bluuebunny/crossref_metadata_2025_split huggingface dataset:
HDP-101, an Anti-BCMA Antibody–Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells
Authors: Figueroa-Vazquez Vianihuini , Ko Jonathan , Breunig Christian , Baumann Anja , Giesen Nicola , Pálfi Anikó , Müller Christoph , Lutz Christian , Hechler Torsten , Kulke Michael , Müller-Tidow Carsten , Krämer Alwin , Goldschmidt Hartmut , Pahl Andreas , Raab Marc S. 
Published: December 2020

Abstract
Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target in both proliferating and dormant cancer cells. Alpha-amanitin, a toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti–B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative. HDP-101 displayed high efficacy against both proliferating and resting myeloma cells in vitro, sparing BCMA-negative cells. In subcutaneous and disseminated murine xenograft models, HDP-101 induced tumor regression at low doses, including durable complete remissions after a single intravenous dose. In cynomolgus monkeys, HDP-101 was well tolerated with a promising therapeutic index. In conclusion, HDP-101 safely and selectively delivers amanitin to myeloma cells and provides a novel therapeutic approach to overcome drug resistance in this disease.
EMT-Induced Gemcitabine Resistance in Pancreatic Cancer Involves the Functional Loss of Equilibrative Nucleoside Transporter 1
Authors: Weadick Brenna , Nayak Debasis , Persaud Avinash K. , Hung Sau Wai , Raj Radhika , Campbell Moray J. , Chen Wei , Li Junan , Williams Terence M. , Govindarajan Rajgopal 
Published: December 2020

Abstract
Epithelial–mesenchymal transition (EMT) in cancer cells drives cancer chemoresistance, yet the molecular events of EMT that underpin the acquisition of chemoresistance are poorly understood. Here, we demonstrate a loss of gemcitabine chemosensitivity facilitated by human equilibrative nucleoside transporter 1 (ENT1) during EMT in pancreatic cancer and identify that cadherin switching from the epithelial (E) to neuronal (N) type, a hallmark of EMT, contributes to this loss. Our findings demonstrate that N-cadherin decreases ENT1 expression, membrane localization, and gemcitabine transport, while E-cadherin augments each of these. Besides E- and N-cadherin, another epithelial cell adhesion molecule, EpCAM, played a more prominent role in determining ENT1 membrane localization. Forced expression of EpCAM opposed cadherin switching with restored ENT1 expression, membrane localization, and gemcitabine transport in EMT-committed pancreatic cancer cells. In gemcitabine-treated mice, EpCAM-positive tumors had high ENT1 expression and reduced metastasis, whereas tumors with N-cadherin expression resisted gemcitabine treatment and formed extensive secondary metastatic nodules. Tissue microarray profiling and multiplexed IHC analysis of pancreatic cancer patient-derived primary tumors revealed EpCAM and ENT1 cell surface coexpression is favored, and ENT1 plasma membrane expression positively predicted median overall survival times in patients treated with adjuvant gemcitabine. Together, our findings identify ENT1 as an inadvertent target of EMT signaling mediated by cadherin switching and provide a mechanism by which mesenchymal pancreatic cancer cells evade gemcitabine therapy during EMT.
Identification and Characterization of Plasmin-Independent Thrombolytic Enzymes
Authors: Hassan Md. Mehedi , Sharmin Shirina , Kim Hyeon-Jin , Hong Seong-Tshool 
Published: December 2020

Rationale:
Current thrombolytic agents activate plasminogen to plasmin which triggers fibrinolysis to dissolve thrombi. Since plasmin is a nonspecific proteolytic enzyme, all of the current plasmin-dependent thrombolytics lead to serious hemorrhagic complications, demanding a new class of fibrinolytic enzymes independent from plasmin activation and undesirable side effects. We speculated that the mammalian version of bacterial heat-shock proteins could selectively degrade intravascular thrombi, a typical example of a highly aggregated protein mixture.

Objective:
The objective of this study is to identify enzymes that can dissolve intravascular thrombi specifically without affecting fibrinogen and fibronectin so that the wound healing processes remain uninterrupted and tissues are not damaged. In this study, HtrA (high-temperature requirement A) proteins were tested for its specific proteolytic activity on intravascular thrombi independently from plasmin activation.

Methods and Results:
HtrA1 and HtrA2/Omi proteins, collectively called as HtrAs, lysed ex vivo blood thrombi by degrading fibrin polymers. The thrombolysis by HtrAs was plasmin-independent and specific to vascular thrombi without causing the systemic activation of plasminogen and preventing nonspecific proteolysis of other proteins including fibrinogen and fibronectin. As expected, HtrAs did not disturb clotting and wound healing of excised wounds from mouse skin. It was further confirmed in a tail bleeding and a rebleeding assay that HtrAs allowed normal clotting and maintenance of clot stability in wounds, unlike other thrombolytics. Most importantly, HtrAs completely dissolved blood thrombi in tail thrombosis mice, and the intravenous injection of HtrAs to mice with pulmonary embolism completely dissolved intravascular thrombi and thus rescued thromboembolism.

Conclusions:
Here, we identified HtrA1 and HtrA2/Omi as plasmin-independent and highly specific thrombolytics that can dissolve intravascular thrombi specifically without bleeding risk. This work is the first report of a plasmin-independent thrombolytic pathway, providing HtrA1 and HtrA2/Omi as ideal therapeutic candidates for various thrombotic diseases without hemorrhagic complications.
Science and the Pragmatist Image of Humanity: Lessons from Wilfrid Sellars and Beyond
Authors: Višňovský Emil 
Published: December 2020

Abstract
The paper focuses on the pragmatist image of humanity based on a re-reading of the philosophical “manifesto” of Wilfrid Sellars (1963) in which he became entangled in the dichotomy between “scientific” and “manifest” images. The key to solving this problem, according to the author, is the new pragmatist understanding of science as a cultural practice, which provide us with a new framework for transcending this dichotomy. By reconstructing Sellars in an anthropological rather than a scientistic way and by drawing on humanistic philosophical intentions that are present both in pragmatism and in Sellars, it becomes possible to outline a concept of “science with a human face.” The purpose of all kinds of images, including scientific ones, is to serve the enrichment of human understanding and life.
Stereoscopic Monitoring: A Promising Strategy to Advance Diagnostic and Prediction of Air Pollution
Authors: Liu Cheng , Gao Meng , Hu Qihou , Brasseur Guy P. , Carmichael Gregory R. 
Published: December 2020

AbstractMonitoring and modeling/predicting air pollution are crucial to understanding the links between emissions and air pollution levels, to supporting air quality management, and to reducing human exposure. Yet, current monitoring networks and modeling capabilities are unfortunately inadequate to understand the physical and chemical processes above ground and to support attribution of sources. We highlight the need for the development of an international stereoscopic monitoring strategy that can depict three-dimensional (3D) distribution of atmospheric composition to reduce the uncertainties and to advance diagnostic understanding and prediction of air pollution. There are three reasons for the implementation of stereoscopic monitoring: 1) current observation networks provide only partial view of air pollution, and this can lead to misleading air quality management actions; 2) satellite retrievals of air pollutants are widely used in air pollution studies, but too often users do not acknowledge that they have large uncertainties, which can be reduced with measurements of vertical profiles; and 3) air quality modeling and forecasting require 3D observational constraints. We call on researchers and policymakers to establish stereoscopic monitoring networks and share monitoring data to better characterize the formation of air pollution, optimize air quality management, and protect human health. Future directions for advancing monitoring and modeling/predicting air pollution are also discussed.
Dominant Characteristics of Early Autumn Arctic Sea Ice Variability and Its Impact on Winter Eurasian Climate
Authors: Ding Shuoyi , Wu Bingyi , Chen Wen 
Published: December 2020

AbstractThe present study investigated dominant characteristics of autumn Arctic sea ice concentration (SIC) interannual variations and impacts of September–October (SO) mean SIC anomalies in the East Siberian–Chukchi–Beaufort (EsCB) Seas on winter Eurasian climate variability. Results showed that the decreased SO EsCB sea ice is favorable for tropospheric warming and positive geopotential height anomaly over the Arctic region one month later through transporting much more heat flux to the atmosphere from the open water. When entering the early winter (November–January), enhanced upward propagation of quasi-stationary planetary waves in the mid-high latitudes generates anomalous Eliassen–Palm flux convergence in the upper troposphere, which decelerates the westerly winds and maintains the positive geopotential height anomaly in the Arctic region. This anticyclonic anomaly extends southward into central-western Eurasia and leads to evident surface cooling there. Two months later, it further develops downstream accompanied by a deepened trough, making northeastern China experience a colder late winter (January–March). Meanwhile, an anticyclonic anomaly over the eastern North Pacific excites a horizontal eastward wave train and contributes to a positive (negative) geopotential height anomaly around Greenland (Europe), favoring a negative surface temperature anomaly over western Europe. In addition, the stratospheric polar vortex is also significantly weakened in the wintertime, which is attributed to a decreased meridional temperature gradient, and decelerated westerly winds provide a favorable condition for more quasi-stationary planetary waves propagating into the stratosphere. Some major features of atmospheric responses to EsCB sea ice loss are well reproduced in the CAM4 sensitivity experiments.
Small bowel wall edema induced by regorafenib is associated with regorafenib intolerance and shorter survival in patients with metastatic colorectal cancer: A retrospective study
Authors: Karakurt Eryılmaz Melek , Kerimoğlu Ülkü , Karaağaç Mustafa , Yalçın Müsri Fatma , Araz Murat , Artaç Mehmet 
Published: December 2020

Introduction Regorafenib, a receptor tyrosine kinase inhibitor, is a routinely used targeted agent in the current treatment of patients with refractory metastatic colorectal carcinoma (mCRC). The aims of this study were to detect the presence of bowel wall edema during regorafenib treatment via computed tomography (CT) and to assess the relationship between survival and regorafenib-induced bowel wall edema in patients with mCRC receiving regorafenib. Patients and methods We retrospectively evaluated the presence of bowel wall edema on CT of 25 mCRC patients who received regorafenib and analyzed its relationship with progression free survival (PFS) and overall survival (OS). Results Among the 25 patients, 25 had small bowel wall edema (SBWE) and 14 had large bowel wall edema (LBWE) on at least one CT examination. The median SBWE value was 4.85 milimeters (mm). Of the 25 patients, 14 had SBWE ≤4.85 mm and 11 had SBWE >4.85 mm. Regorafenib intolerance was significantly higher at SBWE >4.85 mm patients (p = 0.03). The median PFS was 4.6 months (95% CI: 2.4–6.8) and median OS was 9.3 months (95% CI: 3.1–15.4). Median PFS and OS were shorter in patients with SBWE > 4.85 mm than in those with ≤4.85 mm, but not statistically significant (median PFS: 3.9 vs 4.6 months, p: 0.523; median OS: 5.6 vs 9.3 months, p: 0.977). Conclusions Regorafenib caused SBWE in patients with mCRC. Patients who developed more SBWE had a higher regorafenib intolerance and a shorter survival. Further studies are needed to confirm the predictor value of SBWE on the survival outcomes of patients with mCRC receiving regorafenib.
Acute erythroid leukemia is enriched in NUP98 fusions: a report from the Children’s Oncology Group
Authors: Chisholm Karen M. , Heerema-McKenney Amy E. , Choi John K. , Smith Jenny , Ries Rhonda E. , Hirsch Betsy A. , Raimondi Susana C. , Alonzo Todd A. , Wang Yi-Cheng , Aplenc Richard , Sung Lillian , Gamis Alan S. , Meshinchi Soheil , Kahwash Samir B. 
Published: December 2020

Abstract
Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) primarily affecting older adults and was previously classified into erythroid/myeloid and pure erythroid subtypes. In this pediatric AEL study, we evaluated morphologic, immunophenotypic, cytogenetic, molecular, and clinical data of 24 (1.2%) cases from all cases undergoing central pathology review in Children’s Oncology Group trials AAML0531 and AAML1031. Of 24 cases, 5 had a pure erythroid phenotype, and 19 had an erythroid/myeloid phenotype. NUP98 fusions were highly enriched in patients with AEL, occurring in 7 of 22 cases for which molecular data were available (31.8% vs 6.7% in other AML subtypes). Of 5 cases of pure erythroid leukemias (PELs), 3 had NUP98 fusions, and 4 had complex karyotypes. Erythroid/myeloid leukemias were reclassified by using the 2017 World Health Organization hematopathology classification as: myelodysplastic syndrome (MDS) with excess blasts-1 (n = 3), MDS with excess blasts-2 (n = 7), AML (nonerythroid, n = 5), and unknown MDS/AML (n = 4); the 5 cases of nonerythroid AML included 1 with an NUP98–NSD1 fusion, 2 with myelodysplasia-related changes, and 1 with a complex karyotype. Three cases of MDS with excess blasts-2 also had NUP98 rearrangements. WT1 mutations were present in 5 of 14 cases, all erythroid/myeloid leukemia. Outcomes assessment revealed statistically poorer overall survival (5-year, 20% ± 36% vs 66% ± 23%; P = .004) and event-free survival (5-year, 20% ± 36% vs 46% ± 23%; P = .019) for those with PEL than those with erythroid/myeloid leukemia. Our study supports that AEL is a morphologically and genetically heterogeneous entity that is enriched in NUP98 fusions, with the pure erythroid subtype associated with particularly adverse outcomes.
International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease
Authors: van Rhee Frits , Oksenhendler Eric , Srkalovic Gordan , Voorhees Peter , Lim Megan , Dispenzieri Angela , Ide Makoto , Parente Sophia , Schey Stephen , Streetly Matthew , Wong Raymond , Wu David , Maillard Ivan , Brandstadter Joshua , Munshi Nikhil , Bowne Wilbur , Elenitoba-Johnson Kojo S. , Fössa Alexander , Lechowicz Mary Jo , Chandrakasan Shanmuganathan , Pierson Sheila K. , Greenway Amy , Nasta Sunita , Yoshizaki Kazuyuki , Kurzrock Razelle , Uldrick Thomas S. , Casper Corey , Chadburn Amy , Fajgenbaum David C. 
Published: December 2020

AbstractCastleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)–associated MCD, POEMS-associated MCD, and HHV-8−/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti–interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.
Sensitivity of Influential Factors on Needle Insertion Experiments: A Quantitative Analysis on Phantom Deformations and Needle Deflections
Authors: Li Murong , Lei Yong , Xu Tian 
Published: December 2020

AbstractHigh repeatability of needle insertion experiments is essential to the needle-phantom interaction model validation. However, the influential factors governing the accuracy of the phantom and needle deformations have not been systematically studied. In this paper, the impact of influential factors, including phantom characteristic represented by the ratio of DMSO and thawing time (TT), needle properties represented by needle external diameter (NED) and operating factors such as needle insertion velocity (IV), insertion positions (IP) and repeated insertion times (RITs) are analyzed by orthogonal experiment design. The range calculation shows the most sensitive parameters to phantom deformations are RITs, IV and DMSO while the most sensitive parameters to needle deflection are DMSO, TT and NED. By variance analysis, the significant factors on maximum tissue deformation (MTD) are IV, followed by RITs, DMSO and IP. And NED and TT have nearly no significant impact on MTD. The significant sequence on maximum needle deflection (MND) is as follows: DMSO, TT and NED. Results show that, among all impacting factors, phantom deformation is susceptible to both material properties and operative factors while the needle deflection is more susceptible to material properties of the phantom, which can help researchers in related fields to conduct experiments in a more precise manner and better understand the needle-phantom interaction mechanism.
Complications of intravesical BCG therapy in non-muscle invasive bladder cancer: our tertiary care centre experience
Authors: Sharma Vivek , Thakur Avinash P. S. , Ramasamy Vasantharaja , Shukla Pushpendra Kumar , Solanki Fanindra Singh , Choudhary Arpan , Patel Prashant 
Published: December 2020

Abstract
Background
Urothelial bladder carcinoma accounts for around 3.9% cases of all the male cancers in India. Non-muscle-invasive bladder carcinoma (NMIBC) is predominant group which constitute approximately three fourth of the urothelial bladder cancer. Intravesical BCG immunotherapy is the corner stone of today’s NMIBC management. However, as with any other therapy it has its own complications and its interruption due to these adverse effects is a major cause of suboptimal efficacy. The aim of this study was to assess the complications of intravesical BCG therapy and their management in NMIBC patients.

Methods
This was a retrospective descriptive study conducted between October 2016 and November 2019; a backward review of 149 patients with diagnosis of NMIBC that undergone intravesicle BCG therapy was performed. Patient’s demographical, clinical, diagnostic and procedural data regarding bladder tumour, BCG therapy, its complications and management were collected and analysed.

Results
Total 149 patients were analysed, comprising 116 males and 33 females. The mean age was of 57.2 ± 6.7 years. Total 85.23% were primary and 14.76% were recurrent tumours. Total 96 patients (64.42%) completed the planned course, while 53 (35.57%) interrupted. The reasons for BCG interruption includes adverse effects (15.4%), progression of disease (6.7%), disease refractory to BCG (4.6%) and disease recurrence during BCG (3.3%). Most of the adverse events occurred in first 6 months and most interruptions occurred after the induction period. Cystitis was the most common observed adverse effect seen in 39.6% patients. Frequency, urgency, haematuria were common presentation. Radical cystectomy was the most common (16.10%) further treatment with patients whose treatment was interrupted.

Conclusion
BCG is an indispensable therapy available for NMIBC, but it is associated with array of adverse effects and complications, which are the main reasons for poor compliance to BCG therapy. Although BCG-related complications can affect any organ in the body, potentially life-threatening systemic BCG-related infections are encountered in only < 5% of patients. There are some difficulties in diagnosis of the BCG complications because acid-fast staining, culture and PCR test are not always positive; tissue biopsies should be indicated sometimes to evaluate histopathology and presence of M. bovis. A persistently monitored multidisciplinary approach with high index of suspicion and prompt anti-TB therapy can help to derive the maximum benefits while keeping the complications at check.
So you think you can PLS-DA?
Authors: Ruiz-Perez Daniel , Guan Haibin , Madhivanan Purnima , Mathee Kalai , Narasimhan Giri 
Published: December 2020

Abstract
Background
Partial Least-Squares Discriminant Analysis (PLS-DA) is a popular machine learning tool that is gaining increasing attention as a useful feature selector and classifier. In an effort to understand its strengths and weaknesses, we performed a series of experiments with synthetic data and compared its performance to its close relative from which it was initially invented, namely Principal Component Analysis (PCA).

Results
We demonstrate that even though PCA ignores the information regarding the class labels of the samples, this unsupervised tool can be remarkably effective as a feature selector. In some cases, it outperforms PLS-DA, which is made aware of the class labels in its input. Our experiments range from looking at the signal-to-noise ratio in the feature selection task, to considering many practical distributions and models encountered when analyzing bioinformatics and clinical data. Other methods were also evaluated. Finally, we analyzed an interesting data set from 396 vaginal microbiome samples where the ground truth for the feature selection was available. All the 3D figures shown in this paper as well as the supplementary ones can be viewed interactively at http://biorg.cs.fiu.edu/plsda

Conclusions
Our results highlighted the strengths and weaknesses of PLS-DA in comparison with PCA for different underlying data models.