum with $$(\varepsilon > 0, \mu <0)$$

(
ε
>
0
,
μ
<
0
)

, which corresponds to a ferrimagnetic material. Secondly, the permittivity and susceptibility induced by nonlinearities are considered in order to obtain the refractive index via the dispersion relation for logarithmic electrodynamics. Finally, we consider the electromagnetic radiation produced by a moving charged particle interacting with a medium characterized by nonlinearities of the electromagnetic field. To this end we consider logarithmic electrodynamics. The result shows that the radiation is driven by the medium through which the particle travels like the one that happens in the Cherenkov effect.
Searching for wormholes with gravitational wave scattering
Authors: Zhang Hong , Hou Shaoqi , Bao Shou-shan 
Published: February 2023

AbstractWe propose using the gravitational wave scattering off spherical wormholes to search for their existence. We carefully calculate the reflected and transmitted waveforms with time-independent scattering theory. Our results quantitatively show the echo signatures in the two universes on both sides of the wormhole. In a certain wormhole mass range, the transmitted wave has a unique isolated chirp without an inspiral waveform, and the reflected wave has the anti-chirp behavior, i.e., the missing of the chirping signal. We also calculate the searching range of the current and projected gravitational wave telescopes. Our method can be adapted to efficiently calculate the templates to search for wormholes.
Observation of two zeros of the real amplitude in pp scattering at LHC energies
Authors: Kohara Anderson Kendi 
Published: February 2023

AbstractElastic scattering of charged hadrons is described by the combination of nuclear and Coulomb amplitudes. It is well know that at the very forward range the nuclear real and Coulomb parts interplay a crucial role in the determination of the magnitude of the real part at $$|t|=0$$

|
t
|
=
0

. However, beyond $$|t|=0$$

|
t
|
=
0

the real and imaginary nuclear amplitudes have different t dependencies and we show that at LHC energies the zeros formed by the combination $$T_C(t)+T_R^N(s,t)=0$$

T
C

(
t
)

+

T
R
N

(
s
,
t
)

=
0

in pp process can be potentially observed when the background due to the imaginary part is removed. This observation constrains the real part at this forward range.
An introduction to ice ages, climate dynamics and biotic events: the Late Pennsylvanian world
Authors: Lucas Spencer G. , DiMichele William A. , Opluštil Stanislav , Wang Xiangdong 
Published: February 2023

Abstract
The Late Pennsylvanian was a time of ice ages and climate dynamics that drove biotic changes in the marine and non-marine realms. The apex of late Paleozoic glaciation in southern Gondwana was during the Late Pennsylvanian, rather than the early Permian as inferred from more equatorial Pangaea. Waxing and waning of ice sheets drove cyclothemic sedimentation in the Pangaean tropics, providing an astrochronology tuned to Earth-orbital cycles, tied to climatic changes, reflected in aeolian loess and palaeosol archives. Vegetation change across the Middle–Late Pennsylvanian boundary was not a ‘Carboniferous rainforest collapse’, but instead a complex and drawn out step-wise change from one kind of rainforest to another. Changes in marine invertebrate and terrestrial vertebrate animals occurred across the Middle–Late Pennsylvanian boundary, but these did not lead to substantive changes in the organization of those communities. The base of the Upper Pennsylvanian is the base of the Kasimovian Stage, and this boundary needs a GSSP to standardize and stabilize chronostratigraphic usage. To avoid further chronostratigraphic confusion, the Cantabrian Substage should be abandoned, and the traditional Westphalian–Stephanian boundary should be returned to and recognized as the time of major floristic change, the lycospore extinction event.
Assessing the Early Bird Heuristic (for Predicting Project Quality)
Authors: C. Shrikanth N. , Menzies Tim 
Published: February 2023

Before researchers rush to reason across all available data or try complex methods, perhaps it is prudent to first check for simpler alternatives. Specifically, if the historical data has the most information in some small region, then perhaps a model learned from that region would suffice for the rest of the project.
To support this claim, we offer a case study with 240 projects, where we find that the information in those projects “clumps” towards the earliest parts of the project. A quality prediction model learned from just the first 150 commits works as well, or better than state-of-the-art alternatives. Using just this “early bird” data, we can build models very quickly and very early in the project life cycle. Moreover, using this early bird method, we have shown that a simple model (with just a few features) generalizes to hundreds of projects.
Based on this experience, we doubt that prior work on generalizing quality models may have needlessly complicated an inherently simple process. Further, prior work that focused on later-life cycle data needs to be revisited, since their conclusions were drawn from relatively uninformative regions.
Replication note: All our data and scripts are available here: https://github.com/snaraya7/early-bird.
Biochemical Predictors of New-Onset Atrial Fibrillation after Ascending Aorta Replacement Surgery in Acute Type A Aortic Dissection Patients
Authors: Shi Jian , Cheng Yong-Qing , Zhu Xi-Yu , Zhou Ze-Yi , Jiang Yi , Xue Yun-Xing , Cao Hai-Long , Wang Dong-Jin 
Published: February 2023

Objective. This study aimed to determine the risk factors of new-onset postoperative atrial fibrillation after ascending aortic replacement in acute type A aortic dissection patients, with emphasis on biochemical parameters. Methods. From Jan 2020 to Dec 2021, a total of 435 acute type A aortic dissection patients who underwent ascending aortic replacement and without a history of atrial fibrillation were retrospectively analyzed in this study. Perioperative data of these patients were obtained from the hospital’s database. The 30-day follow-up was via telephone interviews. The multivariate regression analysis was used to identify risk factors that may be predictive of postoperative atrial fibrillation. Results. 218 (50.1%) patients experienced postoperative atrial fibrillation after ascending aorta replacement surgery. Older age (OR = 1.081 (1.059–1.104),

p
<
0.001

), higher total bile acid (OR = 1.064 (1.024–1.106),

p

= 0.002), glucose (OR = 1.180 (1.038–1.342),

p

= 0.012), and serum potassium (OR = 2.313 (1.078–4.960),

p

= 0.031) were identified by multivariate regression analysis as risk factors of postoperative atrial fibrillation. The multivariate regression analysis prediction model incorporating these four factors had a good prediction effect (AUC = 0.769 (0.723–0.816),

p
<
0.001

). Conclusions. Older age, higher total bile acid, glucose, and serum potassium were risk factors of postoperative atrial fibrillation after ascending aortic replacement surgery in acute type A aortic dissection patients.
An In Vitro Comparison of Clinpro™ XT and Duraphat Varnish for Protecting Teeth from Discoloration during Orthodontic Treatment
Authors: Xu Lin , Zou Yuchun , Lin Hanyu , Yang Xinhan , Xu Linyu 
Published: February 2023

Objective. During orthodontic treatment, a higher caries risk has been reported, so fluorides and other remineralizing compounds have been proposed. Currently, fluoride varnish is commonly available in conventional and light-curable forms. This in vitro study was performed to evaluate the effectiveness of two different materials, Clinpro™ XT (light-curable forms) and Duraphat (conventional forms) varnish, whose main active principle according to their manufacturers is fluoride in preventing tooth discoloration during orthodontic treatment with appliances attached with metal brackets or resin. Materials and Methods. This study included 120 premolars free of white spot lesions and caries that were randomly divided into the following six groups (n = 20): resin control (RCTR), resin Clinpro (RC), resin Duraphat (RD), bracket control (BCTR), bracket Clinpro (BC), and bracket Duraphat (BD). All the samples were exposed to 180 ml of coffee (4 times × 5 min/day) for 7 or 28 days. When not immersed in coffee, the teeth were stored in artificial saliva, which was replaced every day. The lightness (

L

∗

), red/green axis (

a

∗

), and yellow/blue axis (

b

∗

) values were recorded with a dental spectrophotometer (Easy shade Advance 4.0) on days 0 (baseline), 7, and 28. The color difference (

Δ

E

∗

) on days 7 and 28 was also calculated. Results. The data were statistically analyzed using one-way ANOVA and Bonferroni’s test (α = 0.05). Significant differences were observed between the

Δ

E

∗

,

L

∗

,

a

∗

, and

b

∗

values of the Clinpro™ XT and Duraphat groups and those of the control groups after 7 and 28 days regardless of the attachment type (

P

< 0.001). On day 7, no significant differences were observed between the Clinpro™ XT and Duraphat groups, whereas on day 28, the Duraphat groups with metal and resin attachments exhibited significant differences from the Clinpro™ XT groups (

P

< 0.001). No significant differences correlated to the attachment type were observed throughout the discoloration procedure. Conclusions. The application of fluoride varnish during orthodontic treatment can significantly reduce tooth discoloration caused by the staining solution. Clinpro™ XT varnish showed a longer period of efficacy in protecting teeth from discoloration than Duraphat. No differences in tooth discoloration were observed between the groups with fixed and clear appliances.
Mutated HRAS Activates YAP1–AXL Signaling to Drive Metastasis of Head and Neck Cancer
Authors: Jagadeeshan Sankar , Prasad Manu , Badarni Mai , Ben-Lulu Talal , Liju Vijayasteltar Belsamma , Mathukkada Sooraj , Saunders Claire , Shnerb Avital Beeri , Zorea Jonathan , Yegodayev Ksenia M. , Wainer Monica , Vtorov Liza , Allon Irit , Cohen Ofir , Gausdal Gro , Friedmann-Morvinski Dinorah , Cheong Sok Ching , Ho Alan L. , Rosenberg Ari J. , Kessler Linda , Burrows Francis , Kong Dexin , Grandis Jennifer R. , Gutkind J. Silvio , Elkabets Moshe 
Published: February 2023

AbstractThe survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.Significance:Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1–AXL axis and to stimulate lymphovascular angiogenesis.
The Elongin BC Complex Negatively Regulates AXL and Marks a Differentiated Phenotype in Melanoma
Authors: Schieven Sebastiaan M. , Traets Joleen J.H. , Vliet Alex v. , Baalen Martijn v. , Song Ji-Ying , Guimaraes Marcos Da Silva , Kuilman Thomas , Peeper Daniel S. 
Published: February 2023

Abstract

High expression of the receptor tyrosine kinase AXL is implicated in epithelial-to-mesenchymal transition, cancer progression, and therapy resistance. For example, AXL is abundant in BRAF mutant melanomas progressing on targeted BRAF/MEK inhibition. Therefore, AXL is thought to represent an attractive therapeutic target. This notwithstanding, little is known about the mechanisms governing expression of AXL. Here, we describe a FACS-based whole-genome-wide CRISPR-Cas9 screen to uncover regulators of AXL expression. We identified several genes, inactivation of which led to increased AXL expression. Most remarkable was the identification of five components that associate with the Elongin BC heterodimer. Elongin B/C engage in multiple protein–protein interactions, including the transcription factor complex subunit Elongin A, the von Hippel-Lindau (VHL) tumor suppressor protein, and members of the SOCS-box protein family. The screen identified ELOB, ELOC, SOCS5, UBE2F, and RNF7, each of which we demonstrate to serve as an inhibitor of AXL expression. Although the AXL promoter contains hypoxia response elements and Elongin B/C are found in the VHL complex, Elongin B/C unexpectedly regulate AXL independently of hypoxia. Instead, we demonstrate that the Elongin BC complex interacts with AXL through ELOB, and contributes to proteasomal AXL turnover. RNA-sequencing and IHC analyses of melanoma patient-derived xenografts and clinical samples revealed a negative association between Elongin B/C and dedifferentiation. Together, the Elongin BC complex regulates AXL and marks a differentiated melanoma phenotype.

Implications:
This study identifies the Elongin BC complex as a key regulator of AXL expression and marker of melanoma differentiation.
Dynamics of Age- versus Therapy-Related Clonal Hematopoiesis in Long-term Survivors of Pediatric Cancer
Authors: Hagiwara Kohei , Natarajan Sivaraman , Wang Zhaoming , Zubair Haseeb , Mulder Heather L. , Dong Li , Plyler Emily M. , Thimmaiah Padma , Ma Xiaotu , Ness Kristen K. , Li Zhenghong , Mulrooney Daniel A. , Wilson Carmen L. , Yasui Yutaka , Hudson Melissa M. , Easton John , Robison Leslie L. , Zhang Jinghui 
Published: February 2023

AbstractWe present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5 years. Deep sequencing over 39 CH-related genes reveals mutations in 15% of the survivors, significantly higher than the 8.5% in 324 community controls. CH in survivors is associated with exposures to alkylating agents, radiation, and bleomycin. Therapy-related CH shows significant enrichment in STAT3, characterized as a CH gene specific to survivors of Hodgkin lymphoma, and TP53. Single-cell profiling of peripheral blood samples revealed STAT3 mutations predominantly present in T cells and contributed by SBS25, a mutational signature associated with procarbazine exposure. Serial sample tracking reveals that larger clone size is a predictor for future expansion of age-related CH clones, whereas therapy-related CH remains stable decades after treatment. These data depict the distinct dynamics of these CH subtypes and support the need for longitudinal monitoring to determine the potential contribution to late effects.Significance:This first comprehensive CH analysis in long-term survivors of pediatric cancer presents the elevated prevalence and therapy exposures/diagnostic spectrum associated with CH. Due to the contrasting dynamics of clonal expansion for age-related versus therapy-related CH, longitudinal monitoring is recommended to ascertain the long-term effects of therapy-induced CH in pediatric cancer survivors.See related commentary by Collord and Behjati, p. 811.This article is highlighted in the In This Issue feature, p. 799