bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioinformatic reanalysis of public proteomics data reveals that nuclear proteins are recurrent in cancer secretomes
Authors: De Morais Juliana A. , Zelanis André 
Published: November 2021

AbstractProteins secreted by tumoral cells (cancer secretomes) have been continuously associated with cancer development and progression processes. In this context, secreted proteins contribute to the signaling mechanisms related to tumor growth and spreading and studies on tumor secretomes provide valuable clues on putative tumor biomarkers. Although the in vitro identification of intracellular proteins in cancer secretome studies has usually been associated with contamination derived from cell lysis or fetal bovine serum, accumulated evidence reports on intracellular proteins with moonlighting functions in the extracellular environment. In this study, we performed a systematic reanalysis of public proteomics data regarding different cancer secretomes, aiming to identify intracellular proteins potentially secreted by tumor cells via unconventional secretion pathways. We found a similar repertoire of unconventionally secreted proteins, including the recurrent identification of nuclear proteins secreted by different cancer cells. In addition, in some cancer types, immunohistochemical data were in line with proteomics identifications and suggested that nuclear proteins might relocate from the nucleus to the cytoplasm. Both the presence of nuclear proteins and the likely unconventional secretion of such proteins may comprise biological signatures of malignant transformation in distinct cancer types and may be targeted for further analysis aiming at the prognostic/therapeutic value of such features.
Hadean zircon formed due to hydrated ultramafic protocrust melting
Authors: Borisova Anastassia Y. , Nédélec Anne , Zagrtdenov Nail R. , Toplis Michael J. , Bohrson Wendy A. , Safonov Oleg G. , Bindeman Ilya N. , Melnik Oleg E. , Pokrovski Gleb S. , Ceuleneer Georges , Jochum Klaus Peter , Stoll Brigitte , Weis Ulrike , Bychkov Andrew Y. , Gurenko Andrey A. 
Published: November 2021

Abstract
Hadean zircons, from the Jack Hills (Western Australia) and other localities, are currently the only window into the earliest terrestrial felsic crust, the formation of which remains enigmatic. Based upon new experimental results, generation of such early crust has been hypothesized to involve the partial melting of hydrated peridotite interacting with basaltic melt at low pressure (&lt;10 km), but it has yet to be demonstrated that such liquids can indeed crystallize zircons comparable to Jack Hills zircon. We used thermodynamic and geochemical modeling to test this hypothesis. The predicted zircon saturation temperatures of &lt;750 °C, together with the model zircon Th, U, Nb, Hf, Y, and rare earth element (REE) contents at 700 °C, δ18OVSMOW (Vienna standard mean ocean water) signatures, and co-crystallizing mineral assemblage were compared to those of the Jack Hills zircon. This comparison was favorable with respect to crystallization temperature, most trace-element contents, and mineral inclusions in zircon. The discrepancy in δ18OVSMOW signatures may be explained by hotter conditions of Hadean protocrust hydration. Our work supports the idea that felsic magma generation at shallow depths involving a primordial weathered ultramafic protocrust and local basaltic intrusions is indeed a viable mechanism for the formation of felsic crust on early Earth.
Mississippian southern Laurentia tuffs came from a northern Gondwana arc
Authors: Tian Hepeng , Fan Majie , Valencia Victor A. , Chamberlain Kevin , Stern Robert J. , Waite Lowell 
Published: November 2021

AbstractA Paleozoic arc that formed by southward subduction of the Rheic oceanic plate beneath northern Gondwana has long been inferred, but its history and geochemical signatures remain poorly understood. New U-Pb ages, juvenile εHf signatures, and trace-element composition data of young zircons from tuffs at two southern Laurentia sites indicate their derivation from a continental arc that was active from ca. 328 to ca. 317 Ma and permit correlation of sedimentary sequences 800 km apart in southern Laurentia. These include the Stanley tuffs in the Ouachita Mountains of southeastern Oklahoma and southwestern Arkansas and the newly discovered Barnett tuff in the subsurface of the Midland Basin in west Texas (USA). The Barnett tuff has a zircon chemical abrasion–isotope dilution–thermal ionization mass spectrometry U-Pb date of 327.8 ± 0.8 Ma, similar to the oldest Stanley tuff in the Ouachita Mountains. Zircon Hf isotope depleted mantle model ages further suggest that the source was a continental arc on basement with both Grenville and Pan-African affinities, pointing to northern Gondwana or peri-Gondwana terranes. The new data link the tuffs to granitoids (326 Ma) of the Maya block in southern Mexico, which was part of northern Gondwana. Correlation of the Stanley-Barnett tuffs across southern Laurentia suggests the likely presence of Mississippian tuffs over a broad region in southern Laurentia, and their usefulness for constraining absolute ages of basin fills and characterizing the Gondwanan arc.
Decreased eosinophil counts and elevated lactate dehydrogenase predict severe COVID-19 in patients with underlying chronic airway diseases
Authors: Chen Dian , Zhang Shuchen , Feng Yuchen , Wu Wenliang , Chang Chenli , Chen Shengchong , Zhen Guohua , Yi Lingling 
Published: November 2021

AbstractBackgroundSeveral predictors of COVID-19 severity have been reported. However, chronic airway inflammation characterised by accumulated lymphocytes or eosinophils may affect the pathogenesis of COVID-19.MethodsIn this retrospective cohort study, we reviewed the medical records of all patients with laboratory-confirmed COVID-19 with chronic bronchitis, chronic obstructive pulmonary disease (COPD) and asthma admitted to the Sino-French New City Branch of Tongji Hospital, a large regional hospital in Wuhan, China, from 26 January to 3 April. The Tongji Hospital Ethics Committee approved this study.ResultsThere were 59 patients with chronic bronchitis, COPD and asthma. When compared with non-severe patients, severe patients were more likely to have decreased lymphocyte counts (0.6×10⁹/L vs 1.1×10⁹/L, p&lt;0.001), eosinopaenia (&lt;0.02×10⁹/L; 73% vs 24%, p&lt;0.001), increased lactate dehydrogenase (LDH) (471.0 U/L vs 230.0 U/L, p&lt;0.001) and elevated interleukin 6 level (47.4 pg/mL vs 5.7 pg/mL, p=0.002) on admission. Eosinopaenia and elevated LDH were significantly associated with disease severity in both univariate and multivariate regression models including the above variables. Moreover, eosinophil count and LDH level tended to return to normal range over time in both groups after treatment and severe patients recovered slower than non-severe patients, especially in eosinophil count.ConclusionsEosinopaenia and elevated LDH are potential predictors of disease severity in patients with COVID-19 with underlying chronic airway diseases. In addition, they could indicate disease progression and treatment effectiveness.
Some results on ∗-differential identities in prime rings
Authors: Kumar Deepak , Bhushan Bharat , Sandhu Gurninder S. 
Published: November 2021

Let [Formula: see text] be a prime ring with involution ∗ of the second kind. An additive mapping [Formula: see text] is called generalized derivation if there exists a unique derivation [Formula: see text] such that [Formula: see text] for all [Formula: see text] In this paper, we investigate the structure of [Formula: see text] and describe the possible forms of generalized derivations of [Formula: see text] that satisfy specific ∗-differential identities. Precisely, we study the following situations: (i) [Formula: see text] (ii) [Formula: see text] (iii) [Formula: see text] (iv) [Formula: see text] for all [Formula: see text] Moreover, we construct some examples showing that the restrictions imposed in the hypotheses of our theorems are not redundant.
Repurposing Ceritinib Induces DNA Damage and Enhances PARP Inhibitor Responses in High-Grade Serous Ovarian Carcinoma
Authors: Kanakkanthara Arun , Hou Xiaonan , Ekstrom Thomas L. , Zanfagnin Valentina , Huehls Amelia M. , Kelly Rebecca L. , Ding Husheng , Larson Melissa C. , Vasmatzis George , Oberg Ann L. , Kaufmann Scott H. , Mansfield Aaron S. , Weroha S. John , Karnitz Larry M. 
Published: November 2021

AbstractPARP inhibitors (PARPi) have activity in homologous recombination (HR) repair-deficient, high-grade serous ovarian cancers (HGSOC). However, even responsive tumors develop PARPi resistance, highlighting the need to delay or prevent the appearance of PARPi resistance. Here, we showed that the ALK kinase inhibitor ceritinib synergizes with PARPis by inhibiting complex I of the mitochondrial electron transport chain, which increases production of reactive oxygen species (ROS) and subsequent induction of oxidative DNA damage that is repaired in a PARP-dependent manner. In addition, combined treatment with ceritinib and PARPi synergized in HGSOC cell lines irrespective of HR status, and a combination of ceritinib with the PARPi olaparib induced tumor regression more effectively than olaparib alone in HGSOC patient-derived xenograft (PDX) models. Notably, the ceritinib and olaparib combination was most effective in PDX models with preexisting PARPi sensitivity and was well tolerated. These findings unveil suppression of mitochondrial respiration, accumulation of ROS, and subsequent induction of DNA damage as novel effects of ceritinib. They also suggest that the ceritinib and PARPi combination warrants further investigation as a means to enhance PARPi activity in HGSOC, particularly in tumors with preexisting HR defects.Significance:The kinase inhibitor ceritinib synergizes with PARPi to induce tumor regression in ovarian cancer models, suggesting that ceritinib combined with PARPi may be an effective strategy for treating ovarian cancer.
BAFF Attenuates Immunosuppressive Monocytes in the Melanoma Tumor Microenvironment
Authors: Liu Wei , Stachura Paweł , Xu Haifeng C. , Váraljai Renáta , Shinde Prashant , Ganesh Nikkitha Umesh , Mack Matthias , Van Lierop Anke , Huang Anfei , Sundaram Balamurugan , Lang Karl S. , Picard Daniel , Fischer Ute , Remke Marc , Homey Bernhard , Roesch Alexander , Häussinger Dieter , Lang Philipp A. , Borkhardt Arndt , Pandyra Aleksandra A. 
Published: November 2021

AbstractEmerging evidence indicates B-cell activating factor (BAFF, Tnfsf13b) to be an important cytokine for antitumor immunity. In this study, we generated a BAFF-overexpressing B16.F10 melanoma cell model and found that BAFF-expressing tumors grow more slowly in vivo than control tumors. The tumor microenvironment (TME) of BAFF-overexpressing tumors had decreased myeloid infiltrates with lower PD-L1 expression. Monocyte depletion and anti-PD-L1 antibody treatment confirmed the functional importance of monocytes for the phenotype of BAFF-mediated tumor growth delay. RNA sequencing analysis confirmed that monocytes isolated from BAFF-overexpressing tumors were characterized by a less exhaustive phenotype and were enriched for in genes involved in activating adaptive immune responses and NF-κB signaling. Evaluation of patients with late-stage metastatic melanoma treated with inhibitors of the PD-1/PD-L1 axis demonstrated a stratification of patients with high and low BAFF plasma levels. Patients with high BAFF levels experienced lower responses to anti-PD-1 immunotherapies. In summary, these results show that BAFF, through its effect on tumor-infiltrating monocytes, not only impacts primary tumor growth but can serve as a biomarker to predict response to anti-PD-1 immunotherapy in advanced disease.Significance:The BAFF cytokine regulates monocytes in the melanoma microenvironment to suppress tumor growth, highlighting the importance of BAFF in antitumor immunity.
Cardiometabolic Risk in Childhood Cancer Survivors: A Report from the Children's Oncology Group
Authors: Lipshultz Emma R. , Chow Eric J. , Doody David R. , Armenian Saro H. , Asselin Barbara L. , Baker K. Scott , Bhatia Smita , Constine Louis S. , Freyer David R. , Kopp Lisa M. , Schwartz Cindy L. , Lipshultz Steven E. , Vrooman Lynda M. 
Published: November 2021

Abstract

Background:
Childhood cancer survivors are at risk for cardiovascular disease. We assessed the burden of potentially modifiable cardiometabolic risk factors (CRF) among survivors compared with population-matched controls.

Methods:
Survivors previously enrolled on Pediatric Oncology Group protocols 9404, 9425, 9426, 9754, and Dana-Farber Cancer Institute 95-01 from 1996 to 2001 with acute lymphoblastic leukemia/lymphoma, Hodgkin lymphoma, or osteosarcoma were prospectively assessed for the prevalence of CRFs and compared with an age, sex, and race/ethnicity-matched 2013 National Health and Nutrition Examination Survey (NHANES) population. We estimated future predicted cardiovascular risk based on general population (e.g., Framingham) and Childhood Cancer Survivor Study (CCSS) models.

Results:
Compared with NHANES (n = 584), survivors [n = 164; 44.5% female, median age 28 years (range, 16–38 years); median 17.4 years (range, 13–22 years) since cancer diagnosis; median doxorubicin dose 300 mg/m2; 30.5% chest radiation] had similar rates of obesity, diabetes, and dyslipidemia, but more prehypertension/hypertension (38.4% vs. 30.1%, P = 0.044). Survivors had fewer metabolic syndrome features compared with NHANES (≥2 features: 26.7% vs. 55.9%; P &lt; 0.001). Survivors were more physically active and smoked tobacco less (both P &lt; 0.0001). Therefore, general population cardiovascular risk scores were lower for survivors versus NHANES. However, with CCSS models, 30.5% of survivors were at moderate risk of ischemic heart disease, and &gt;95% at moderate/high risk for heart failure, with a 9% to 12% predicted incidence of these conditions by age 50 years.

Conclusions:
Childhood cancer survivors exhibited similar or better cardiometabolic and lifestyle profiles compared with NHANES, but nonetheless are at risk for future clinically significant cardiovascular disease.

Impact:
Further strategies supporting optimal CRF control are warranted in survivors.
See related commentary by Mulrooney, p. 515
Multiple Primary Cancers in Patients Undergoing Tumor-Normal Sequencing Define Novel Associations
Authors: Liu Ying L. , Cadoo Karen A. , Mukherjee Semanti , Khurram Aliya , Tkachuk Kaitlyn , Kemel Yelena , Maio Anna , Belhadj Sami , Carlo Maria I. , Latham Alicia , Walsh Michael F. , Dubard-Gault Marianne E. , Wang Yuhan , Brannon A. Rose , Salo-Mullen Erin , Sheehan Margaret , Fiala Elise , Devolder Bryan , Dandiker Sita , Mandelker Diana , Zehir Ahmet , Ladanyi Marc , Berger Michael F. , Solit David B. , Bandlamudi Chaitanya , Ravichandran Vignesh , Bajorin Dean F. , Stadler Zsofia K. , Robson Mark E. , Vijai Joseph , Seshan Venkatraman , Offit Kenneth 
Published: November 2021

Abstract

Background:
Cancer survivors are developing more subsequent tumors. We sought to characterize patients with multiple (≥2) primary cancers (MPC) to assess associations and genetic mechanisms.

Methods:
Patients were prospectively consented (01/2013–02/2019) to tumor-normal sequencing via a custom targeted panel (MSK-IMPACT). A subset consented to return of results of ≥76 cancer predisposition genes. International Agency for Research on Cancer (IARC) 2004 rules for defining MPC were applied. Tumor pairs were created to assess relationships between cancers. Age-adjusted, sex-specific, standardized incidence ratios (SIR) for first to second cancer event combinations were calculated using SEER rates, adjusting for confounders and time of ascertainment. Associations were made with germline and somatic variants.

Results:
Of 24,241 patients, 4,340 had MPC (18%); 20% were synchronous. Most (80%) had two primaries; however, 4% had ≥4 cancers. SIR analysis found lymphoma–lung, lymphoma–uterine, breast–brain, and melanoma–lung pairs in women and prostate–mesothelioma, prostate–sarcoma, melanoma–stomach, and prostate–brain pairs in men in excess of expected after accounting for synchronous tumors, known inherited cancer syndromes, and environmental exposures. Of 1,580 (36%) patients who received germline results, 324 (21%) had 361 pathogenic/likely pathogenic variants (PV), 159 (44%) in high penetrance genes. Of tumor samples analyzed, 55% exhibited loss of heterozygosity at the germline variant. In those with negative germline findings, melanoma, prostate, and breast cancers were common.

Conclusions:
We identified tumor pairs without known predisposing mutations that merit confirmation and will require novel strategies to elucidate genetic mechanisms of shared susceptibilities.

Impact:
If verified, patients with MPC with novel phenotypes may benefit from targeted cancer surveillance.
Mode of Death in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF Trial
Authors: Desai Akshay S. , Vaduganathan Muthiah , Cleland John G. , Claggett Brian L. , Barkoudah Ebrahim , Finn Peter , McCausland Finnian R. , Yilmaz Mehmet B. , Lefkowitz Martin , Shi Victor , Pfeffer Marc A. , McMurray John J.V. , Solomon Scott D. 
Published: November 2021

Background:
Patients with heart failure (HF) and preserved left ventricular ejection fraction comprise a heterogeneous group including some with mildly reduced EF. We hypothesized that mode of death differs by EF in ambulatory patients with HF and preserved left ventricular ejection fraction.

Methods:
PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor With Angiotensin-Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) compared clinical outcomes in 4796 patients with chronic HF and EF ≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the mode of death in relation to baseline EF in logistic regression models and the effect of randomized treatment on cause-specific death in Cox regression models. Nonlinear relationships with continuous EF were modelled using quadratic and cubic terms.

Results:

Of 691 deaths during the trial, 416 (60%) were ascribed to cardiovascular, 220 (32%) to noncardiovascular, and 55 (8%) to unknown causes. Of cardiovascular deaths, 154 (37%) were due to sudden death, 118 (28%) were due to HF, 35 (8%) to stroke, 27 (6%) to myocardial infarction, and 82 (20%) to other cardiovascular causes. Rates of all-cause, cardiovascular, and sudden death were higher in those with lower left ventricular ejection fraction (all
P
<0.001), while rates of non-cardiovascular death were greater in patients with higher EF. Sacubitril/valsartan did not reduce overall death, cardiovascular death, or sudden death compared with valsartan, irrespective of baseline EF (all
P
for interaction >0.30).

Conclusions:
Among patients with HF and preserved left ventricular ejection fraction enrolled in PARAGON-HF, the proportion of cardiovascular and sudden death were higher in those with lower left ventricular EF, and the proportion of noncardiovascular death rose with EF. Regardless of EF, sacubitril/valsartan did not reduce death from any cause compared with valsartan.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01920711.
Abstract MP245: Tet Proteins Regulate Second Heart Field Multipotent Progenitors Differentiating To Myocytes
Authors: Fang Shaohai , Li Jia , Steimle Jeff D , Guo Lei , Yang Yuhan , Hong Tingting , Wang Rui , Han Wei , Zhou Yubin , Wang Jun , Martin James F , Huang Yun 
Published: November 2021

DNA methylation and demethylation play an important role in shaping the epigenetic landscape and chromatin accessibility to control gene expression during development in mammals. Ten-eleven Translocation (Tet1, Tet2 and Tet3) is a family of dioxygenases that catalyze DNA methylation oxidation with ultimate DNA demethylation. Our previous study showed that cardiac-specific deletion of Tet2 and Tet3 could disrupt YY1-mediated long range chromatin interactions during heart development and lead to ventricular non-compaction cardiomyopathy. However, it is still unclear whether and how Tet protein mediated epigenetic modifications contribute to cardiac lineage specification during embryonic development.
In this study, we generated cardiac specific Tet1-3 triple deficient (Tet-TKO) mouse lines using various cardiac specific Cres to evaluate the function of Tet protein in regulating cardiac lineage specification. We observed developmental defects at outflow tract (OFT) in Tet-TKO embryos, suggesting that Tet deficiency affects the second heart field (SHF) development. Single cell RNA-seq analysis further revealed the accumulation of multipotent SHF progenitors and subsequent halt of myocyte differentiation upon Tet depletion. At the molecular level, we found that Tet ablation perturbs the transcriptional network of Islet1, a transcription factor that is crucial for cardiac development in embryos. Overall, our study demonstrates a critical role of Tet-mediated epigenetic regulation for embryonic cardiac development.
Abstract P400: Treatment With The AMPK Agonist AICAR Alleviates Age-associated Cardiac Defects In The Mouse By Distinct Sex-specific Mechanisms
Authors: Angelini Aude , Ortiz-Urbina Jesus , Trial JoAnn , Entman Mark L , Taffet George E , Cieslik Katarzyna A 
Published: November 2021

Heart failure is a major cause of mortality in the elderly. Features of cardiac aging include diastolic dysfunction and interstitial fibrosis with sex-specific differences.
We treated old male and female mice (21 months-old) 3 times a week for 3 months with the AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR, 0.166 mg/g BW). We previously reported that AICAR normalizes the aged fibroblast phenotype.
In a longitudinal study, we found that AICAR attenuates the age-associated increase in left atrial volume, an indirect indicator of diastolic dysfunction, in female AICAR-treated mice (-29% ±5%) but not in males (-7% ±6%). Cardiac fibroblasts from AICAR-treated mice expressed decreased pro-collagen levels by 42% (mean fluorescence intensity, P=0.0003 for females, and P=0.05 for males). Cardiac fibroblasts cultured on decellularized cardiac matrices also had a reduced expression of pro-collagen when treated with AICAR (0.5mM, 7 days). Myocardial hydroxyproline level (an indicator of total collagen content) was reduced in female hearts (from 0.83 ± 0.07 in controls to 0.48 ± 0.05 in AICAR-treated, P=0.006). Female cells also exhibited a reduced expression of periostin after treatment (by 65%, P=0.02). By contrast, age-matched control males had a lower cardiac level of hydroxyproline (-65%, P=0.0002) and periostin (-45%, P=0.0004) than females, and were not affected by the treatment.
Accumulation of defective mitochondria is a hallmark of aging. Since AICAR can favor mitophagy, we isolated mitochondrial fractions from the hearts of old mice undergoing treatment. We found that AICAR decreased Parkin level in the small mitochondria fraction (0.75±0.09, P=0.028) in males, but no significant change was found between the groups of females. The reduction of Parkin may suggest improved clearance of defective mitochondria.For all experiments, we used 4-10 animals per group. One-way Anova or student’s T-test evaluated statistical significance.
In conclusion, age-associated cardiac remodeling leads to distinct patterns between male and female mice. AICAR treatment can have sex-specific effects: it reduces fibrosis in females but may promote mitophagy in males, translating into an improvement of heart function via distinct mechanisms.