bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic regulation of EXO1 promotes the progression from liver fibrosis to HCC through TGF-β1/Smad signaling feedback loop
Authors: Li Mengting , Huang Fengxing , Zhu Weining , Peng Yanan , Xu Fei , Li Wenjie , Zhao Qiu , Liu Lan 
Published: December 2023

Background:
HSCs are the main stromal cells in the process of liver fibrosis and accelerate HCC progression. Previous studies determined that highly expressed exonuclease 1 (EXO1) increases the malignant behavior of HCC cells and is closely related to liver cirrhosis. This study aimed to explore the roles and mechanisms of EXO1 in the development of liver cirrhosis and HCC.

Methods:
We fully demonstrated that EXO1 expression was positively correlated with liver fibrosis and cirrhotic HCC by combining bioinformatics, hepatic fibrosis mouse models, and human HCC tissues. The role of EXO1 in a murine HCC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated by employing an adeno-associated virus-mediated EXO1 knockdown technique.

Results:
The knockdown of EXO1 promoted a regression of HCC in AKT/Ras mice and reduced the degree of liver fibrosis. Downregulated EXO1 inhibited LX-2 cell activation and inhibited the proliferation and migration of HCC cells. Moreover, conditioned medium of LX-2 cells with EXO1 overexpression increased the proliferation and migration of HCC cells, which was attenuated after EXO1 knockout in LX-2 cells. EXO1 knockdown attenuated the role of LX-2 in promoting HepG2 xenograft growth in vivo. Mechanistically, EXO1 promotes the activation of the downstream TGF-β-smad2/3 signaling in LX-2 and HCC cells. Interestingly, increased TGF-β-smad2/3 signaling had a feedback effect on EXO1, which sustains EXO1 expression and continuously stimulates the activation of HSCs.

Conclusions:
EXO1 forms a positive feedback circuit with TGF-β-Smad2/3 signaling and promotes the activation of HSCs, which accelerates HCC progression. Those findings indicate EXO1 may be a promising target for the diagnosis and treatment of cirrhotic HCC.
Aging aggravates liver fibrosis through downregulated hepatocyte SIRT1-induced liver sinusoidal endothelial cell dysfunction
Authors: Dai Qingqing , Qing Xin , Jiang Wei , Wang Shouwen , Liu Shengsheng , Liu Xuesheng , Huang Fan , Zhao Hongchuan 
Published: December 2023

Background:
Aging increases the susceptibility to chronic liver diseases and hastens liver fibrosis deterioration, but the underlying mechanisms remain partially understood. The aim of this study was to investigate the effect of aging and chronic liver diseases on hepatocyte Sirtuin 1 (SIRT1) and LSECs and their contribution to liver fibrosis pathogeneses.

Methods:
Young (8–12 wk) and aged (18–20 mo) mice were subjected to carbon tetrachloride–induced liver fibrosis. Primary HSCs and LSECs were isolated and cocultured for in vitro experiments. Liver tissues and blood samples from healthy controls and patients with liver fibrosis were analyzed.

Results:
Downregulated hepatocytes SIRT1 in aged mice increased high mobility group box 1 acetylation, cytoplasmic translocation, and extracellular secretion, causing LSECs dysfunction by means of the toll-like receptor 4/AK strain transforming (AKT)/endothelial nitric oxide synthase pathway, ultimately activating HSCs and increasing susceptibility to liver injury and fibrosis. Adeno-associated virus-mediated overexpression of SIRT1 in hepatocytes suppressed the abovementioned alterations and attenuated carbon tetrachloride–induced liver injury and fibrosis in liver fibrosis mice, and there were no significant differences in liver injury and fibrosis indicators between young and aged mice after SIRT1 overexpression treatment. In vitro experiments demonstrated that SIRT1 overexpression and endothelial nitric oxide synthase agonist YC-1 improved LSECs function and inhibited HSCs activation, mediated by nitric oxide. Similarly, downregulated hepatocytes SIRT1 and LSECs dysfunction were observed in the livers of aged individuals compared to young individuals and were more pronounced in aged patients with liver fibrosis.

Conclusions:
Aging aggravates liver fibrosis through downregulated hepatocytes SIRT1-induced LSECs dysfunction, providing a prospective curative approach for preventing and treating liver fibrosis.
Risk of HCC decreases in HBV-related patients with cirrhosis acquired recompensation: A retrospective study based on Baveno VII criteria
Authors: Zhang Yiheng , Liu Xu , Li Shu , Lin Chunlei , Ye Qian , Wang Yuying , Wu Juanli , Zhang Yushuang , Gao Han , Li Tao , Qu Yundong , Wang Yan 
Published: December 2023

Background:
Antiviral therapy improves the clinical outcomes of patients with HBV-related cirrhosis. In this study, we aimed to evaluate the incidence rate of HCC in patients with HBV-related recompensated, compensated, or decompensated cirrhosis based on the latest Baveno VII criteria.

Methods:
In this two-center retrospective study, HBV-related patients with cirrhosis were enrolled and treated with first-line nucleos(t)ide analogues therapy for at least 12 months. Participants were classified into 3 groups: (1) compensated group, (2) decompensated group, or (3) recompensated group according to Baveno VII criteria. Multivariate regression models and propensity score matching were used to identify the predictors of HCC.

Results:
Of the 404 patients recruited, during a median follow-up of 44.5 months (interquartile range 26.8, 57.0 months), 233 (57.7%), 100 (24.8%), and 71(17.6%) patients had compensated, recompensated, and decompensated cirrhosis. In total, 38 developed HCC. The cumulative incidence of HCC development at 2, 4, and 6 years was 1.3%, 5.4%, and 20.0% in the compensated group, 1.2%, 5.2%, and 24.5% in the recompensated group, and 2.1%, 23.6%, and 41.8% in the decompensated group, respectively. In the multivariate Cox regression model, compared with the recompensated group, the decompensated group had a significant increased risk for the development of HCC (aHR 2.55; 95% CI: 1.240–5.240; p = 0.027), while the compensated group had similar HCC risk for the development of HCC (aHR 1.41; 95% CI: 0.540–3.730; p = 0.835). Propensity score-matching analysis between the recompensated and compensated groups (84 pairs) and propensity score-matching analysis between the recompensated and decompensated groups (62 pairs) showed similar results.

Conclusions:
Achieving recompensation reduced the risk of HCC in patients with HBV-related decompensated cirrhosis, while the risk remained comparable to that of compensated cirrhosis.
Descemet Membrane Endothelial Keratoplasty: 10-Year Cell Loss and Failure Rate Compared With Descemet Stripping Endothelial Keratoplasty and Penetrating Keratoplasty
Authors: Price Marianne O. , Kanapka Lauren , Kollman Craig , Lass Jonathan H. , Price Francis W. 
Published: December 2023

Purpose:
The aim of this study was to assess long-term endothelial cell loss (ECL) and graft failure with Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping endothelial keratoplasty (DSEK) versus penetrating keratoplasty (PK) performed for the same indications (primarily Fuchs dystrophy and pseudophakic corneal edema) in the Cornea Donor Study.

Methods:
This retrospective study included consecutive primary DMEK (529 recipients, 739 eyes) and DSEK cases (585 recipients, 748 eyes) with 1 or more endothelial cell density (ECD) measurements at 6 months to 16 years. Main outcomes were ECD, longitudinal ECL, and graft failure.

Results:
Between 6 months and 8 years the ECD declined linearly by approximately 118 cells/mm2/yr after DMEK and 112 cells/mm2/yr after DSEK. Beyond 8 years postoperatively the rate of decline slowed substantially. Selective dropout from graft failure did not significantly affect the ECD trend. At 10 years, median ECL (interquartile range) was 63% (45, 73) with DMEK, 68% (48, 78) with DSEK, and 76% (70, 82) with PK (P = 0.01 DMEK vs. DSEK, P <0.001 DMEK vs. PK, and P < 0.001 DSEK vs. PK). The proportion of surviving grafts with 10-year ECD <500 cells/mm2 was 1.4% with DMEK, 7.3% with DSEK, and 23.9% with PK. The cumulative risk of graft failure between 6 months and 10 years was 5% with DMEK, 11% with DSEK, and 19% with PK (P < 0.001).

Conclusions:
Compared with PK and DSEK, DMEK had significantly lower ECL and significantly lower risk of secondary graft failure through 10 years.
Efficacy of continuous arterial perfusion chemotherapy combined with transarterial chemoembolization regional arterial thermal perfusion in the treatment of pancreatic cancer with liver metastases
Authors: Zhong Zhuo , Yang Jian , Luo Jing-Zi , Xie Xiong , Huang Zhi-Mei , Long De 
Published: December 2023

Abstract

Background
The aim of the study was to investigate the efficacy of continuous transcatheter arterial infusion chemotherapy combined with transarterial chemoembolization (TACE) for the treatment of advanced pancreatic cancer with liver metastasis.

Methods
Sixty patients with advanced pancreatic cancer and liver metastases were enrolled in this study. In the treatment group, 31 patients underwent continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial thermal perfusion, whereas 29 patients included in the control group received intravenous chemotherapy with gemcitabine and S-1. All patients received maintenance chemotherapy with S-1 after 4 cycles of the study regimen. Treatment efficacy, quality of life, survival, and toxicity were evaluated.

Results
Efficacy was better in the treatment group than in the control group, as reflected by the objective remission, partial remission, and disease progression rates (all P < 0.05). The Eastern Cooperative Oncology Group and Numerical Rating Scale pain scores were also higher in the treatment group (both P < 0.05). In survival analysis, the 1-year overall survival rates in the treatment and control groups were 64.516% and 10.345%, respectively, whereas the median overall survival times were 16 and 6 months, respectively (both P < 0.05). The 6-month progression-free survival rates in the treatment and control groups were 77.419% and 13.790%, respectively, and the median progression-free survival times were 12 and 3 months, respectively (both P < 0.05). The rates of hematological and nonhematological toxicological adverse effects were also lower in the treatment group (both P < 0.05). Although the rate of liver dysfunction was higher in the treatment group, this finding had no adverse effects on prognosis.

Conclusions
Continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial perfusion chemotherapy resulted in better efficacy and safety outcomes in patients with pancreatic cancer and liver metastasis, suggesting its utility as a reference method for the clinical treatment of advanced pancreatic cancer.
Assessing transmission attribution risk from simulated sequencing data in HIV molecular epidemiology
Authors: Nascimento Fabrícia F. , Mehta Sanjay R. , Little Susan J. , Volz Erik M. 
Published: December 2023

Background:
HIV molecular epidemiology (ME) is the analysis of sequence data together with individual-level clinical, demographic, and behavioral data to understand HIV epidemiology. The use of ME has raised concerns regarding identification of the putative source in direct transmission events. This could result in harm ranging from stigma to criminal prosecution in some jurisdictions. Here we assessed the risks of ME using simulated HIV genetic sequencing data.

Methods:
We simulated social networks of men-who-have-sex-with-men, calibrating the simulations to data from San Diego. We used these networks to simulate consensus and next-generation sequence (NGS) data to evaluate the risks of identifying direct transmissions using different HIV sequence lengths, and population sampling depths. To identify the source of transmissions, we calculated infector probability and used phyloscanner software for the analysis of consensus and NGS data, respectively.

Results:
Consensus sequence analyses showed that the risk of correctly inferring the source (direct transmission) within identified transmission pairs was very small and independent of sampling depth. Alternatively, NGS analyses showed that identification of the source of a transmission was very accurate, but only for 6.5% of inferred pairs. False positive transmissions were also observed, where one or more unobserved intermediaries were present when compared to the true network.

Conclusion:
Source attribution using consensus sequences rarely infers direct transmission pairs with high confidence but is still useful for population studies. In contrast, source attribution using NGS data was much more accurate in identifying direct transmission pairs, but for only a small percentage of transmission pairs analyzed.
Exercise interventions for frail older adults with cancer
Authors: Sattar Schroder , Haase Kristen R. , Lee Kayoung , Campbell Kristin L. 
Published: December 2023

Purpose of reviewFrailty is prevalent in older adults with cancer and can lead to complications during cancer treatment and poor health outcomes. Exercise has been shown to be a promising strategy to mitigate frailty and slow the accumulation of functional impairment in the general geriatric population. In this review, we present a discussion on the state of the science of exercise interventions for frail older adults with cancer. This review is timely and relevant given the aging of the population and corresponding increase in proportion of older adults living with cancer.Recent findingsExisting research related to exercise interventions for frail older adults with cancer appear to show some promise in feasibility and efficacy in both surgical and systemic treatment settings.SummaryMore research on this topic and testing rigorously structured exercise interventions for older adults with cancer may help inform cancer-specific guidelines and create a foundation of evidence to enable implementation of exercise interventions. These interventions can support cancer care to attenuate frailty-related outcomes while extending its benefit to overall health of this population.
Optic Nerve Sheath Meningiomas: A National Surveillance, Epidemiology, and End Results (SEER) Database Analysis
Authors: Hussain Zain S. , Loya Asad , Riaz Kamran M. , Lee Andrew G. 
Published: December 2023

Background:
Optic nerve sheath meningioma (ONSM) is a rare optic nerve cancer with considerable morbidity. This national analysis validates previously known ONSM concepts while providing insight into novel risk factors.

Methods:
The Surveillance, Epidemiology, and End Results (SEER) Program was queried from 2000 to 2019 for all histologic subtypes of meningioma primary to the optic nerve. Relevant clinical and demographic variables were analyzed. Asymptotic one-sample test for binomial proportions and Cox proportional hazards modeling evaluated the significance of factor associations.

Results:
A total of 51 ONSM cases were extracted. A greater proportion of cases were observed in females (N = 37, 73%, P < 0.001) and individuals with age 50 years or more (N = 29, 57%, P < 0.001); the mean number of months from diagnosis to treatment was 4.6 months (SD 4.1, range 13). Psychosocial epidemiologic parameter analysis demonstrated a greater proportion of patients with married status on diagnosis (N = 31, 61%, P < 0.001), listed total family income between $55,000 and $74,999 (N = 24, 47%, P < 0.001). Relative to cases diagnosed clinically only, cases diagnosed radiologically without microscopic confirmation experienced decreased all-cause mortality (HR = 0.041, P = 0.050).

Conclusions:
Our SEER national analysis affirms previously characterized ONSM concepts. Upon ONSM diagnosis and if needed, treatment protocols are not significantly delayed. Novel psychosocial factors for ONSM were identified, including marital status, total family income, and non-Hispanic white race. Additional ONSM diagnostics may reduce longitudinal mortality burden.
Training in cortically-blind fields confers patient-specific benefit against retinal thinning after occipital stroke
Authors: Fahrenthold Berkeley K. , Cavanaugh Matthew R. , Tamhankar Madhura , Lam Byron L. , Feldon Steven E. , Johnson Brent A. , Huxlin Krystel R. 
Published: December 2023

AbstractPurposeDamage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of trans-synaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness, and asked if perceptual training in the intact or blind field impacts its progression.MethodsWe performed a meta-analysis of optical coherence tomography (OCT) data in 48 participants with unilateral V1 stroke and homonymous visual defects, who completed clinical trialNCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layers (GCL-IPL), and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ∼6 months of daily motion discrimination training in the intact- or blind-field. Increasingly positive LI denoted greater layer thinning in retinal regions affectedversusunaffected by the cortical damage.ResultsPre-training, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact-field exhibited increased LIGCL-IPL. Those trained in their blind-field had no significant change in LIGCL-IPL. LIRNFLdid not change in either group.ConclusionsRelative shrinkage of the affectedversusunaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training, but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.
Structural elucidation of how ARF small GTPases induce membrane tubulation for vesicle fission
Authors: Pang Xiaoyun , Zhang Yan , Park Kunyou , Liao Zhenyu , Li Jian , Xu Jiashu , Hong Minh-Triet , Yin Guoliang , Zhang Tongming , Wang Yaoyu , Egelman Edward H. , Fan Jun , Park Seung-Yeol , Hsu Victor W. , Sun Fei 
Published: December 2023

SUMMARYThe ADP-Ribosylation Factor (ARF) small GTPases have been found to act in vesicle fission through a direct ability to tubulate membrane. Here, we have used cryo-electron microscopy (EM) to solve the structure of an ARF6 protein lattice assembled on tubulated membrane to 3.9 Å resolution. ARF6 forms tetramers that polymerize into helical arrays to form this lattice. We identify, and confirm functionally, protein contacts critical for this lattice formation. The solved structure also suggests how the ARF amphipathic helix is positioned in the lattice for membrane insertion, and how a GTPase-activating protein (GAP) docks onto the lattice to catalyze ARF-GTP hydrolysis in completing membrane fission. As ARF1 and ARF6 are structurally conserved, we have also modeled ARF1 onto the ARF6 lattice, which has allowed us to pursue the reconstitution of Coat Protein I (COPI) vesicles to confirm more definitively that the ARF lattice acts in vesicle fission. Our findings are notable for having achieved the first detailed glimpse of how a small GTPase bends membrane and having provided a molecular understanding of how an ARF protein acts in vesicle fission.
AnArabidopsisSR protein relieving ABA inhibition of seedling establishment represses ABA-responsive alternative splicing
Authors: Laloum Tom , Martín Guiomar , Lewinski Martin , Yanez Romana J. R. , Köster Tino , Staiger Dorothee , Duque Paula 
Published: December 2023

AbstractThe phytohormone abscisic acid (ABA) inhibits postgerminative growth under unfavorable conditions to delay the transition to the autotrophic stage and promote plant survival. While stress-induced ABA accumulation is well established to trigger extensive transcriptional changes, it is becoming clear that it also relies on alternative splicing to enhance stress tolerance. However, the upstream components modulating posttranscriptional regulation of the ABA response remain largely unknown. Here, we show that loss of function of theArabidopsisSR34a protein enhances sensitivity to ABA during seedling establishment. Individual-nucleotide crosslinking and immunoprecipitation (iCLIP) combined with RNA-sequencing revealed that SR34a is an alternative splicing regulator that binds predominantly GCU-rich exonic sequences near splice sites. We find that SR34a targets all alternative splicing event types, including in RNAs encoding known determinants of ABA sensitivity, to prevent ABA-responsive splicing in germinated seeds. Our study sheds mechanistic light on how plant SR proteins regulate alternative splicing and counteract ABA inhibition of early plant growth.
Task-Dependent Representation of Feature Binding within the Same Dimension in Visual Working Memory
Authors: Cao Ruoyi , Deouell Leon Y. 
Published: December 2023

AbstractWorking memory (WM) serves as a neurocognitive system responsible for temporarily storing and manipulating information when its source has disappeared. Previous investigations into whether features within the same dimension were stored separately or conjoined into objects have yielded conflicting findings. Based on increasing evidence on the adaptivity of the working memory system, we conjectured that the format in which objects from the same dimension are stored in Visual Working Memory (VWM) might be contingent on the specific task demands, and subtle distinctions across experiments may account for the disparities in results. In the current study, we introduced modifications to the paradigm used by Luck and Vogel (1997) and Wheeler and Treisman (2002), where the same paradigm led to different conclusions, to assess whether implicit task requirements could influence the storage format of objects in visual working memory. In two conditions, we manipulated the relevance of conjunction between two colors by varying the proportions of Mis-conjunct probes, a probe type depending on conjunction information for accurate responses. The results showed that in both conditions, performance was primarily determined by the number of features rather than the number of objects, aligning with the results of Wheeler and Treisman. Nevertheless, we observed that Mis-conjunct probes, which require conjunction information, exhibited improved performance when tested more frequently. This suggests that the format of retention in working memory, whether in separate or conjoined form, is influenced by the task demands.
Inverse folding of protein complexes with a structure-informed language model enables unsupervised antibody evolution
Authors: Shanker Varun R. , Bruun Theodora U.J. , Hie Brian L. , Kim Peter S. 
Published: December 2023

AbstractLarge language models trained on sequence information alone are capable of learning high level principles of protein design. However, beyond sequence, the three-dimensional structures of proteins determine their specific function, activity, and evolvability. Here we show that a general protein language model augmented with protein structure backbone coordinates and trained on the inverse folding problem can guide evolution for diverse proteins without needing to explicitly model individual functional tasks. We demonstrate inverse folding to be an effective unsupervised, structure-based sequence optimization strategy that also generalizes to multimeric complexes by implicitly learning features of binding and amino acid epistasis. Using this approach, we screened ∼30 variants of two therapeutic clinical antibodies used to treat SARS-CoV-2 infection and achieved up to 26-fold improvement in neutralization and 37-fold improvement in affinity against antibody-escaped viral variants-of-concern BQ.1.1 and XBB.1.5, respectively. In addition to substantial overall improvements in protein function, we find inverse folding performs with leading experimental success rates among other reported machine learning-guided directed evolution methods, without requiring any task-specific training data.