bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating the outcomes of donor-recipient age differences in young adults undergoing liver transplantation
Authors: Snyder Abigail , Kojima Lisa , Imaoka Yuki , Akabane Miho , Kwong Allison , Melcher Marc L. , Sasaki Kazunari 
Published: February 2023

The current liver allocation system may be disadvantaging younger adult recipients as it does not incorporate the donor-recipient age difference. Given the longer life expectancy of younger recipients, the influences of older donor grafts on their long-term prognosis should be elucidated. This study sought to reveal the long-term prognostic influence of the donor-recipient age difference in young adult recipients. Adult patients who received initial liver transplants from deceased donors between 2002 and 2021 were identified from the UNOS database. Young recipients (patients 45 years old or below) were categorized into 4 groups: donor age younger than the recipient, 0–9 years older, 10–19 years older, or 20 years older or above. Older recipients were defined as patients 65 years old or above. To examine the influence of the age difference in long-term survivors, conditional graft survival analysis was conducted on both younger and older recipients. Among 91,952 transplant recipients, 15,170 patients were 45 years old or below (16.5%); these were categorized into 6,114 (40.3%), 3,315 (21.9%), 2,970 (19.6%), and 2,771 (18.3%) for groups 1–4, respectively. Group 1 demonstrated the highest probability of survival, followed by groups 2, 3, and 4 for the actual graft survival and conditional graft survival analyses. In younger recipients who survived at least 5 years post-transplant, inferior long-term survival was observed when there was an age difference of 10 years or above (86.9% vs. 80.6%, log-rank p<0.01), whereas there was no difference in older recipients (72.6% vs. 74.2%, log-rank p=0.89). In younger patients who are not in emergent need of a transplant, preferential allocation of younger aged donor offers would optimize organ utility by increasing postoperative graft survival time.
Radiographic Sigmoid Sinus Wall Abnormalities and Pulsatile Tinnitus: A Case-Control Study
Authors: Cass Nathan D. , Lindquist Nathan R. , Patro Ankita , Smetak Miriam R. , Perkins Elizabeth L. , O'Malley Matthew R. , Bennett Marc L. , Haynes David S. , Tawfik Kareem O. 
Published: February 2023

Objective
Compare incidence of sigmoid sinus wall abnormalities (SSWAs) and other radiographic abnormalities in patients with pulsatile tinnitus (PT) versus controls.

Study Design
Retrospective case-control.

Setting
Tertiary referral center.

Patients
Adults with PT and high-resolution computed tomography imaging were compared with adults undergoing cochlear implant workup including high-resolution computed tomography imaging.

Main Outcome Measures
Incidence of SSWA in PT cohort (n = 141) compared with control (n = 149, n = 298 ears). Secondary outcome measures included differences in demographics and in other radiographic abnormalities between cohorts.

Results
Patients with PT had a higher incidence of SSWA (34% versus 9%, p < 0.001) and superior canal dehiscence (23% versus 12%, p = 0.017) than controls. Spearman product component correlations demonstrated that ipsilateral PT was weakly associated with SSWA (r = 0.354, p < 0.001). When SSWA was present in the PT cohort (n = 48 patients, n = 59 ears), in 31 cases (64.6%), the SSWA correlated with PT laterality (e.g., left SSWA, left PT); in 12 (25.0%), SSWA partially correlated with PT laterality (e.g., bilateral SSWA, right PT); and in 5 (10.4%), the SSWA did not correlate with PT laterality (e.g., right SSWA, left PT).

Conclusions
For our patients with both PT and SSWA, the SSWA is likely a contributing factor in approximately 65% of cases. For a third of patients with PT and concomitant SSWA, the association between the two is either not causative or not solely causative. Surgeons counseling patients with PT and SSWA may be optimistic overall regarding sigmoid resurfacing procedures but must appreciate the possibility of treatment failure, likely because of untreated comorbid conditions.
Predicting Breast Cancer Events in Ductal Carcinoma In Situ (DCIS) using Generative Adversarial Network Augmented Deep Learning Model
Authors: Ghose Soumya , Cho Sanghee , Ginty Fiona , McDonough Elizabeth , Davis Cynthia , Zhang Zhanpan , Mitra Jhimli , Harris Adrian L. , Thike Aye Aye , Tan Puay Hoon , Gökmen-Polar Yesim , Badve Sunil S. 
Published: February 2023

AbstractStandard clinicopathological parameters (age, growth pattern, tumor size, margin status and grade) have been shown to have limited value in predicting recurrence in ductal carcinoma in situ (DCIS) patients. Early and accurate recurrence prediction would facilitate a more aggressive treatment policy for high-risk patients (mastectomy or adjuvant radiation therapy), and simultaneously reduce over-treatment of low-risk patients. Generative adversarial networks (GAN) are a class of DL models in which two adversarial neural networks, generator and discriminator, compete with each other to generate high quality images. In this work, we have developed a deep learning (DL) classification network that predicts breast cancer events (BCEs) in DCIS patients using hematoxylin and eosin (H&E) images. The DL classification model was trained on 67 patients using image patches from the actual DCIS cores and GAN generated image patches to predict breast cancer events (BCEs). The hold-out validation dataset (n= 66) had an AUC of 0.82. Bayesian analysis further confirmed the independence of the model from classical clinico-pathological parameters. DL models of H&E images may be used as a risk stratification strategy for DCIS patients to personalize therapy.Simple SummaryDuctal carcinoma in situ (DCIS) patients have an excellent overall survival rate and over-treatment is always a cause for concern due to potential side-effects. Standard clinicopathological parameters have limited value in predicting breast cancer events (BCEs) and stratification of high and low risk patients. Herein, we have developed a deep learning (DL) classification framework to predict BCEs in DCIS patients. A generative adversarial network (GAN) augmented deep learning (DL) classification of histological features associated with aggressive disease was trained on hematoxylin and eosin (H&E) tissue microarray (TMA) images of DCIS to predict BCEs. The area under the curve (AUC) for BCE’s in the validation set was 0.82. Early and accurate prediction of DCIS BCEs would facilitate a personalized approach to therapy.
Sub-second fluctuations in extracellular dopamine encode reward and punishment prediction errors in humans
Authors: Sands L. Paul , Jiang Angela , Liebenow Brittany , DiMarco Emily , Laxton Adrian W. , Tatter Stephen B. , Montague P. Read , Kishida Kenneth T. 
Published: February 2023

AbstractIn the mammalian brain, midbrain dopamine neuron activity is hypothesized to encode reward prediction errors that promote learning and guide behavior by causing rapid changes in dopamine levels in target brain regions. This hypothesis (and alternatives regarding dopamine’s role in punishment-learning) has limited direct evidence in humans. We report intracranial, sub-second measurements of dopamine release in human striatum measured while volunteers (i.e., patients undergoing deep brain stimulation (DBS) surgery) performed a probabilistic reward- and punishment-learning choice task designed to test whether dopamine release encodes only reward prediction errors or whether dopamine release may also encode adaptive punishment-learning signals. Results demonstrate that extracellular dopamine levels can encode both reward and punishment prediction errors, but may do so via by independent valence-specific pathways in the human brain.One-Sentence SummaryDopamine release encodes reward and punishment prediction errors via independent pathways in the human brain.
Estimating single cell clonal dynamics in human blood using coalescent theory
Authors: Johnson Brian , Shuai Yubo , Schweinsberg Jason , Curtius Kit 
Published: February 2023

AbstractWhile evolutionary approaches to medicine show promise, measuring evolution itself is difficult due to experimental constraints and the dynamic nature of body systems. In cancer evolution, continuous observation of clonal architecture is impossible, and longitudinal samples from multiple timepoints are rare. Increasingly available DNA sequencing datasets at single cell resolution enable the reconstruction of past evolution using mutational history, allowing for a better understanding of dynamics prior to detectable disease. We derive methods based on coalescent theory for estimating the net growth rate of clones from either reconstructed phylogenies or the number of shared mutations. Using single-cell datasets from blood, we apply and validate our analytical methods for estimating the net growth rate of hematopoietic clones, eliminating the need for complex simulations. We show that our estimates may have broad applications to improve mechanistic understanding and prognostic ability. Compared to clones with a single or unknown driver mutation, clones with multiple drivers have significantly increased growth rates (median 0.94 vs. 0.25 per year; p = 1.6 × 10-6). Further, stratifying patients with a myeloproliferative neoplasm (MPN) by the growth rate of their fittest clone shows that higher growth rates are associated with shorter time from clone initiation to MPN diagnosis (median 13.9 vs. 26.4 months; p = 0.0026).
Acquired epithelial WNT secretion drives niche independence of developing gastric cancer
Authors: Teriyapirom Isaree , Kim Jihoon , Lee Heetak , Merker Sebastian R. , Andersson-Rolf Amanda , Jahn Stephan R. , Ada Anne-Marlen , Kim Sang-Min , Lim Joo Yeon , Schmäche Tim , Wetterling Nancy , Stegert Saskia , Park Ji-Yeon , Cheong Jae-Ho , Kim Hyunki , Stange Daniel E. , Koo Bon-Kyoung 
Published: February 2023

AbstractRecent studies have shed light on the signaling pathways required for gastric tissue maintenance and how aberrations in these key pathways lead to gastric cancer development. Although it has been shown that the WNT pathway is important for gastric epithelial homeostasis, the identity and source of the responsible canonical WNT ligands remain unknown. Furthermore, it is unclear how gastric cancer acquires WNT niche independence - an important early step in tumorigenesis. Using human and mouse gastric organoids andin vivomouse models, we found that mesenchymal WNT2B and WNT7B maintain gastric epithelium in homeostasis. Next, mouse genetic studies and single-cell multi-omics analyses revealed that activation of MAPK signaling induces secretion of WNT7B in the epithelium itself. We further confirmed that in human gastric cancer, MAPK pathway activation through HER2 overexpression or copy number gains ofWNT2confers WNT independence. Importantly, the epithelium-intrinsic WNT expression could be therapeutically inhibited. Taken together, our results reveal that normal gastric epithelial turnover relies on WNT ligands secreted by niche mesenchymal cells, while transformation involves acquisition of a WNT secretory phenotype in the epithelium - representing a potential target for therapeutic interventions.
Multimodal decoding of human liver regeneration
Authors: Matchett KP , Wilson-Kanamori JR , Portman JR , Kapourani CA , Fercoq F , May S , Mackey JBG , Brice M , Zajdel E , Beltran M , Sutherland EF , Wilson GC , Wallace SJ , Kitto L , Younger NT , Dobie R , Oniscu GC , Wigmore SJ , Ramachandran P , Vallejos CA , Carragher NO , Simpson KJ , Kendall TJ ,   Acute Liver Failure Study Group, Rule JA , Lee WM , Hoare M , Weston CJ , Marioni JC , Teichmann ST , Bird TG , Carlin LM , Henderson NC 
Published: February 2023

AbstractThe liver has a unique ability to regenerate1,2, however in the setting of acute liver failure (ALF) this regenerative capacity is often overwhelmed and emergency liver transplantation is the only curative option3-5. To advance our understanding of human liver regeneration and to inform design of pro-regenerative therapies, we use paired single-nuclei RNA sequencing (snRNA-seq) combined with spatial profiling of healthy and ALF explant human livers to generate the first single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+migratory hepatocyte subpopulation which emerges during human liver regeneration, and a corollary migratory hepatocyte subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Importantly, interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. 4-D intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 expression reduces HGF-induced human and mouse hepatocyte migrationin vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Taken together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation which mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may open up new areas of therapeutic discovery in regenerative medicine.
Traumatic brain injury-induced fear generalization in mice involves hippocampal memory trace dysfunction and is alleviated by (R,S)-ketamine
Authors: McGowan Josephine C. , Ladner Liliana R. , Shubeck Claire X. , Tapia Juliana , LaGamma Christina T. , Anqueira-González Amanda , DeFrancesco Ariana , Chen Briana K. , Hunsberger Holly C. , Sydnor Ezra J. , Logan Ryan W. , Yu Tzong-Shiue , Kernie Steven G. , Denny Christine A. 
Published: February 2023

ABSTRACTINTRODUCTIONTraumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization, the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI.METHODSTo identify the neural ensembles mediating fear generalization, we utilized the ArcCreERT2x enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact (CCI) model of TBI. Mice were then administered a contextual fear discrimination (CFD) paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if (R,S)-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice.RESULTSTBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the DG, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, (R,S)-ketamine facilitated fear discrimination and this behavioral improvement was reflected in DG memory trace activity.CONCLUSIONSThese data show that TBI induces fear generalization by altering fear memory traces, and that this deficit can be improved with a single injection of (R,S)-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.
Secreted soluble factors from tumor-activated mesenchymal stromal cells confer platinum chemoresistance to ovarian cancer cells
Authors: Carmi Yifat Koren , Khamaisi Hazem , Adawi Rina , Gopas Jacob , Mahajna Jamal 
Published: February 2023

AbstractOvarian cancer (OC) ranks as the second most common type of gynecological malignancy, has poor survival rates, and is frequently diagnosed at an advanced stage. Platinum-based chemotherapy, such as carboplatin, represents the standard-of-care for OC. However, toxicity and acquired resistance to therapy have proven challenging in the treatment of patients, most of who will experience relapse, mainly due to chemoresistance. Chemoresistance, a principal obstacle to durable response in OC patients, is attributed to alterations within the cancer cells, and can also be mediated by the tumor microenvironment (TME).In this study, we report that conditioned medium (CM) derived from murine and human stromal cells, MS-5 and HS-5 respectively, and tumor-activated HS-5, was active in conferring platinum chemoresistance to OC cells. Moreover, CM derived from differentiated murine pre-adipocyte (3T3-L1), but not undifferentiated pre-adipocyte cells, confers platinum chemoresistance to OC cells. Interestingly, CM derived from tumor-activated HS-5 was more effective in conferring chemoresistance than was CM derived from HS-5 cells.Various OC cells exhibit variable sensitivity to CM activity. Moreover, exposure of OC to CM affected ERK1/2 phosphorylation in a non-consistent pattern and in a cell-specific manner, and does not correlate with platinum chemoresistance. Exploring CM content revealed the enrichment of a number of soluble factors in the tumor-activated HS-5, such as soluble uPAR (SuPAR), IL-6, and hepatocyte growth factor (HGF). FDA-approved JAK inhibitors were mildly effective in restoring platinum sensitivity in two of the three OC cell lines in the presence of CM. Exposure to increasing concentrations of HGF resulted in increased proliferation and reduced platinum sensitivity. Crizotinib, an ALK and c-MET inhibitor, in combination with platinum, blocked HGF’s ability to promote platinum resistance and restore platinum sensitivity to OC cells. Finally, exposure to 2-hydroxyestardiol (2HE2) was effective in restoring platinum sensitivity to OC cells exposed to CM.Our results showed the significance of soluble factors found in TME in promoting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity to OC cells.
Heat stress response and transposon control in plant shoot stem cells
Authors: Nguyen Vu Hoang , Mittelsten Scheid Ortrun , Gutzat Ruben 
Published: February 2023

SummaryPost-embryonic plant development must be coordinated in response to and with environmental feedback. Development of above-ground organs is orchestrated from stem cells in the center of the shoot apical meristem (SAM). Heat can pose significant stress to plants and induces a rapid heat response, developmental alterations, chromatin decondensation, and activation of transposable elements (TEs). However, most plant heat-stress studies are conducted with whole plants, not resolving cell-type-specific responses. Heat stress consequences in stem cells are of particular significance, as they can potentially influence the next generation. Here we use fluorescent-activated nuclear sorting to isolate and characterize stem cells after heat exposure and after a recovery period in wild type and mutants defective in TE defense and chromatin compaction. Our results indicate that stem cells can suppress the heat response pathways that dominate surrounding somatic cells and maintain their developmental program. Furthermore, mutants defective in DNA methylation recover less efficiently from heat stress and persistently activate heat response factors and heat-inducible TEs. Heat stress also induces epimutations at the level of DNA methylation, and we find hundreds of DNA methylation changes three weeks after stress. Our results underline the importance of disentangling cell type-specific environmental responses for understanding plant development.
Modeling of Intracellular Taurine Levels Associated with Ovarian Cancer Reveals Activation of p53, ERK, mTOR and DNA-damage-sensing-dependent Cell Protection
Authors: Centeno Daniel , Farsinejad Sadaf , Kochetkova Elena , Volpari Tatiana , Gladych-Macioszek Alexandra , Klupczynska – Gabryszak Agnieszka , Polotaye Teagan , Greenberg Michael , Kung Douglas , Hyde Emily , Alshehri Sarah , Pavlovic Tonja , Sullivan William , Plewa Szymon , Vakifahmetoglu-Norberg Helin , Monsma Frederick J , Muller Patricia A. J. , Matysiak Jan , Zaborowski Mikolaj , DiFeo Analisa , Norberg Erik , Martin Laura A. , Iwanicki Marcin 
Published: February 2023

ABSTRACTTaurine, a non-proteogenic amino acid, and commonly used nutritional supplement can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We have found that OC ascites-derived cells contained significantly more intracellular taurine than cell cultures modeling OC. In culture, elevation of intracellular taurine concentration to OC ascites-cells-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant- or wild-type p53 binding to DNA, and activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurine’s suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurine’s ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurine’s cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth, metabolism, and activate cell protective mechanisms involving mTOR and DNA damage sensing signal transduction.