bluuebunny/crossref_metadata_2025_split huggingface dataset:
A High-Content Screen for C/EBPα Expression Identifies Novel Therapeutic Agents in Dedifferentiated Liposarcoma
Authors: Angeles Christina V. , Velez Ana , Rios Jordan , Laxa Bernadette , Shum David , Ruiz Penelope D. , Shen Yawei , Ostrovnaya Irina , Gularte-Mérida Rodrigo , Nacev Benjamin A. , Dickson Mark A. , Djaballah Hakim , Okada Tomoyo , Singer Samuel 
Published: October 2021

Abstract

Purpose:
Dedifferentiated liposarcoma (DDLS), one of the most common and aggressive sarcomas, infrequently responds to chemotherapy. DDLS survival and growth depend on underexpression of C/EBPα, a tumor suppressor and transcriptional regulator controlling adipogenesis. We sought to screen and prioritize candidate drugs that increase C/EBPα expression and may therefore serve as differentiation-based therapies for DDLS.

Experimental Design:
We screened known bioactive compounds for the ability to restore C/EBPα expression and inhibit proliferation selectively in two DDLS cell lines but not in normal adipose-derived stem cells (ASC). Selected hits' activity was validated, and the mechanism of the most potent, SN-38, was investigated. The in vivo efficacy of irinotecan, the prodrug of SN-38, was evaluated in DDLS xenograft models.

Results:
Of 3,119 compounds, screen criteria were met by 19. Validation experiments confirmed the DDLS selectivity of deguelin, emetine, and SN-38 and showed that they induce apoptosis in DDLS cells. SN-38 had the lowest IC50 (approximately 10 nmol/L), and its pro-apoptotic effects were countered by knockdown of CEBPA but not of TP53. Irinotecan significantly inhibited tumor growth at well-tolerated doses, induced nuclear expression of C/EBPα, and inhibited HIF1α expression in DDLS patient-derived and cancer cell line xenograft models. In contrast, doxorubicin, the most common treatment for nonresectable DDLS, reduced tumor growth by 30% to 50% at a dose that caused weight loss.

Conclusions:
This high-content screen revealed potential treatments for DDLS. These include irinotecan, which induces apoptosis of DDLS cells in a C/EBPα-dependent, p53-independent manner, and should be clinically evaluated in patients with advanced DDLS.
Morphologic and Genomic Characteristics of Breast Cancers Occurring in Individuals with Lynch Syndrome
Authors: Schwartz Christopher J. , da Silva Edaise M. , Marra Antonio , Gazzo Andrea M. , Selenica Pier , Rai Vikas K. , Mandelker Diana , Pareja Fresia , Misyura Maksym , D'Alfonso Timothy M. , Brogi Edi , Drullinsky Pamela , Razavi Pedram , Robson Mark E. , Drago Joshua Z. , Wen Hannah Y. , Zhang Liying , Weigelt Britta , Shia Jinru , Reis-Filho Jorge S. , Zhang Hong 
Published: October 2021

Abstract

Purpose:
Lynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals.

Experimental Design:
A retrospective analysis of 20,110 patients with cancer who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in MLH1, MSH2, MSH6, or PMS2 who developed breast cancers. The histologic characteristics and IHC assessment of breast cancers for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (≥468 key cancer genes). Microsatellite instability (MSI) status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA.

Results:
A total of 272 individuals with Lynch syndrome were identified, 13 (5%) of whom had primary breast cancers. The majority of breast cancers (92%) were hormone receptor–positive tumors. Five (42%) of 12 breast cancers displayed loss of MMR proteins by IHC. Four (36%) of 11 breast cancers subjected to tumor-normal sequencing showed dominant MSI mutational signatures, high tumor mutational burden, and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd breast cancer received anti-PD1 therapy and achieved a robust and durable response.

Conclusions:
A subset of breast cancers developing in individuals with Lynch syndrome are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy.
Neoadjuvant Chemotherapy and Immunotherapy in Luminal B-like Breast Cancer: Results of the Phase II GIADA Trial
Authors: Dieci Maria Vittoria , Guarneri Valentina , Tosi Anna , Bisagni Giancarlo , Musolino Antonino , Spazzapan Simon , Moretti Gabriella , Vernaci Grazia Maria , Griguolo Gaia , Giarratano Tommaso , Urso Loredana , Schiavi Francesca , Pinato Claudia , Magni Giovanna , Lo Mele Marcello , De Salvo Gian Luca , Rosato Antonio , Conte Pierfranco 
Published: October 2021

Abstract

Purpose:
The role of immunotherapy in hormone receptor (HR)-positive, HER2-negative breast cancer is underexplored.

Patients and Methods:
The neoadjuvant phase II GIADA trial (NCT04659551, EUDRACT 2016-004665-10) enrolled stage II–IIIA premenopausal patients with Luminal B (LumB)-like breast cancer (HR-positive/HER2-negative, Ki67 ≥ 20%, and/or histologic grade 3). Patients received: three 21-day cycles of epirubicin/cyclophosphamide followed by eight 14-day cycles of nivolumab, triptorelin started concomitantly to chemotherapy, and exemestane started concomitantly to nivolumab. Primary endpoint was pathologic complete response (pCR; ypT0/is, ypN0).

Results:
A pCR was achieved by 7/43 patients [16.3%; 95% confidence interval (CI), 7.4–34.9]; the rate of residual cancer burden class 0–I was 25.6%. pCR rate was significantly higher for patients with PAM50 Basal breast cancer (4/8, 50%) as compared with other subtypes (LumA 9.1%; LumB 8.3%; P = 0.017). Tumor-infiltrating lymphocytes (TIL), immune-related gene-expression signatures, and specific immune cell subpopulations by multiplex immunofluorescence were significantly associated with pCR. A combined score of Basal subtype and TILs had an AUC of 0.95 (95% CI, 0.89–1.00) for pCR prediction. According to multiplex immunofluorescence, a switch to a more immune-activated tumor microenvironment occurred following exposure to anthracyclines. Most common grade ≥3 treatment-related adverse events (AE) during nivolumab were γ-glutamyltransferase (16.7%), alanine aminotransferase (16.7%), and aspartate aminotransferase (9.5%) increase. Most common immune-related AEs were endocrinopathies (all grades 1–2; including adrenal insufficiency, n = 1).

Conclusions:
Luminal B-like breast cancers with a Basal molecular subtype and/or a state of immune activation may respond to sequential anthracyclines and anti–PD-1. Our data generate hypotheses that, if validated, could guide immunotherapy development in this context.
The Road to Personalized Myeloma Medicine: Patient-specific Single-domain Antibodies for Anti-idiotypic Radionuclide Therapy
Authors: Puttemans Janik , Stijlemans Benoit , Keyaerts Marleen , Vander Meeren Sam , Renmans Wim , Fostier Karel , Debie Pieterjan , Hanssens Heleen , Rodak Magdalena , Pruszynski Marek , De Veirman Kim , Vanderkerken Karin , Lahoutte Tony , Morgenstern Alfred , Bruchertseifer Frank , Devoogdt Nick , D'Huyvetter Matthias 
Published: October 2021

AbstractTo this day, multiple myeloma remains an incurable cancer. For many patients, recurrence is unavoidably a result of lacking treatment options in the minimal residual disease stage. This is due to residual and treatment-resistant myeloma cells that can cause disease relapse. However, patient-specific membrane-expressed paraproteins could hold the key to target these residual cells responsible for disease recurrence. Here, we describe the therapeutic potential of radiolabeled, anti-idiotypic camelid single-domain antibody fragments (sdAbs) as tumor-restrictive vehicles against a membrane-bound paraprotein in the syngeneic mouse 5T33 myeloma model and analogously assess the feasibility of sdAb-based personalized medicine for patients with multiple myeloma. Llamas were immunized using extracts containing paraprotein from either murine or human sera, and selective sdAbs were retrieved using competitive phage display selections of immune libraries. An anti-5T33 idiotype sdAb was selected for targeted radionuclide therapy with the β−-particle emitter 177Lu and the α-particle emitter 225Ac. sdAb-based radionuclide therapy in syngeneic mice with a low 5T33 myeloma lesion load significantly delayed tumor progression. In five of seven patients with newly diagnosed myeloma, membrane expression of the paraprotein was confirmed. Starting from serum-isolated paraprotein, for two of three selected patients anti-idiotype sdAbs were successfully generated.
A FZD7-specific Antibody–Drug Conjugate Induces Ovarian Tumor Regression in Preclinical Models
Authors: Do Myan , Wu Christina C.N. , Sonavane Pooja R. , Juarez Edwin F. , Adams Stephen R. , Ross Jason , Rodriguez y Baena Alessandra , Patel Charmi , Mesirov Jill P. , Carson Dennis A. , Advani Sunil J. , Willert Karl 
Published: October 2021

Abstract
Although WNT signaling is frequently dysregulated in solid tumors, drugging this pathway has been challenging due to off-tumor effects. Current clinical pan-WNT inhibitors are nonspecific and lead to adverse effects, highlighting the urgent need for more specific WNT pathway–targeting strategies. We identified elevated expression of the WNT receptor Frizzled class receptor 7 (FZD7) in multiple solid cancers in The Cancer Genome Atlas, particularly in the mesenchymal and proliferative subtypes of ovarian serous cystadenocarcinoma, which correlate with poorer median patient survival. Moreover, we observed increased FZD7 protein expression in ovarian tumors compared with normal ovarian tissue, indicating that FZD7 may be a tumor-specific antigen. We therefore developed a novel antibody–drug conjugate, septuximab vedotin (F7-ADC), which is composed of a chimeric human–mouse antibody to human FZD7 conjugated to the microtubule-inhibiting drug monomethyl auristatin E (MMAE). F7-ADC selectively binds human FZD7, potently kills ovarian cancer cells in vitro, and induces regression of ovarian tumor xenografts in murine models. To evaluate F7-ADC toxicity in vivo, we generated mice harboring a modified Fzd7 gene where the resulting Fzd7 protein is reactive with the human-targeting F7-ADC. F7-ADC treatment of these mice did not induce acute toxicities, indicating a potentially favorable safety profile in patients. Overall, our data suggest that the antibody–drug conjugate approach may be a powerful strategy to combat FZD7-expressing ovarian cancers in the clinic.
Relative Prognostic Significance of Positron Emission Tomography Myocardial Perfusion Imaging Markers in Cardiomyopathy
Authors: Thomas Merrill , Sperry Brett W. , Peri-Okonny Poghni , Malik Ali O. , McGhie A. Iain , Saeed Ibrahim M. , Chan Paul S. , Spertus John A. , Thompson Randall C. , Bateman Timothy M. , Patel Krishna K. 
Published: October 2021

Background:
Rubidium-82 positron emission tomography myocardial perfusion imaging provides measurements of perfusion, myocardial blood flow and reserve (MBFR), and changes in left ventricular ejection fraction (LVEF) at rest and peak stress. Although all of these variables are known to provide prognostic information, they have not been well studied in patients with heart failure due to reduced LVEF.

Methods:
Between 2010 and 2016, 1255 consecutive unique patients with LVEF≤40% were included in this study who underwent rubidium-82 positron emission tomography myocardial perfusion imaging and did not have subsequent revascularization within 90 days. Perfusion assessment was scored semiquantitatively, and LVEF reserve (stress-rest LVEF) and global MBFR (stress/rest MBF) were quantified using automated software. Cox proportional hazards models adjusted for 14 clinical and 7 test characteristics were used to define the independent prognostic significance of MBFR on all-cause mortality.

Results:

Of 1255 patients followed for a mean of 3.2 years, 454 (36.2%) died. After adjusting for clinical variables, the magnitude of fixed and reversible perfusion defects was prognostic of death (
P
=0.02 and 0.01, respectively), while the rest LVEF was not (
P
=0.18). The addition of LVEF reserve did not add any incremental value, while the addition of MBFR revealed incremental prognostic value (hazard ratio per 0.1 unit decrease in MBFR=1.08 [95% CI, 1.05–1.11],
P
<0.001) with fixed and reversible defects becoming nonsignificant (
P
=0.07 and 0.29, respectively). There was no interaction between MBFR and cause of cardiomyopathy (ischemic versus nonischemic).

Conclusions:
In patients with a known cardiomyopathy who did not require early revascularization, reduced MBFR as obtained by positron emission tomography myocardial perfusion imaging is associated with all-cause mortality while other positron emission tomography myocardial perfusion imaging measures were not.
Perception of Portuguese Mid Vowels by Heritage Speakers of Brazilian Portuguese
Authors: Osborne Denise Maria 
Published: October 2021

Abstract
The main goal of this study is to investigate the perception of Portuguese mid-vowel contrasts (/ɛ/-/e/ and /ɔ/-/o/) by heritage speakers (HS s) of Brazilian Portuguese (BP) who grew up in the United States. This study shows, for instance, an asymmetry in categorization as a function of degree of language dominance for mid-back vowel contrast, but not for mid-front vowel contrast.
Meeting the Challenge of Transmission Delay: Communication Protocols for Space Operations
Authors: Mosier Kathleen L. , Fischer Ute M. 
Published: October 2021

Objective Several studies were conducted to assess media-specific communication protocols as a countermeasure to challenges of asynchronous space–ground communication. Background Previous research demonstrated that transmission delay can negatively impact space–ground communication, collaboration, and task performance. We created media-specific protocols designed to mitigate identified problems associated with asynchronous communication and examined their effects on team communication and task performance. Methods The lab study included 24 teams of three who collaborated remotely via voice or text on computer-based tasks simulating failures in a spacecraft’s life support system. Training and availability of communication protocols was the between-groups variable. Perceived usability, criticality, and effectiveness of the communication protocols were also assessed in space–analog simulations. Results Lab study data revealed that communication protocols facilitated some aspects of team communication; specifically, they reduced threats to common ground and information splitting but not instances of miscommunication. Analog data indicated that protocol compliance was high, participants evaluated most elements as highly important, and protocols maintained perceived communication effectiveness between space crews and mission control during time delay comparably to no-time-delay conditions. Conclusion Converging data attest to the feasibility, usability, and effectiveness of empirically derived communication protocols as a countermeasure to the negative impacts of transmission delay and also point to technological solutions. Application The communication protocols have been adopted for training in NASA analog simulations involving time-delayed communication. They could also support communication among remote team members in medical operations, command-and-control teams, or disaster response under asynchronous conditions or when time is limited and precise communication is critical.
Recommended Reading
Authors: Halloran S. Michael 
Published: October 2021

How do you communicate clearly to a reader without boring him? How do you prod his imagination without confusing him? The answer, I suppose, is to be a highly skilled writer and work very hard at your craft. But while there may be no simple and absolute rules for effective communication, there is an art called rhetoric that can help. I offer the following brief passage from Aristotle's words about rhetoric in the hope that some who are unfamiliar with that ancient art may be moved to read further. A good starting point would be Readings in Classical Rhetoric, edited by Thomas W. Benson and Michael H. Prosser (Bloomington: Indiana University Press, 1969). As you read, bear in mind that this is a translation from a Greek text thought by scholars to be lecture notes – perhaps those of Aristotle himself, perhaps those of one of his students. Consider whether notes from any lectures you have given or attended are likely to look this insightful and clear 2300 years hence. Then notice Aristotle's very subtle understanding of how verbal style can shape an audience's awareness of what is being communicated.
Predicting Decisional Determinants of Physical Activity Among Older Adults: An Integrated Behavior Approach
Authors: Preissner Christian E. , Charles Kathleen , Knäuper Bärbel , Kaushal Navin 
Published: October 2021

Objectives The present study applied the Integrated Behavior Change Model to investigate how behavioral decisions are predicted, namely, intention, planning, and habits, with respect to physical activity. Methods: Participants were older adults (ages 65+) residing in the U.S. ( N = 667) who completed online measures of behavioral determinants (autonomous motivation, perceived behavioral control, subjective norms, attitudes, intention, habit, and consistency), in addition to past behavior. Results: A structural equation model revealed that intention was predicted by past behavior and social-cognitive determinants. Social cognitive determinants mediated between past behavior and habit, as well as between autonomous motivation and habit. Intention mediated between past behavior and planning. Discussion: This study highlights the importance of multiple processes (social cognitive, habit/automatic, and post-intentional/planning) that formulate physical activity intentions. Mediation pathways revealed the importance of autonomous motivation for establishing intentions and habit. Facilitating these processes among older adults could be effective for promoting physical activity.
Synergistic effects of sinapic acid and ellagic acid ameliorate streptozotocin-induced diabetic nephropathy by inhibiting apoptosis, DNA damage, and structural deterioration in rats
Authors: Altındağ F , Özdek U 
Published: October 2021

Introduction Diabetic nephropathy (DN), a global problem that threatens human health, is an important reason for chronic kidney disease and kidney failure. In our study, it was aimed to investigate the individual and combined effects of SA and EA in streptozotocin (STZ)-induced rats. Methods The groups are as follows: Control, untreated diabetic, diabetic treated with Sinapic acid (SA), diabetic treated with Ellagic acid (EA), diabetic treated with SA and EA, treated with SA, treated with EA, and treated with SA and EA. Total kidney volume, total glomerulus volume, total filtration space volume, caspase-3, and 8-OHdG immunoreactivity, Malondialdehyde (MDA), Glutathione (GSH), Catalase (CAT), serum urea, and creatinine levels were evaluated by stereological, immunohistochemical, and biochemical methods. Results The findings of the study showed that total kidney volume, total glomerulus volume, total filtration gap volume, caspase-3, and 8-OHdG immunoreactivity, MDA, serum urea, and creatinine levels significantly increased in the untreated diabetic group compared to the control group. Also, severe mesangial and glomerular enlargement, extracellular matrix accumulation, and glomerular and tubular basal membrane thickness were observed in the tubulointerstitial and glomerular of the diabetic rats. However, individual and combined treatments of SA and EA ameliorated these histological changes. Additionally, decreased GSH and CAT in the untreated diabetic group increased by SA and EA treatment. Conclusions The findings suggest that treatment of SA and EA prevent apoptosis and DNA damage and structural changes in STZ-induced DN. However, the combined treatment of SA and EA were more effective than their individual treatments in all parameters except serum urea and creatinine.
Synthesis of thermally protective PET–PEG multiblock copolymers as food packaging materials
Authors: Güngör Ertuğral Tuğba , Alkan Cemil 
Published: October 2021

One of the storage conditions affecting quality of food stuffs due to short shelf life is temperature. Thermal insulation can be achieved by adding phase change materials (PCMs) to packaging materials. PCMs store and release latent heat of phase change during melting and crystallization operations, respectively. Thus, they can provide thermal protection for packaged foods. The aim of this study is to prepare new food packaging materials poly (ethylene terephthalate)–poly (ethylene glycol) (PET–PEG) multiblock copolymers as solid–solid phase change materials (SSPCM) as potential food packaging materials with thermal energy storage (TES) property. Polyesterification was carried out with PEG at different average molecular weights (1000, 4000 and 10,000 g/mol), ethylene glycol (EG) and terephthaloyl chloride (TPC). Synthesized PET–PEG multiblock copolymers were characterized using Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) methods. The crystal structures of PET–PEG multiblock copolymers were characterized by polarized optical microscopy (POM) and their surface properties were determined by performing contact angle tests. TES capacity of the PET–PEG multiblock copolymers was found in range of 26.1–150.5 J/g. Consequently, this study demonstrates the potential of PET–PEG multiblock copolymers suitable for effective thermal preservation in packaging material applications to maintain the quality of packaged food stuffs.
Neural Correlates of Hiccups in Patients with Lateral Medullary Infarction
Authors: Prabhakar Appaswamy Thirumal , Rabi Tephilah , Shaikh Atif I. A. , Aaron Sanjith , Benjamin Rohit , Mani Arun Mathai , Sivadasan Ajith , Mathew Vivek 
Published: October 2021

Background Hiccups is a known presentation of lateral medullary infarction. However, the region in the medulla associated with this finding is not clearly known. In this study, we aimed to study the neural correlates of hiccups in patients with lateral medullary infarction (LMI). Methods This retrospective study included all patients who presented with lateral medullary infarction between January 2008 and May 2018. Patients with hiccups following LMI were identified as cases and those with no hiccups but who had LMI were taken as controls. The magnetic resonance imaging of the brain was done viewed and individual lesions were mapped manually to the template brain. Voxel-based lesion-symptom mapping employing nonparametric permutation testing was performed using MRIcron. Results There were a total of 31 patients with LMI who presented to the hospital during the study period. There were 11 (35.5%) patients with hiccups. Using the voxel-based lesion-symptom mapping analysis, the dorso-lateral region of the middle medulla showed significant association with hiccups. Conclusion In patients with LMI, we postulate that damage to the dorsolateral aspect on the middle medulla could result in hiccups.