bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lenvatinib with or Without Everolimus in Patients with Metastatic Renal Cell Carcinoma After Immune Checkpoint Inhibitors and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapies
Authors: Wiele Andrew J. , Bathala Tharakeswara K. , Hahn Andrew W. , Xiao Lianchun , Duran Munevver , Ross Jeremy A. , Jonasch Eric , Shah Amishi Y. , Campbell Matthew T. , Msaouel Pavlos , Tannir Nizar M. 
Published: April 2021

Abstract

Introduction
Lenvatinib (Len) plus everolimus (Eve) is an approved therapy for metastatic renal cell carcinoma (mRCC) after first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), but limited data exist on the efficacy of Len ± Eve after progression on immune checkpoint inhibitors (ICIs) and VEGFR-TKIs.

Methods
We retrospectively reviewed the records of patients with mRCC at our institution who were treated with Len ± Eve after ICI and VEGFR-TKI. A blinded radiologist assessed objective response as defined by RECIST version 1.1. Descriptive statistics and the Kaplan-Meier method were used.

Results
Fifty-five patients were included in the analysis. Of these patients, 81.8% had clear-cell histology (ccRCC), and 76.4% had International Metastatic RCC Database Consortium intermediate-risk disease. Median number of prior therapies was four (range, 2–10); all patients had prior ICIs and VEGFR-TKIs, and 80% were previously treated with ICI and at least two VEGFR-TKIs, including cabozantinib. One patient (1.8%) achieved a complete response, and 11 patients (20.0%) achieved a partial response, for an overall response rate (ORR) of 21.8%; 35 patients (63.6%) achieved stable disease. In all patients, median progression-free survival (PFS) was 6.2 months (95% confidence interval [CI], 4.8–9.4) and median overall survival (OS) was 12.1 months (95% CI, 8.8–16.0). In patients with ccRCC, ORR was 24.4%, PFS was 7.1 months (95% CI, 5.0–10.5), and OS was 11.7 months (95% CI, 7.9–16.1). 50.9% of patients required dose reductions and 7.3% discontinued treatment because of toxicity.

Conclusion
Len ± Eve demonstrated meaningful clinical activity and tolerability in heavily pretreated patients with mRCC after disease progression with prior ICIs and VEGFR-TKIs.

Implications for Practice
As the therapeutic landscape for patients with metastatic renal cell carcinoma continues to evolve, this single-center, retrospective review highlights the real-world efficacy of lenvatinib with or without everolimus in heavily pretreated patients. This article supports the use of lenvatinib with or without everolimus as a viable salvage strategy for patients whose disease progresses after treatment with immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies, including cabozantinib.
Crystal structure and supramolecular arrangement of heterochiral tripeptides
Authors: Dolai Gobinda , Giri Rajat Subhra , Roy Sayanta , Mandal Bhubaneswar 
Published: April 2021

AbstractThe self‐assembly properties of all possible stereoisomers of terminally protected Boc‐Val‐Phe‐Phe‐OMe, having sequence homogeneity with Alzheimer's amyloid‐beta (Aβ18‐20) peptide was investigated. The morphology analysis by field emission scanning microscope (FE‐SEM) revealed that protected VFF and vff (small letters denote one letter code ofd‐amino acids) exhibited a ribbon‐like fibrous network, vFF, Vff, VfF, and vFf formed rod‐like structures. Although VFf exhibited a mixture of two morphologies (rod‐like and spherical), vfF showed spherical structures predominantly. The single‐crystal X‐ray diffraction (SC‐XRD) indicated that five of the stereoisomers formed a parallel beta‐sheet arrangement. In higher‐order packing, while Vff, VfF, and vFf exhibited supramolecular sheet‐like architecture, VFf and vfF pair showed helical sheet‐like arrangement. All corresponding enantiomers displayed identical morphology but opposite conformation. The chirality of amino acids in peptides played a significant role in their supramolecular arrangements. Interestingly, all self‐aggregated peptides can bind with amyloid binding dye thioflavin T.
A novel role for milk fat globule‐EGF factor 8 protein (MFGE8) in the mediation of mouse sperm–extracellular vesicle interactions
Authors: Trigg Natalie A. , Stanger Simone J. , Zhou Wei , Skerrett‐Byrne David A. , Sipilä Petra , Dun Matthew D. , Eamens Andrew L. , De Iuliis Geoffry N. , Bromfield Elizabeth G. , Roman Shaun D. , Nixon Brett 
Published: April 2021

AbstractSpermatozoa transition to functional maturity as they are conveyed through the epididymis, a highly specialized region of the male excurrent duct system. Owing to their transcriptionally and translationally inert state, this transformation into fertilization competent cells is driven by complex mechanisms of intercellular communication with the secretory epithelium that delineates the epididymal tubule. Chief among these mechanisms are the release of extracellular vesicles (EV), which have been implicated in the exchange of varied macromolecular cargo with spermatozoa. Here, we describe the optimization of a tractable cell culture model to study the mechanistic basis of sperm–extracellular vesicle interactions. In tandem with receptor inhibition strategies, our data demonstrate the importance of milk fat globule‐EGF factor 8 (MFGE8) protein in mediating the efficient exchange of macromolecular EV cargo with mouse spermatozoa; with the MFGE8 integrin‐binding Arg‐Gly‐Asp (RGD) tripeptide motif identified as being of particular importance. Specifically, complementary strategies involving MFGE8 RGD domain ablation, competitive RGD‐peptide inhibition and antibody‐masking of alpha V integrin receptors, all significantly inhibited the uptake and redistribution of EV‐delivered proteins into immature mouse spermatozoa. These collective data implicate the MFGE8 ligand and its cognate integrin receptor in the mediation of the EV interactions that underpin sperm maturation.
Investigation on the products distribution, reaction pathway, and discharge mechanism of low‐pressure CO2 discharge by employing a 1D simulation model
Authors: Wang Cong , Fu Qiang , Chang Zhengshi , Zhang Guanjun 
Published: April 2021

AbstractMars has a special carbon dioxide environment. The surface and atmosphere of Mars contain a large amount of solid and gaseous carbon dioxide, which makes the in‐situ resource utilization of Martian carbon dioxide attract widespread attention. The conversion of carbon dioxide into fuel or high value‐added products through electrical discharge has become a research focus, in which numerical simulation is one of the important means to explain the experimental phenomenon and the mechanism. Therefore, a one‐dimensional fluid model was established in this paper to simulate the discharge and conversion of carbon dioxide under simulated Martian atmospheric pressure. The discharge mode, particle distribution, and discharge mechanism were studied by considering CO2 vibrational states and vibration relaxation reaction in the model. The results show that the discharge mode is glow discharge with an obvious cathode fall region, negative glow space, and positive column. The density of the four discharge products, C, O2, CO, and O, shows a step‐up trend, showing a significant cumulative effect, and the peak values appear near both electrodes. The density of vibrational states of CO2 molecule, which is highest in the neutral products, increases during the discharge stage and decreases after the discharge is extinguished. The temporal and spatial distribution of reaction rates shows that vibrational excitation, electronic excitation, and vibrational relaxation reactions dominate the loss and formation of CO2. The density of ground‐state CO2 decreases obviously in the discharge stage, and the minimum density appears near the instantaneous cathode. After the discharge is extinguished, the CO2 near the instantaneous cathode increases gradually.
Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer
Authors: Ledet Elisa M. , Burgess Earle F. , Sokolova Alexandra O. , Jaeger Ellen B. , Hatton Whitley , Moses Marcus , Miller Patrick , Cotogno Patrick , Layton Jodi , Barata Pedro , Lewis Brian E. , Nakazawa Mari , Zhu Jason , Dellinger Beth , Elrefai Sara , Nafissi Nellie N. , Egan Jan B. , Shore Neal , McKay Rana R. , Bryce Alan H. , Cheng Heather H. , Antonarakis Emmanuel S. , Sartor Oliver 
Published: April 2021

AbstractBackgroundThe goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations.MethodsAfrican American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed.ResultsA total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely‐pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non‐BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African‐Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men.ConclusionsIn metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non‐BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.
A whole‐body circulatory neutrophil model with application to predicting clinical neutropenia from in vitro studies
Authors: Chen Wenbo , Boras Britton , Sung Tae , Hu Wenyue , Spilker Mary E. , D’Argenio David Z. 
Published: April 2021

AbstractA circulatory model of granulopoiesis and its regulation is presented that includes neutrophil trafficking in the lungs, liver, spleen, bone marrow, lymph nodes, and blood. In each organ, neutrophils undergo transendothelial migration from vascular to interstitial space, clearance due to apoptosis, and recycling via the lymphatic flow. The model includes cell cycling of progenitor cells in the bone marrow, granulocyte colony‐stimulating factor (G‐CSF) kinetics and its neutrophil regulatory action, as well as neutrophil margination in the blood. From previously reported studies, 111In‐labeled neutrophil kinetic data in the blood and sampled organs were used to estimate the organ trafficking parameters in the model. The model was further developed and evaluated using absolute neutrophil count (ANC), band cell, and segmented neutrophil time course data from healthy volunteers following four dose levels of pegfilgrastim (r2 = 0.77–0.99), along with ANC time course responses following filgrastim (r2 = 0.96). The baseline values of various cell types in bone marrow and blood, as well as G‐CSF concentration in the blood, predicted by the model are consistent with available literature reports. After incorporating the mechanism of action of both paclitaxel and carboplatin, as determined from an in vitro bone marrow studies, the model reliably predicted the observed ANC time course following paclitaxel plus carboplatin observed in a phase I trial of 46 patients (r2 = 0.70). The circulatory neutrophil model may provide a mechanistic framework for predicting multi‐organ neutrophil homeostasis and dynamics in response to therapeutic agents that target neutrophil dynamics and trafficking in different organs.
Incorporating historical information to improve phase I clinical trials
Authors: Zhou Yanhong , Lee J. Jack , Wang Shunguang , Bailey Stuart , Yuan Ying 
Published: April 2021

AbstractIncorporating historical data has a great potential to improve the efficiency of phase I clinical trials and to accelerate drug development. For model‐based designs, such as the continuous reassessment method (CRM), this can be conveniently carried out by specifying a “skeleton,” that is, the prior estimate of dose limiting toxicity (DLT) probability at each dose. In contrast, little work has been done to incorporate historical data into model‐assisted designs, such as the Bayesian optimal interval (BOIN), Keyboard, and modified toxicity probability interval (mTPI) designs. This has led to the misconception that model‐assisted designs cannot incorporate prior information. In this paper, we propose a unified framework that allows for incorporating historical data into model‐assisted designs. The proposed approach uses the well‐established “skeleton” approach, combined with the concept of prior effective sample size, thus it is easy to understand and use. More importantly, our approach maintains the hallmark of model‐assisted designs: simplicity—the dose escalation/de‐escalation rule can be tabulated prior to the trial conduct. Extensive simulation studies show that the proposed method can effectively incorporate prior information to improve the operating characteristics of model‐assisted designs, similarly to model‐based designs.
Improving sample size recalculation in adaptive clinical trials by resampling
Authors: Herrmann Carolin , Kluge Corinna , Pilz Maximilian , Kieser Meinhard , Rauch Geraldine 
Published: April 2021

AbstractSample size calculations in clinical trials need to be based on profound parameter assumptions. Wrong parameter choices may lead to too small or too high sample sizes and can have severe ethical and economical consequences. Adaptive group sequential study designs are one solution to deal with planning uncertainties. Here, the sample size can be updated during an ongoing trial based on the observed interim effect. However, the observed interim effect is a random variable and thus does not necessarily correspond to the true effect. One way of dealing with the uncertainty related to this random variable is to include resampling elements in the recalculation strategy. In this paper, we focus on clinical trials with a normally distributed endpoint. We consider resampling of the observed interim test statistic and apply this principle to several established sample size recalculation approaches. The resulting recalculation rules are smoother than the original ones and thus the variability in sample size is lower. In particular, we found that some resampling approaches mimic a group sequential design. In general, incorporating resampling of the interim test statistic in existing sample size recalculation rules results in a substantial performance improvement with respect to a recently published conditional performance score.
The effects and mechanisms of aloe‐emodin on reversing adriamycin‐induced resistance of MCF‐7/ADR cells
Authors: Cheng Guorong , Pi Zifeng , Zhuang Xiaoyu , Zheng Zhong , Liu Shu , Liu Zhiqiang , Song Fengrui 
Published: April 2021

Multidrug resistance (MDR) is one of the major obstacles for clinical effective chemotherapy. In this study, the effects and possible mechanisms of aloe‐emodin (AE) were investigated on reversing the adriamycin (ADR)‐induced resistance of MCF‐7/ADR cells. AE could significantly reverse the ADR resistance in MCF‐7/ADR cells. The combination of AE (20 μM) and ADR had no effect on the P‐glycoprotein (P‐gp) level, but notably promoted the accumulation of ADR in drug‐resistant cells. The efflux function of P‐gp required ATP, but AE reduced the intracellular ATP level. AE played a reversal role might through inhibiting the efflux function of P‐gp. The research result of energy metabolism pathways indicated that combination of AE and ADR could inhibit glycolysis, tricarboxylic acid (TCA) cycle, glutamine metabolism, and related amino acid synthesis pathways. Moreover, we found AE not only reversed ADR‐induced resistant but also induced autophagy as a defense mechanism. In addition, the combination of AE and ADR arrested G2/M cell cycle and induced apoptosis through DNA damage, ROS generation, caspase‐3 activation. Our study indicated that AE could be a potential reversal agent to resensitize ADR resistant in tumor chemotherapy and inhibiting autophagy might be an effective strategy to further enhance the reversal activity of AE.
A case of multiple squamous papillomas in the trachea treated by rigid bronchoscopy
Authors: Torii Atsushi , Nishimura Rieko , Oki Masahide 
Published: April 2021

Key messageTracheal papilloma is a rare benign lung tumour. It often recurs and sometimes transforms into a malignant tumour. While historically radical resection has been the primary treatment, endobronchial resection, a less invasive procedure to manage the airway using a flexible and rigid bronchoscope, was effectively used in our patient.
Features of HLA class I expression and its clinical relevance in SARS‐CoV‐2: What do we know so far?
Authors: Bouayad Abdellatif 
Published: April 2021

SummaryModifications in HLA‐I expression are found in many viral diseases. They represent one of the immune evasion strategies most widely used by viruses to block antigen presentation and NK cell response, and SARS‐CoV‐2 is no exception. These alterations result from a combination of virus‐specific factors, genetically encoded mechanisms, and the status of host defences and range from loss or upregulation of HLA‐I molecules to selective increases of HLA‐I alleles. In this review, I will first analyse characteristic features of altered HLA‐I expression found in SARS‐CoV‐2. I will then discuss the potential factors underlying these defects, focussing on HLA‐E and class‐I‐related (like) molecules and their receptors, the most documented HLA‐I alterations. I will also draw attention to potential differences between cells transfected to express viral proteins and those presented as part of authentic infection. Consideration of these factors and others affecting HLA‐I expression may provide us with improved possibilities for research into cellular immunity against viral variants.
Gift economy and well‐being: A mode of economy playing out in recovery from Rwandan tragedies
Authors: Otake Yuko , Hagenimana Fabien 
Published: April 2021

AbstractPrevious studies challenge the assumption that economic growth improves subjective well‐being, and argue that economic growth is incompatible with not only nature conservation but also subjective well‐being. To achieve SDGs, a mode of economy that sustains both subjective well‐being and the natural environment needs to be investigated. This ethnographic study explored community‐based economy systems in post‐genocide Rwanda, and elaborated the process and mechanisms by which the contemporary gift economy facilitated subjective well‐being in culture and natural landscape. Findings showed that subjective well‐being can be achieved by applying alternative modes of economy (gift economy, sharing economy) and having access to direct sources of well‐being (natural environment, social cohesion, cultural identity, and spirituality), when basic needs are satisfied by well‐established infrastructure and social services. This study contributes to understanding why and how people can be happy without money, and illuminate a mode of economy that can benefit the sustainable development of local communities.
Sex Disparity in Skin Carcinogenesis and Potential Influence of Sex Hormones
Authors: Collier V. , Musicante M. , Patel T. , Liu-Smith F. 
Published: April 2021

Abstract

Background
Sex or gender disparity in skin cancer has been documented for a long time at the population level. UV radiation (UVR) is a common environmental risk for all three major types of skin cancer: cutaneous melanoma (CM), basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). The underlying mechanism for sex disparity has been largely attributed to sex-differentiated behaviour patterns related to UVR. Non-UVR factors such as intrinsic physiological differences have been suggested but remain understudied.

Aims, Materials and Methods
This review summarizes and compares the known sex differences in three skin cancer types with regard to body site distribution and age influence.

Results
We found a similar age-dependent sex difference pattern in CM and BCC. Specifically, CM and BCC tend to show higher incidence in young women and old men, with a switching age around menopause. The switching age suggests involvement of sex hormones, which has shown controversial influence on skin cancers at epidemiological level. Literatures regarding sex hormone receptors for oestrogen, androgen and progesterone are summarized for potential explanations at molecular level.

Discussion
Overall, more and more evidence suggests non-UVR factors such as sex hormones play critical roles in skin cancer (especially CM and BCC), yet solid population and molecular evidence are required. Incidences of skin cancer are increasing which suggests limited effect for the current UVR-avoidance prevention methods.

Conclusion
Fully understanding the causes of sex disparities in incidence is necessary for developing a comprehensive prevention strategy.
Manganese Doping Promotes the Synthesis of Bismuth‐based Perovskite Nanocrystals While Tuning Their Band Structures
Authors: Liu Maning , Ali‐Löytty Harri , Hiltunen Arto , Sarlin Essi , Qudsia Syeda , Smått Jan‐Henrik , Valden Mika , Vivo Paola 
Published: April 2021

AbstractThe doping of halide perovskite nanocrystals (NCs) with manganese cations (Mn2+) has recently enabled enhanced stability, novel optical properties, and modulated charge carrier dynamics of the NCs host. However, the influence of Mn doping on the synthetic routes and the band structures of the host has not yet been elucidated. Herein, it is demonstrated that Mn doping promotes a facile, safe, and low‐hazard path toward the synthesis of ternary Cs3Bi2I9 NCs by effectively inhibiting the impurity phase (i.e., CsI) resulting from the decomposition of the intermediate Cs3BiI6 product. Furthermore, it is observed that the deepening of the valence band level of the host NCs upon doping at Mn concentration levels varying from 0 to 18.5% (atomic ratio) with respect to the Bi content. As a result, the corresponding Mn‐doped NCs solar cells show a higher open‐circuit voltage and longer electron lifetime than those employing the undoped perovskite NCs. This work opens new insights on the role of Mn doping in the synthetic route and optoelectronic properties of lead‐free halide perovskite NCs for still unexplored applications.