bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of RAS Mutations in Liquid Biopsies of Patients With Multi-Treated Metastatic Colorectal Cancer
Authors: Albuquerque Joana , Neto da Silva Diana , Padrão Teresa , Leal-Costa Luísa , Bizarro Rita , Correia Jorge , Baptista Carlota , Machete Madalena , Prazeres Gil , Margarido Inês , Fernandes Gonçalo , Simões Pedro , Timóteo Teresa , Lopes Fábio , Godinho João , Moreira-Pinto João , Rodrigues Tânia , Faria Ana , Pulido Catarina , Cirnes Luís , Teixeira José A , Passos Coelho José L 
Published: December 2023

Abstract

Background
Liquid biopsy (LB) is a non-invasive tool to evaluate the heterogeneity of tumors. Since RAS mutations (RAS-mut) play a major role in resistance to antiepidermal growth factor receptor inhibitors (EGFR) monoclonal antibodies (Mabs), serial monitoring of RAS-mut with LB may be useful to guide treatment. The main aim of this study was to evaluate the prognostic value of the loss of RAS-mut (NeoRAS-wt) in LB, during the treatment of metastatic colorectal cancer (mCRC).

Methods
A retrospective study was conducted on patients with mCRC between January 2018 and December 2021. RAS-mut were examined in tissue biopsy, at mCRC diagnosis, and with LB, during treatment.

Results
Thirty-nine patients with RAS-mut mCRC were studied. LB was performed after a median of 3 lines (0-7) of systemic treatment including anti-vascular endothelial growth factor (anti-VEGF) Mabs. NeoRAS-wt was detected in 13 patients (33.3%); 9 (69.2%) of them received further treatment with anti-EGFR Mabs with a disease control rate of 44.4%. Median overall survival (OS), from the date of LB testing, was 20 months in the NeoRAS-wt group and 9 months in the persistent RAS-mut group (log-rank 2.985; P = .08), with a 12-month OS of 84.6% and 57.7%, respectively. NeoRAS-wt was identified as a predictor of survival (HR = 0.29; P = .007), with an 11-month improvement in median OS and a 71% decrease in risk of death, in heavily pretreated patients

Conclusions
In conclusion, monitoring clonal evolution in mCRC by LB may provide an additional treatment line for patients with NeoRAS-wt in advanced disease.
Spatial variability in size and lipid content of the marine copepod Calanus finmarchicus across the Northwest Atlantic continental shelves: implications for North Atlantic right whale prey quality
Authors: Helenius Laura K , Head Erica J H , Jekielek Phoebe , Orphanides Christopher D , Pepin Pierre , Perrin Geneviève , Plourde Stéphane , Ringuette Marc , Runge Jeffrey A , Walsh Harvey J , Johnson Catherine L 
Published: December 2023

Abstract
Copepod size and energy content are influenced by regional and seasonal variation in temperature and food conditions, with implications for planktivorous consumers such as the endangered North Atlantic right whale (Eubalaena glacialis). Historical data (1990–2020) on Calanus finmarchicus stage CV copepodite prosome length and oil sac metrics were analyzed to determine the extent of variation in individual body size and estimated lipid and energy content in five regions of the Northwest Atlantic continental shelves [Gulf of Maine (GoM), Scotian Shelf (SS), Gulf of St. Lawrence (GSL), St. Lawrence Estuary (SLE) and Newfoundland Shelf]. Large-scale spatial patterns in size and lipid content were related to latitude, indicating that C. finmarchicus CV in the GSL and SLE were historically larger in body size, and had significantly higher lipid content compared with those in the GoM and the SS. The observed patterns of C. finmarchicus CV size and lipid storage capacity suggest that regional variation in whale prey energy content can play a role in the suitability of current and future whale foraging habitats in the Northwest Atlantic, with the larger lipid-rich individuals in the GSL providing a high-quality diet compared with those in southern areas.
ROS-responsive hydrogels with spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs for the repair of MRSA-infected wounds
Authors: Qiao Bowen , Wang Jiaxin , Qiao Lipeng , Maleki Aziz , Liang Yongping , Guo Baolin 
Published: December 2023

Abstract
For the treatment of MRSA-infected wounds, the spatiotemporally sequential delivery of antibacterial and anti-inflammatory drugs is a promising strategy. In this study, ROS-responsive HA-PBA/PVA (HPA) hydrogel was prepared by phenylborate ester bond cross-linking between hyaluronic acid-grafted 3-amino phenylboronic acid (HA-PBA) and polyvinyl alcohol (PVA) to achieve spatiotemporally controlled release of two kinds of drug to treat MRSA-infected wound. The hydrophilic antibiotic moxifloxacin (M) was directly loaded in the hydrogel. And hydrophobic curcumin (Cur) with anti-inflammatory function was first mixed with Pluronic F127 (PF) to form Cur-encapsulated PF micelles (Cur-PF), and then loaded into the HPA hydrogel. Due to the different hydrophilic and hydrophobic nature of moxifloxacin and Cur and their different existing forms in the HPA hydrogel, the final HPA/M&Cur-PF hydrogel can achieve different spatiotemporally sequential delivery of the two drugs. In addition, the swelling, degradation, self-healing, antibacterial, anti-inflammatory, antioxidant property, and biocompatibility of hydrogels were tested. Finally, in the MRSA-infected mouse skin wound, the hydrogel-treated group showed faster wound closure, less inflammation and more collagen deposition. Immunofluorescence experiments further confirmed that the hydrogel promoted better repair by reducing inflammation (TNF-α) and promoting vascular (VEGF) regeneration. In conclusion, this HPA/M&Cur-PF hydrogel that can spatiotemporally sequential deliver antibacterial and anti-inflammatory drugs showed great potential for the repair of MRSA-infected skin wounds.
Landscape of immune cells in systematic lupus erythematosus patients with Epstein–Barr virus infection: assessed by single-cell sequencing
Authors: Hu Lingzhen , Tu Jianxin , Gui Jiajun , Fang Mengyuan , Sun Li 
Published: December 2023

Abstract

Objectives
To analyse the immune cell and B-cell receptor (BCR) profiles of patients with SLE, with or without EBV infection, and identify the differences between them.

Methods
We included two patients with SLE and positive detection of EBV infections (SLE-EBV+), four with SLE with negative detection of EBV infections (SLE-EBV–) and two healthy controls. Single-cell RNA sequencing was used to investigate the heterogeneity of cell populations by combining the transcriptomic profiles and BCR repertoires.

Results
A total of 83 478 cells were obtained and divided into 31 subtypes. The proportion of CD8+ proliferation T cells was higher in the SLE-EBV+ group than in the SLE-EBV– group. The IFN-α/β pathways were upregulated in most T cells, monocytes and B cells in the SLE-EBV+ group, compared with the SLE-EBV– group. Moreover, T-cell trajectory indicated CD4+ Tregs may play crucial roles in SLE combined with EBV infection. In the BCR heavy chain, the IGHV3 and IGHV4 gene families were frequently present in all groups. Additionally, IgM was the largest component of five Ig isotypes, but its proportion was significantly decreased in the SLE-EBV+ group.

Conclusion
This study provides a comprehensive characterization of the immune cell profiles and BCR repertoires of patients with SLE, both with and without concurrent EBV infections, contributing to a better understanding of the mechanism underlying the immune response to EBV infection in patients with SLE.
Expert Revision of Key Elements for Clinical-Grade Production and Qualification of Perinatal Derivatives
Authors: Gramignoli Roberto , Hofmann Nicola , Agudo-Barriuso Marta , Antica Mariastefania , Flores Ana I , Girandon Lenart , Kerdjoudj Halima , Navakauskiene Ruta , Schiavi Jessica , Scholz Hanne , Shablii Volodymyr , Lafarge Xavier , Nicolás Francisco J , Gindraux Florelle 
Published: December 2023

Abstract
Perinatal derivatives have been proposed as adjunct therapeutic strategies or innovative treatments. Undoubtedly, perinatal derivatives can offer the opportunity and source material to isolate multipotent stem cells, but both maternal- and fetal-derived tissues can be processed and transformed into engineered tissues or advanced biomedical devices, whose potential remains to be fully elucidated. Promising preclinical and clinical results collected so far clearly foresee an escalation of such novel treatments. Market forecasts predict exponential growth in such advanced medicinal products during the next decade, with a pragmatic innovation for medicine into a more advanced biomedical version, enlarging the portfolio for treating a wide range of congenital and acute conditions. However, all these promising and fascinating therapeutic possibilities cannot gain a solid and recognized role in established medical practice without rigid and harmonized manufacturing strategies. The implementation of strategies according to guidelines and directives compiled by Regulatory Agencies, in conformity to (European) Pharmacopoeia and for Good Manufacturing Practice -conforming production of such products, represent critical steps required to translate perinatal technologies into effective therapeutic approaches. During the past 5 years, a panel of European experts and developers, gathered under the umbrella of the COST Sprint Action, supported by the European Cooperation in Science and Technology action, had the opportunity to revise and summarize experience and recommendations for a fruitful and proficient generation of perinatal biomedical products. In order to facilitate the creation and potential commercialization of perinatal bioengineered and advanced pharmaceutical products and technologies, such a collection of data and recommendations is described and discussed here.
A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Non-HLA Matched, Unrelated Donor, Cord Blood Infusion for Ischemic Stroke
Authors: Laskowitz Daniel T , Troy Jesse , Poehlein Emily , Bennett Ellen R , Shpall Elizabeth J , Wingard John R , Freed Brian , Belagaje Samir R , Khanna Anna , Jones William , Volpi John J , Marrotte Eric , Kurtzberg Joanne 
Published: December 2023

Abstract
Stroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center. Study product was infused 3-10 days following index stroke. The primary endpoint was change in modified Rankin Scale (mRS) from baseline to day 90. Key secondary outcomes included functional independence, NIHSS, the Barthel Index, and assessment of adverse events. The trial was terminated early due to slow accrual and logistical concerns associated with the COVID-19 pandemic, and a total of 73 of a planned 100 participants were included in primary analyses. The median (range) of the change in mRS was 1 point (–2, 3) in UCB and 1 point (-1,4) in Placebo (P = 0.72). A shift analysis comparing the mRS at day 90 utilizing proportional odds modeling showed a common odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline NIHSS and randomization strata. The distribution of adverse events was similar between arms. Although this study did not suggest any safety concerns related to UCB in ischemic stroke, we did not show a clinical benefit in the reduced sample size evaluated.
Short-term responses of meat ewes facing an acute nutritional challenge in early-mid lactation
Authors: González-García Eliel , Gindri Marcelo , Durand Christian , Lafon Noëllie , Douls Sébastien , Bonafe Gaëtan , Coulon Valentin , Hazard Dominique , Bonnal Laurent , Tesnière Anne , Llach Irene , Parisot Sara , Puillet Laurence 
Published: December 2023

Abstract
Simulating a consequence of a climate change event on feed availability, responses of Mediterranean meat ewes facing an acute undernutritional challenge (CHA; i.e., fed only low nutritional value cereal straw) were evaluated at a sensitive physiological stage (i.e., early suckling). Forty Romane ewes were chosen at early-mid pregnancy (around 2 mo) according to parity (20 primiparous, PRIM; 20 multiparous, MULT); feed efficiency genetic line of their sires (residual feed intake [RFI]; efficient, RFI−, n = 10 per parity; inefficient, RFI+, n = 10 per parity); litter size (i.e., bearing twins, diagnosed by ultrasonography); body weight (BW, kg) and body condition score (BCS) (initial BW and BCS [mean ± SD]: 51.6 ± 7.41 kg; 2.5 ± 0.20, respectively; representing flock’ averages per parity). Effects on dry matter intake (DMI), ewes’ BW and BCS, subcutaneous dorsal fat thickness (DFT), energy metabolism (plasma non-esterified fatty acids [NEFA], β-hydroxybutyrate (β-OHB), glucose, urea, triiodothyronine [T3]), and lambs’ growth (BW and average daily gain [ADG]; g/d) were examined before, during and after CHA. Individuals’ profiles of the response-recovery to CHA were described using a piecewise mixed-effects model. The fixed effect of parity and genetic line and the random effect of individual (ewe) were considered. A linear mixed-effects model was fitted to explore the effects on lambs’ growth. The 2-d straw-only CHA had significant effects on most of the recorded parameters. Meaningful drops and recoveries were observed on ewes’ DMI, BW, and DFT with effect on postchallenge levels. BW, BCS, DFT, or DMI were also affected by parity (MULT &gt; PRIM) but not by genetic line. Plasma NEFA, β-OHB, glucose, urea, and T3 responded well to CHA with drops in T3, urea, and glucose levels, whereas NEFA and β-OHB significantly increased after CHA. MULT ewes presented sharper β-OHB recovery from CHA than PRIM (P ≤ 0.05). With this study, we provide tangible and necessary data for an emerging field of research. Our results give new insights into how such a short and abrupt CHA affects some key zootechnical and physiological parameters, and to what extent the impacts of CHA and the ewes’ response-recovery are influenced. It also revealed potential between-individual differences in the adaptive capacities of ewes, which require further exploration.
Caveolin‐1 promotes mitochondrial health and limits mitochondrial ROS through ROCK/AMPK regulation of basal mitophagic flux
Authors: Timmins Logan R. , Ortiz‐Silva Milene , Joshi Bharat , Li Y. Lydia , Dickson Fiona H. , Wong Timothy H. , Vandevoorde Kurt R. , Nabi Ivan R. 
Published: December 2023

AbstractCaveolin‐1 (CAV1), the main structural component of caveolae, is phosphorylated at tyrosine‐14 (pCAV1), regulates signal transduction, mechanotransduction, and mitochondrial function, and plays contrasting roles in cancer progression. We report that CRISPR/Cas9 knockout (KO) of CAV1 increases mitochondrial oxidative phosphorylation, increases mitochondrial potential, and reduces ROS in MDA‐MB‐231 triple‐negative breast cancer cells. Supporting a role for pCAV1, these effects are reversed upon expression of CAV1 phosphomimetic CAV1 Y14D but not non‐phosphorylatable CAV1 Y14F. pCAV1 is a known effector of Rho‐associated kinase (ROCK) signaling and ROCK1/2 signaling mediates CAV1 promotion of increased mitochondrial potential and decreased ROS production in MDA‐MB‐231 cells. CAV1/ROCK control of mitochondrial potential and ROS is caveolae‐independent as similar results were observed in PC3 prostate cancer cells lacking caveolae. Increased mitochondrial health and reduced ROS in CAV1 KO MDA‐MB‐231 cells were reversed by knockdown of the autophagy protein ATG5, mitophagy regulator PINK1 or the mitochondrial fission protein Drp1 and therefore due to mitophagy. Use of the mitoKeima mitophagy probe confirmed that CAV1 signaling through ROCK inhibited basal mitophagic flux. Activation of AMPK, a major mitochondrial homeostasis protein inhibited by ROCK, is inhibited by CAV1‐ROCK signaling and mediates the increased mitochondrial potential, decreased ROS, and decreased basal mitophagy flux observed in wild‐type MDA‐MB‐231 cells. CAV1 regulation of mitochondrial health and ROS in cancer cells therefore occurs via ROCK‐dependent inhibition of AMPK. This study therefore links pCAV1 signaling activity at the plasma membrane with its regulation of mitochondrial activity and cancer cell metabolism through control of mitophagy.
Estrogen contributes to sex differences in M2a macrophages during multi‐walled carbon nanotube‐induced respiratory inflammation
Authors: Ray Jessica L. , Postma Britten , Kendall Rebekah L. , Ngo Minh Dao , Foo Cheng Xiang , Saunders Brett , Ronacher Katharina , Gowdy Kymberly M. , Holian Andrij 
Published: December 2023

AbstractLung diseases characterized by type 2 inflammation are reported to occur with a female bias in prevalence/severity in both humans and mice. This includes previous work examining multi‐walled carbon nanotube (MWCNT)‐induced eosinophilic inflammation, in which a more exaggerated M2a phenotype was observed in female alveolar macrophages (AMs) compared to males. The mechanisms responsible for this sex difference in AM phenotype are still unclear, but estrogen receptor (ER) signaling is a likely contributor. Accordingly, male AMs downregulated ERα expression after MWCNT exposure while female AMs did not. Thus, ER antagonist Fulvestrant was administered prior to MWCNT instillation. In females, Fulvestrant significantly attenuated MWCNT‐induced M2a gene expression and eosinophilia without affecting IL‐33. In males, Fulvestrant did not affect eosinophil recruitment but reduced IL‐33 and M2a genes compared to controls. Regulation of cholesterol efflux and oxysterol synthesis is a potential mechanism through which estrogen promotes the M2a phenotype. Levels of oxysterols 25‐OHC and 7α,25‐OHC were higher in the airways of MWCNT‐exposed males compared to MWCNT‐females, which corresponds with the lower IL‐1β production and greater macrophage recruitment previously observed in males. Sex‐based changes in cholesterol efflux transporters Abca1 and Abcg1 were also observed after MWCNT exposure with or without Fulvestrant. In vitro culture with estrogen decreased cellular cholesterol and increased the M2a response in female AMs, but did not affect cholesterol content in male AMs and reduced M2a polarization. These results reveal the modulation of (oxy)sterols as a potential mechanism through which estrogen signaling may regulate AM phenotype resulting in sex differences in downstream respiratory inflammation.
Biochemical characterization of the Drosophila insulin receptor kinase and longevity‐associated mutants
Authors: Krishnan Harini , Ahmed Sultan , Hubbard Stevan R. , Miller W. Todd 
Published: December 2023

AbstractDrosophila melanogaster (fruit fly) insulin receptor (D‐IR) is highly homologous to the human counterpart. Like the human pathway, D‐IR responds to numerous insulin‐like peptides to activate cellular signals that regulate growth, development, and lipid metabolism in fruit flies. Allelic mutations in the D‐IR kinase domain elevate life expectancy in fruit flies. We developed a robust heterologous expression system to express and purify wild‐type and longevity‐associated mutant D‐IR kinase domains to investigate enzyme kinetics and substrate specificities. D‐IR exhibits remarkable similarities to the human insulin receptor kinase domain but diverges in substrate preferences. We show that longevity‐associated mutations reduce D‐IR catalytic activity. Deletion of the unique kinase insert domain portion or mutations proximal to activating tyrosines do not influence kinase activity, suggesting their potential role in substrate recruitment and downstream signaling. Through biochemical investigations, this study enhances our comprehension of D‐IR's role in Drosophila physiology, complementing genetic studies and expanding our knowledge on the catalytic functions of this conserved signaling pathway.
SINGLE CELL DISSECTION OF DEVELOPMENTAL ORIGINS AND TRANSCRIPTIONAL HETEROGENEITY IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Iacobucci Ilaria , Zeng Andy G.X. , Gao Qingsong , Garcia-Prat Laura , Baviskar Pradyumna , Shah Sayyam , Murison Alex , Voisin Veronique , Chan-Seng-Yue Michelle , Cheng Cheng , Qu Chunxu , Bailey Colin , Lear Matthew , Witkowski Matthew T. , Zhou Xin , Peraza Airen Zaldivar , Gangwani Karishma , Advani Anjali S. , Luger Selina M. , Litzow Mark R. , Rowe Jacob M , Paietta Elisabeth M. , Stock Wendy , Dick John E. , Mullighan Charles G 
Published: December 2023

ABSTRACTSequencing of bulk tumor populations has improved genetic classification and risk assessment of B-ALL, but does not directly examine intratumor heterogeneity or infer leukemia cellular origins. We profiled 89 B-ALL samples by single-cell RNA-seq (scRNA-seq) and compared them to a reference map of normal human B-cell development established using both functional and molecular assays. Intra-sample heterogeneity was driven by cell cycle, metabolism, differentiation, and inflammation transcriptional programs. By inference of B lineage developmental state composition, nearly all samples possessed a high abundance of pro-B cells, with variation between samples mainly driven by sub-populations. However,ZNF384-r andDUX4-r B-ALL showed composition enrichment of hematopoietic stem cells,BCR::ABL1andKMT2A-r ALL of Early Lymphoid progenitors,MEF2D-r andTCF3::PBX1of Pre-B cells. Enrichment of Early Lymphoid progenitors correlated with high-risk clinical features. Understanding variation in transcriptional programs and developmental states of B-ALL by scRNA-seq refines existing clinical and genomic classifications and improves prediction of treatment outcome.
Expanding the toolbox: Novel class IIb microcins show activity against Gram-negative ESKAPE and plant pathogens
Authors: Mortzfeld Benedikt M. , Bhattarai Shakti K. , Bucci Vanni 
Published: December 2023

AbstractInterspecies interactions involving direct competition via bacteriocin production play a vital role in shaping ecological dynamics within microbial ecosystems. For instance, the ribosomally-produced siderophore bacteriocins, known as class IIb microcins, affect the colonization of host-associated pathogenicEnterobacteriaceaespecies. Notably, to date, only five of these antimicrobials have been identified, all derived from specificEscherichia coliandKlebsiella pneumoniaestrains. We hypothesized that class IIb microcin production extends beyond these specific compounds and organisms. With a customized informatics-driven approach, screening bacterial genomes in public databases with BLAST and manual curation, we have discovered twelve previously unknown class IIb microcins in seven additionalEnterobacteriaceaespecies, encompassing phytopathogens and environmental isolates. We introduce three novel clades of microcins (MccW, MccX, and MccZ), while also identifying eight new variants of the five known class IIb microcins. To validate their antimicrobial potential, we heterologously expressed these microcins inE. coliand demonstrated efficacy against a variety of bacterial isolates, including plant pathogens from the generaBrenneria, Gibbsiella, and Rahnella. Two newly discovered microcins exhibit activity against Gram-negative ESKAPE pathogens, i.e.Acinetobacter baumanniiorPseudomonas aeruginosa, providing the first evidence that class IIb microcins can target bacteria outside of theEnterobacteriaceaefamily. This study underscores that class IIb microcin genes are more prevalent in the microbial world than previously recognized and that synthetic hybrid microcins can be a viable tool to target clinically relevant drug-resistant pathogens. Our findings hold significant promise for the development of innovative engineered live biotherapeutic products tailored to combat these resilient bacteria.