bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deciphering the mechanism of Chaihu Shugan San in the treatment of nonalcoholic steatohepatitis using network pharmacology and molecular docking
Authors: Ren Yi , Xiao Kaihui , Lu Yujia , Chen Wei , Li Li , Zhao Jingjie 
Published: September 2024

Abstract

Objectives
In China, there is a long history and rich clinical experience in treating nonalcoholic steatohepatitis (NASH) with traditional Chinese herbal medicines, including Chai Hu Shu Gan San. This study aims to investigate the potential regulatory effects of Chaihu Shugan San (CSS) on liver lipid metabolism and inflammatory damage in mice with experimental nonalcoholic steatohepatitis (NASH) induced by a choline-deficient high-fat diet (CDHFD). Utilizing network pharmacology, we systematically explore the mechanisms of action and therapeutic potential of CSS against NASH.

Methods
Potential targets in CSS and targets for NASH were identified using online databases. Functional enrichment and protein–protein interaction analyses were conducted to identify hub-targeted genes and elucidate the underlying molecular mechanisms. The affinities of active compounds in CSS with hub-targeted genes were evaluated using molecular docking. Finally, hub-targeted genes were validated through real-time polymerase chain reaction, western blotting, and immunofluorescence in choline-deficient high-fat diet mice, both with and without CSS treatment.

Key findings
CSS reduces serum ALT and AST levels in NASH mice(P &lt; 0.05) and ameliorates ballooning degeneration in the livers of NASH mice, thereby lowering the NAS score(P &lt; 0.05). Including naringenin, high-performance liquid chromatography/mass spectrometrys identified 12 chromatographic peaks. Based on network pharmacology analysis, CSS contains a total of 103 active compounds and 877 target genes. Transferase activity represents a potential mechanism for therapeutic intervention of CSS in NASH. The transcriptional levels and protein expression of the SIRT1 gene in NASH mice are significantly increased by CSS (P &lt; 0.05).

Conclusions
Naringenin is probable active compound in CSS and SIRT1 is the hub gene by which CSS is involved in NASH treatment.
‘Stumped’ by stump appendicitis—a case report and literature review
Authors: Soh Chien Lin , Shetty Shraddha , Abdalla Sala , Soggiu Fiammetta 
Published: September 2024

Abstract
Stump appendicitis, a rare postoperative complication of appendicectomy, is inflammation of the remnant appendix tissue due to incomplete removal of the appendix at the index operation. Due to a past surgical history of appendicectomy, there is often a diagnostic delay. This delay can result in increased morbidity and mortality for patients. This series seeks to describe two cases encountered in a London district general hospital to elucidate the diagnostic, management, and operative challenges of stump appendicitis. Our case series demonstrates the importance of recognition of stump appendicitis as a differential for patients presenting with abdominal pain and previous appendicectomy. Active exclusion of this differential diagnosis in a patient with previous appendicectomy who presents with right iliac fossa pain is vital. Early identification and treatment can prevent morbidity in the patient population. We highlight that complete operative documentation and access to medical records are useful for this diagnosis.
Transcription factor CpWRKY50 enhances anthracnose resistance by promoting jasmonic acid signaling in papaya
Authors: Yang Min , Zhou Chenping , Kuang Ruibin , Wu Xiaming , Liu Chuanhe , He Han , Wei Yuerong 
Published: September 2024

Abstract
Colletotrichum brevisporum is an important fungal pathogen that causes anthracnose and has led to serious postharvest losses of papaya (Carica papaya L.) fruit in recent years. WRKY transcription factors (TFs) play vital roles in regulating plant resistance to pathogens, but their functions in papaya anthracnose resistance need further exploration. In this study, we identified a WRKY TF, CpWRKY50, which belongs to the WRKY IIc subfamily. During infection with C. brevisporum, expression of CpWRKY50 in anthracnose-resistant papaya cultivars was significantly higher than that in susceptible cultivars. CpWRKY50 was induced by methyl jasmonate, and CpWRKY50 localized in the nucleus. In yeast, full-length CpWRKY50 had transactivation activity, but CpWRKY50 variants truncated at the N or C termini did not. CpWRKY50 positively regulated papaya resistance to C. brevisporum, as demonstrated by transient overexpression of CpWRKY50 in papaya and heterologous expression of CpWRKY50 in tomato. Moreover, endogenous jasmonic acid (JA) and JA-isoleucine levels in the fruits of transgenic tomato OE lines were higher than in wild type both before and after inoculation with C. brevisporum, indicating that increased CpWRKY50 expression promotes JA accumulation. Furthermore, our results revealed CpWRKY50 directly binds to W-box motifs (TTGACC) in the promoters of two JA signaling-related genes, CpMYC2 and pathogenesis-related 4 CpPR4, thereby activating their expression. Our data support that CpWRKY50 positively regulates anthracnose resistance in papaya by promoting JA signaling. These results broaden our understanding of papaya disease resistance mechanisms and will facilitate the genetic improvement of papaya through molecular breeding.
Endoplasmic reticulum membrane remodeling by targeting reticulon-4 induces pyroptosis to facilitate antitumor immune
Authors: Zhao Mei-Mei , Ren Ting-Ting , Wang Jing-Kang , Yao Lu , Liu Ting-Ting , Zhang Ji-Chao , Liu Yang , Yuan Lan , Liu Dan , Xu Jiu-Hui , Tu Peng-Fei , Tang Xiao-Dong , Zeng Ke-Wu 
Published: September 2024

Abstract
Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the “bubble” structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to pyruvate kinase M2 (PKM2)-dependent conventional caspase-3/gasdermin E (GSDME) cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-programmed death-1 (anti-PD-1). In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.
Extreme precipitation reduces the recent photosynthetic carbon isotope signal detected in ecosystem respiration in an old-growth temperate forest
Authors: Diao Haoyu , Wu Jiabing 
Published: September 2024

Abstract
The successful utilization of stable carbon isotope approaches in investigating forest carbon dynamics has relied on the assumption that the carbon isotope compositions (δ13C) therein have detectable temporal variations. However, interpreting the δ13C signal transfer can be challenging, given the complexities involved in disentangling the effect of a single environmental factor, the isotopic dilution effect from background CO2 and the lack of high-resolution δ13C measurements. In this study, we conducted continuous in situ monitoring of atmospheric CO2 (δ13Ca) across a canopy profile in an old-growth temperate forest in northeast China during the normal year 2020 and the wet year 2021. Both years exhibited similar temperature conditions in terms of both seasonal variations and annual averages. We tracked the natural carbon isotope composition from δ13Ca to photosynthate (δ13Cp) and to ecosystem respiration (δ13CReco). We observed significant differences in δ13Ca between the two years. Contrary to in 2020, in 2021 there was a δ13Ca valley in the middle of the growing season, attributed to surges in soil CO2 efflux induced by precipitation, while in 2020 values peaked during that period. Despite substantial and similar seasonal variations in canopy photosynthetic discrimination (Δ13Ccanopy) in the two years, the variability of δ13Cp in 2021 was significantly lower than in 2020, due to corresponding differences in δ13Ca. Furthermore, unlike in 2020, we found almost no changes in δ13CReco in 2021, which we ascribed to the imprint of the δ13Cp signal on above-ground respiration and, more importantly, to the contribution of stable δ13C signals from soil heterotrophic respired CO2. Our findings suggest that extreme precipitation can impede the detectability of recent photosynthetic δ13C signals in ecosystem respiration in forests, thus complicating the interpretation of above- and below-ground carbon linkage using δ13CReco. This study provides new insights for unravelling precipitation-related variations in forest carbon dynamics using stable isotope techniques.
Does the Source of FDI Matter? The Case of Tax Havens
Authors: Shpak Solomiya 
Published: September 2024

Abstract
This paper estimates the benefits of FDI for firm performance, differentiating source countries between tax havens and non–tax havens. Using longitudinal data on more than 300,000 initially domestic firms in Ukraine between 1999 and 2013 and employing propensity score matching and panel data methods, this study finds that firms acquired by non–tax haven foreign investors experience substantial increases in employment, productivity, exports, and wages, but the gains are much lower and shorter-lived for firms receiving FDI from tax havens. These findings, based on econometric analysis of nearly the universe of Ukrainian businesses, are consistent with macroeconomic studies and anecdotal evidence that much of the tax-haven FDI in Ukraine actually represents domestic ownership channeled through offshore companies. This “round-trip FDI” results in negligible effects on firm performance and, at a macro level, it overstates the amount of genuine FDI flows into Ukraine.
Unraveling the role of MiR‐181 in skin fibrosis pathogenesis by targeting NUDT21
Authors: Mills Tingting W. , Wu Minghua , Alonso Jerry , Puente Hydia , Charles Julio , Chen Zheng , Yoo Seung‐hee , Mayes Maureen D. , Assassi Shervin 
Published: September 2024

AbstractSystemic sclerosis (SSc) is a life‐threatening autoimmune disease characterized by widespread fibrosis in the skin and several internal organs. Nudix Hydrolase 21 (NUDT2 or CFIm25) downregulation in fibroblasts is known to play detrimental roles in both skin and lung fibrosis. This study aims to investigate the upstream mechanisms that lead to NUDT21 repression in skin fibrosis. We identified transforming growth factor β (TGFβ1) as the primary cytokine that downregulated NUDT21 in normal skin fibroblasts. In the bleomycin‐induced dermal fibrosis model, consistent with the peak activation of TGFβ1 at the late fibrotic stage, NUDT21 was downregulated at this stage, and delayed NUDT21 knockdown during this fibrotic phase led to enhanced fibrotic response to bleomycin. Further investigation suggested TGFβ downregulated NUDT21 through microRNA (miRNA) 181a and 181b induction. Both miR‐181a and miR‐181b were elevated in bleomycin‐induced skin fibrosis in mice and primary fibroblasts isolated from SSc patients, and they directly targeted NUDT21 and led to its downregulation in skin fibroblasts. Functional studies demonstrated that miR‐181a and miR‐181b inhibitors attenuated bleomycin‐induced skin fibrosis in mice in association with decreased NUDT21 expression, while miR‐181a and miR‐181b mimics promoted bleomycin‐induced fibrosis. Overall, these findings suggest a novel role for miR‐181a/b in SSc pathogenesis by repressing NUDT21 expression.
Why Make the Cut? The Anconeus Triceps Hemipeel Approach for Distal Humerus Exposure Without Olecranon Osteotomy
Authors: Rees Andrew B. , Dombrowsky Alexander R. , Posey Samuel L. , Wally Meghan K. , Kempton Laurence B. , Hsu Joseph R. , Phelps Kevin D. 
Published: September 2024

Summary:
Articular visualization is a challenging aspect of treating comminuted intraarticular distal humerus fractures (AO/OTA types 13B and 13C). Multiple surgical approaches have been described to improve articular visualization while minimizing morbidity to the patient. The anconeus hemipeel approach is a modified approach to the distal humerus involving retrograde reflection of the anconeus to provide improved exposure to the distal humerus. The anconeus hemipeel approach can be used in place of the olecranon osteotomy—which adds additional morbidity and complicates future arthroplasty options. This study describes the approach as a technical trick and reports the first clinical outcomes of patients treated with the anconeus hemipeel approach for exposure of the distal humerus without an olecranon osteotomy for the treatment of comminuted, intraarticular distal humerus fractures.
Endocrine therapy for early breast cancer in the era of oral selective estrogen receptor degraders: challenges and future perspectives
Authors: Ascione Liliana , Castellano Grazia , Curigliano Giuseppe , Zagami Paola 
Published: September 2024

Purpose of review
Growth and survival of hormone receptor positive breast cancer cells are dependent on circulating hormones (e.g., estrogen and progesterone). Endocrine therapy improved outcomes in both early and advanced hormone receptor positive breast cancer. These treatments include drugs with different mechanisms of action, namely selective estrogen receptor modulators (SERM), aromatase inhibitors, and selective estrogen receptor degraders (SERDs). SERDs represent estrogen receptor antagonists, favoring its degradation and thus interfering with proliferation genes transcription and activation. Fulvestrant is the first approved SERD, administered intramuscularly for treating advanced breast cancer.

Recent findings
Oral SERDs have been tested to overcome the limitation of the intramuscular administration, and to increase SERD bioavailability. Recently, an oral SERD, Elacestrant, has been approved by the Food and Drug Administration (FDA) for patients carrying an ESR1 mutation. In fact, oral SERDs seem to be effective in tumors harboring ESR1 mutations, a well known mechanism of resistance to endocrine therapy (especially aromatase inhibitors).

Summary
More recently, oral SERDs have been tested in patients with early hormone receptor positive breast cancer, although their impact on survival and in this curative setting compared to standard endocrine therapy still needs to be elucidated. The best timing and duration of SERD administration and specific biomarkers in (neo)adjuvant setting remain largely unknown.
Immunotherapy in first line treatment of adult acute lymphoblastic leukemia
Authors: Torrent Anna , Ribera Josep-Maria 
Published: September 2024

Purpose of review
The use of immunotherapy in recent years has changed the paradigm of treatment in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), improving outcomes in the relapsed/refractory setting. New strategies are incorporating immunotherapy into front-line regimens to reduce the toxicity of chemotherapy, prolong survival and increase the possibility of treating older patients. The aim of this review was to describe the new strategies, which have incorporated these drugs into front-line regimens for BCP-ALL patients.

Recent findings
Recent studies have demonstrated that immunotherapy can be included in front-line induction, consolidation and/or maintenance regimens for the treatment of BCP-ALL patients by its addition to chemotherapy, by substituting some chemotherapy cycles or even including immunotherapy in chemotherapy-free strategies.

Summary
The implications of these relevant findings will allow treating older patients, reducing the toxicity of chemotherapy and increasing patient outcomes. In addition, these findings have raised the possibility of avoiding the need for hematologic stem cell transplant in some selected patients.
When do I ask for a DNA methylation array for primary brain tumor diagnosis?
Authors: Barresi Valeria , Poliani Pietro Luigi 
Published: September 2024

Purpose of review
Despite remarkable advances in molecular characterization, the diagnosis of brain tumors remains challenging, particularly in cases with ambiguous histology or contradictory molecular features. In this context, DNA methylation profiling plays an important role in improving diagnostic and prognostic accuracy. This review aims to provide diagnostic guidance regarding when DNA methylation arrays represent a useful tool for the diagnosis of primary brain tumors.

Recent findings
Large-scale profiling has revealed that DNA methylation profiles of brain tumors are highly reproducible and stable. Therefore, DNA methylation profiling has been successfully used to classify brain tumors and identify new entities. This approach seems to be particularly promising for heterogeneous groups of tumors, such as IDH-wildtype gliomas, and glioneuronal and embryonal tumors, which include a variety of entities that are still under characterization.

Summary
As underlined in the fifth edition of the WHO classification of central nervous system tumors, the diagnosis of brain tumors requires the integration of histological, molecular, clinical, and radiological features. Although advanced imaging and histological examination remain the standard diagnostic tools, DNA methylation analysis can significantly improve diagnostic accuracy, with a substantial impact on patient management.
The emerging role of melflufen and peptide-conjugates in multiple myeloma
Authors: Moukalled Nour , Abou Dalle Iman , El Cheikh Jean , Ye Yishan , Malarad Florent , Mohty Mohamad , Bazarbachi Ali 
Published: September 2024

Purpose of review
The past two decades have witnessed an impressive expansion in the treatment landscape of multiple myeloma, leading to significant improvements in progression-free; as well as overall survival. However, almost all patients still experience multiple relapses during their disease course, with biological and cytogenetic heterogeneity affecting response to subsequent treatments. The purpose of this review is to provide a historical background regarding the role of alkylating agents and an updated data regarding the use of peptide–drug conjugates such as melflufen for patients with multiple myeloma.

Recent findings
The combination of daratumumab–melflufen–dexamethasone evaluated in the LIGHTHOUSE study showed a statistically significant improvement in progression-free survival compared to single-agent daratumumab (not reached vs. 4.9 months respectively; P = 0.0032), with improvement in overall response rate to 59% vs. 30% respectively; P = 0.03.

Summary
There have been an interest in developing and utilizing peptide–drug conjugates such as melflufen for treatment of patients with multiple myeloma, especially in the relapsed setting given historical results with alkylating agents, the use of which has been limited by dose-related toxicities in a disease that remains largely incurable. Single agent melflufen initially showed promising results especially in specific subgroups of heavily pretreated patients before the decision to suspend all clinical trials evaluating this agent after results from the OCEAN phase 3 trial. Subsequent reported analyses especially for melflufen-based combinations appear promising and suggest a potential use of peptide–drug conjugates provided optimal patient selection, as well as identification of the best companion agent.
Duodenal-type follicular lymphoma: comprehensive insights into disease characteristics and established treatment strategies
Authors: Alnughmush Ahmed , Fakih Riad El , Alyamany Ruah , Bakshi Nasir , Alhayli Saud , Aljurf Mahmoud 
Published: September 2024

Purpose of review
This review aims to detail the characteristics and outcomes of duodenal-type follicular lymphoma (DTFL), a rare lymphoma variant. It focuses on integrating recent reports in treatment modalities and highlights emerging insights into the unique biological features of the disease.

Recent finding
Recent studies confirm the indolent nature of DTFL, with extended follow-up periods showing favorable outcomes under watchful waiting strategies and a notable proportion of patients experiencing spontaneous remission. Additionally, advancements in understanding the disease's biology revealed that the tumor microenvironment is marked by specific genomic expressions indicative of chronic inflammation.

Summary
The observations of spontaneous resolution and the generally favorable progression of DTFL call for a conservative approach in initiating treatment. Clinical management should judiciously consider the disease's typically benign course against the potential risks of intervention, promoting customized treatment protocols tailored for cases with clinical necessity. Additionally, the discovery of an inflammatory tumor microenvironment and molecular evidence suggesting an antigen-driven process highlight critical areas for future research.
Advances in the pathogenesis of FLT3-mutated acute myeloid leukemia and targeted treatments
Authors: Travaglini Serena , Gurnari Carmelo , Ottone Tiziana , Voso Maria Teresa 
Published: September 2024

Purpose of review

FLT3 mutations are among the most common myeloid drivers identified in adult acute myeloid leukemia (AML). Their identification is crucial for the precise risk assessment because of the strong prognostic significance of the most recurrent type of FLT3 alterations, namely internal tandem duplications (ITDs). Recent advances in the pathogenesis and biology of FLT3-mutated AML have opened an opportunity for development and application of selective inhibition of FLT3 pathway.

Recent findings
In the last decade, at least three targeted treatments have been approved by regulatory agencies and several others are currently under investigations. Here, we review the latest advance in the role of FLT3 mutations in AML, providing an outline of the available therapeutic strategies, their mechanisms of actions and of resistance, as well as routes for potential improvement.

Summary
The availability of FLT3 inhibitors has improved outcomes in AML harboring such mutations, currently also reflected in disease stratification and recommendations. Newer inhibitors are under investigations, and combinations with chemotherapy or other targeted treatments are being explored to further improve disease outcomes.