bluuebunny/crossref_metadata_2025 huggingface dataset:
Repression of pervasive antisense transcription is the primary role of fission yeast RNA polymerase II CTD serine 2 phosphorylation
Authors: Boulanger Cédric , Haidara Nouhou , Yague-Sanz Carlo , Larochelle Marc , Jacques Pierre-Étienne , Hermand Damien , Bachand Francois
Published: May 2024

The RNA polymerase II carboxy-terminal domain (CTD) consists of conserved heptapeptide repeats that can be phosphorylated to influence distinct stages of the transcription cycle, including RNA processing. Although CTD-associated proteins have been identified, phospho-dependent CTD interactions have remained elusive. Proximity-dependent biotinylation (PDB) has recently emerged as an alternative approach to identify protein-protein associations in the native cellular environment. In this study, we present a PDB-based map of the fission yeast RNAPII CTD interactome in living cells and identify phospho-dependent CTD interactions by using a mutant in which Ser2 was replaced by alanine in every repeat of the fission yeast CTD. This approach revealed that CTD Ser2 phosphorylation is critical for the association between RNAPII and the histone methyltransferase Set2 during transcription elongation, but is not required for 3′ end processing and transcription termination. Accordingly, loss of CTD Ser2 phosphorylation causes a global increase in antisense transcription, correlating with elevated histone acetylation in gene bodies. Our findings reveal that the fundamental role of CTD Ser2 phosphorylation is to establish a chromatin-based repressive state that prevents cryptic intragenic transcription initiation.
The TIMELESS and PARP1 interaction suppresses replication-associated DNA gap accumulation
Authors: Saldanha Joanne , Rageul Julie , Patel Jinal A , Phi Amy L , Lo Natalie , Park Jennifer J , Kim Hyungjin
Published: May 2024

TIMELESS (TIM) in the fork protection complex acts as a scaffold of the replisome to prevent its uncoupling and ensure efficient DNA replication fork progression. Nevertheless, its underlying basis for coordinating leading and lagging strand synthesis to limit single-stranded DNA (ssDNA) exposure remains elusive. Here, we demonstrate that acute degradation of TIM at ongoing DNA replication forks induces the accumulation of ssDNA gaps stemming from defective Okazaki fragment (OF) processing. Cells devoid of TIM fail to support the poly(ADP-ribosyl)ation necessary for backing up the canonical OF processing mechanism mediated by LIG1 and FEN1. Consequently, recruitment of XRCC1, a known effector of PARP1-dependent single-strand break repair, to post-replicative ssDNA gaps behind replication forks is impaired. Physical disruption of the TIM–PARP1 complex phenocopies the rapid loss of TIM, indicating that the TIM–PARP1 interaction is critical for the activation of this compensatory pathway. Accordingly, combined deficiency of FEN1 and the TIM–PARP1 interaction leads to synergistic DNA damage and cytotoxicity. We propose that TIM is essential for the engagement of PARP1 to the replisome to coordinate lagging strand synthesis with replication fork progression. Our study identifies TIM as a synthetic lethal target of OF processing enzymes that can be exploited for cancer therapy.
Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network
Authors: Esparragosa Vazquez Ines , Sanson Marc , Chinot Olivier L , Fontanilles Maxime , Rivoirard Romain , Thomas-Maisonneuve Laure , Cartalat Stéphanie , Tabouret Emeline , Appay Romain , Bonneville-Levard Alice , Darlix Amélie , Meyronet David , Barritault Marc , Gueyffier François , Remontet Laurent , Maucort-Boulch Delphine , Honnorat Jérôme , Dehais Caroline , Ducray François ,   POLA Network, Desenclos C , Guillain N , Menei P , Rousseau A , Cruel T , Lopez S , Abad M , Hamdan N , Adam C , Parker F , Seizeur R , Quintin-Roué I , Chotard G , Bronnimann C , Ricard D , Godfraind C , Khallil T , Cazals-Hatem D , Faillot T , Gaultier C , Tortel M C , Carpiuc I , Richard P , Aubriot-Lorton H , Ghiringhelli F , Djelad A , Maurage C A , Gueye E M , Labrousse F , Ducray F , Meyronet D , Figarella-Branger D , Chinot O , Bauchet L , Rigau V , Gauchotte G , Taillandier L , Campone M , Loussouarn D , Bourg V , Vandenbos-Burel F , Guillamo J-S , Roger P , Blechet C , Adle-Biassette H , Bielle F , Carpentier A , Dehais C , Milin S , Wager M , Colin P , Diebold M D , Chiforeanu D , Vauleon E , Marguet F , Langlois O , Forest F , Motso-Fotso M J , Andraud M , Lhermitte B , Noel G , Bernier M , Younan N , Rousselot-Denis C , Zemmoura I , Joubert C , Cohen-Moyal E , Uro-Coste E , Dhermain F
Published: May 2024

Background

Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population.

Methods

Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%.

Results

Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, P = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, P = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects.

Conclusions

Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.
A viral small interfering RNA-host plant mRNA pathway modulates virus-induced drought tolerance by enhancing autophagy
Authors: Wu Xinyang , Chen Shuting , Zhang Zixin , Zhou Weixin , Sun Ting , Ning Kang , Xu Min , Ke Xubo , Xu Pei
Published: May 2024

Virus-induced drought tolerance presents a fascinating facet of biotic–abiotic interaction in plants, yet its molecular intricacies remain unclear. Our study shows that cowpea mild mottle virus (CPMMV) infection enhances drought tolerance in common bean (Phaseolus vulgaris) plants through a virus-derived small interfering RNA (vsiRNA)-activated autophagy pathway. Specifically, a 21 nt vsiRNA originating from the CPMMV Triple Gene Block1 (TGB1) gene targeted the 5′ untranslated region (UTR) of the host Teosinte branched 1, Cycloidea, Proliferating Cell Factor (TCP) transcription factor gene PvTCP2, independent of the known role of TGB1 as an RNA silencing suppressor. This targeting attenuated the expression of PvTCP2, which encodes a transcriptional repressor, and in turn upregulated the core autophagy-related gene (ATG) PvATG8c, leading to activated autophagy activity surpassing the level induced by drought or CPMMV infection alone. The downstream EARLY RESPONSIVE TO DEHYDRATION (ERD) effector PvERD15 is a homologue of Arabidopsis thaliana AtERD15, which positively regulates stomatal aperture. PvERD15 was degraded in PvATG8c-mediated autophagy. Therefore, we establish a TGB1-PvTCP2-PvATG8c-PvERD15 module as a trans-kingdom fine-tuning mechanism that contributes to virus-induced drought tolerance in plant–drought–virus interactions.
Accurate and rapid molecular subgrouping of high-grade glioma via deep learning-assisted label-free fiber-optic Raman spectroscopy
Authors: Liu Chang , Wang Jiejun , Shen Jianghao , Chen Xun , Ji Nan , Yue Shuhua
Published: May 2024

Molecular genetics is highly related with prognosis of high-grade glioma. Accordingly, the latest WHO guideline recommends that molecular subgroups of the genes, including IDH, 1p/19q, MGMT, TERT, EGFR, Chromosome 7/10, CDKN2A/B, need to be detected to better classify glioma and guide surgery and treatment. Unfortunately, there is no preoperative or intraoperative technology available for accurate and comprehensive molecular subgrouping of glioma. Here, we develop a deep learning-assisted fiber-optic Raman diagnostic platform for accurate and rapid molecular subgrouping of high-grade glioma. Specifically, a total of 2,354 fingerprint Raman spectra was obtained from 743 tissue sites (astrocytoma: 151; oligodendroglioma: 150; glioblastoma (GBM): 442) of 44 high-grade glioma patients. The convolutional neural networks (ResNet) model was then established and optimized for molecular subgrouping. The mean area under receiver operating characteristic curves (AUC) for identifying the molecular subgroups of high-grade glioma reached 0.904, with mean sensitivity of 83.3%, mean specificity of 85.0%, mean accuracy of 83.3%, and mean time expense of 10.6 s. The diagnosis performance using ResNet model was shown to be superior to PCA-SVM and UMAP models, suggesting that high dimensional information from Raman spectra would be helpful. In addition, for the molecular subgroups of GBM, the mean AUC reached 0.932, with mean sensitivity of 87.8%, mean specificity of 83.6%, and mean accuracy of 84.1%. Furthermore, according to saliency maps, the specific Raman features corresponding to tumor-associated biomolecules (e.g. nucleic acid, tyrosine, tryptophan, cholesteryl ester, fatty acid, and collagen) were found to contribute to the accurate molecular subgrouping. Collectively, this study opens up new opportunities for accurate and rapid molecular subgrouping of high-grade glioma, which would assist optimal surgical resection and instant post-operative decision-making.
Human mesenchymal stromal cells ameliorate cisplatin-induced acute and chronic kidney injury via TSG-6
Authors: Tang Ming , Shen Linguo , Tang Maozhi , Liu Ling , Rao Zhengsheng , Wang Zhilin , Wang Yadi , Yin Supei , Li Shujing , Xu Guilian , Zhang Keqin
Published: May 2024

Cisplatin is widely used in tumor chemotherapy, but nephrotoxicity is an unavoidable side effect of cisplatin. Several studies have demonstrated that mesenchymal stromal cells (MSCs) ameliorate cisplatin-induced kidney injury, but the underlying mechanisms are unknown. In this study, the cisplatin-induced kidney injury mouse model was established by subjecting a single intraperitoneal injection with cisplatin. One hour before cisplatin injection, the mice received human bone marrow MSCs (hBM-MSCs) with or without siRNA-transfection, recombinant human tumor necrosis factor-α-stimulated gene/protein 6 (rhTSG-6), or PBS through the tail vein. In addition, cisplatin-stimulated HK-2 cells were treated with hBM-MSCs or rhTSG-6. Human BM-MSCs treatment remarkably ameliorated cisplatin-induced acute and chronic kidney injury, as evidenced by significant reductions in serum creatinine (Scr), blood urea nitrogen, tubular injury, collagen deposition, α-smooth muscle actin accumulation, as well as inflammatory responses, and by remarkable increased anti-inflammatory factor expression and Treg cells infiltration in renal tissues. Furthermore, we found that only a few hBM-MSCs engrafted into damaged kidney and that the level of human TSG-6 in the serum of mice increased significantly following hBM-MSCs administration. Moreover, hBM-MSCs significantly increased the viability of damaged HK-2 cells and decreased the levels of inflammatory cytokines in the culture supernatant. However, the knockdown of the TSG-6 gene in hBM-MSCs significantly attenuated their beneficial effects in vivo and in vitro. On the contrary, treated with rhTSG-6 achieved similar beneficial effects of hBM-MSCs. Our results indicate that systemic administration of hBM-MSCs alleviates cisplatin-induced acute and chronic kidney injury in part by paracrine TSG-6 secretion.
Updating, correcting, and calibrating the narrative about premature ejaculation
Authors: Rowland David L , Tamas Stella , Hevesi Krisztina
Published: May 2024

Introduction

The narrative surrounding premature ejaculation (PE) has developed and solidified over the past 25 years. Unfortunately, portions of that narrative are outdated and do not reflect more recent conceptualizations or empirical findings regarding this disorder.

Objective

In this review we sought to identify existing narratives about PE in need of updating and to provide revised narratives based on the recent research literature.

Method

Five PE narratives in need of revision were identified, including: the prevalence of PE, age-related differences in PE prevalence, a validated ejaculation latency (EL) for diagnosing PE, differences between lifelong and acquired PE subtypes, and the application of PE definitions beyond penile-vaginal intercourse. Extensive literature searches provided information supporting both the original narrative and the need for a revised narrative based on both consideration of more recent studies and reinterpretation of studies conducted since the establishment of the original narratives.

Results

For each selected topic, the prevailing narrative based on the extant literature was first presented, followed by discussion of accumulating evidence that challenges the existing narrative. Each section ends with a suggested revised PE narrative. In 2 instances, the revised narrative required significant corrections (eg, PE prevalence, validated EL for diagnosing PE); in 2 instances, it expanded on the existing narrative (eg, PE subtype differences, inclusion of partnered sexual activities beyond penile-vaginal intercourse); and in 2 other instances, it backed off prior conclusions that have since required rethinking (eg, age-related changes in PE, PE subtype differences). Finally, a brief review of the 3-pronged criteria for PE (EL, ejaculatory control, and bother/distress) is presented and discussed.

Conclusion

This review reiterates the dynamic state of research on PE and demonstrates the need for and value of ongoing research that not only addresses new issues surrounding this dysfunction but also challenges and revises some of the existing narratives about PE.
A taxonomy of didactic roles of dynamic visualization in animated mathematics videos
Authors: ten Voorde Abe , Piroi Margherita , Bos Rogier
Published: May 2024

In recent years, a multitude of innovative educational videos focusing on mathematics and employing dynamic visualization techniques have been published on YouTube. From a sample of videos, we develop a taxonomy of didactical roles of dynamic visuals and supporting animation techniques. The taxonomy is constructed through an open coding approach, involving an iterative process of defining, analysing and refining the codes. Additionally, we conducted an interview with a video creator about the intended roles of dynamic visuals employed in his animations. The taxonomy encompasses the following categories of roles: connect objects, (co)vary objects, dynamic concept visualization, dynamic process visualization, symbol sense, connect to reality and generalization. These roles are implemented through animation techniques like moving and morphing. The nomenclature of these roles suggests their affiliation with various mathematics education research perspectives, including covariational thinking, concept–process duality, symbol sense and conversion between registers. The taxonomy serves as a foundational framework for further research into the learning outcome and effectiveness of dynamic visualization in educational mathematics videos.
The endocannabinoid anandamide activates pro‐resolving pathways in human primary macrophages by engaging both CB2 and GPR18 receptors
Authors: Leuti Alessandro , Fava Marina , Forte Giulia , Pellegrini Niccolò , Oddi Sergio , Scipioni Lucia , Gomez Esteban A. , Dalli Jesmond , Maccarrone Mauro
Published: May 2024

Resolution of inflammation is the cellular and molecular process that protects from widespread and uncontrolled inflammation and restores tissue function in the aftermath of acute immune events. This process is orchestrated by specialized pro‐resolving mediators (SPM), a class of bioactive lipids able to reduce immune activation and promote removal of tissue debris and apoptotic cells by macrophages. Although SPMs are the lipid class that has been best studied for its role in facilitating the resolution of self‐limited inflammation, a number of other lipid signals, including endocannabinoids, also exert protective immunomodulatory effects on immune cells, including macrophages. These observations suggest that endocannabinoids may also display pro‐resolving actions. Interestingly, the endocannabinoid anandamide (AEA) is not only known to bind canonical type 1 and type 2 cannabinoid receptors (CB1 and CB2) but also to engage SPM‐binding receptors such as GPR18. This suggests that AEA may also contribute to the governing of resolution processes. In order to interrogate this hypothesis, we investigated the ability of AEA to induce pro‐resolving responses by classically‐activated primary human monocyte‐derived macrophages (MoDM). We found that AEA, at nanomolar concentration, enhances efferocytosis in MoDMs in a CB2‐ and GPR18‐dependent manner. Using lipid mediator profiling, we also observed that AEA modulates SPM profiles in these cells, including levels of resolvin (Rv)D1, RvD6, maresin (MaR)2, and RvE1 in a CB2‐dependent manner. AEA treatment also modulated the gene expression of SPM enzymes involved in both the formation and further metabolism of SPM such as 5‐lipoxygenase and 15‐Prostaglandin dehydrogenase. Our findings show, for the first time, a direct effect of AEA on the regulation of pro‐resolving pathways in human macrophages. They also provide new insights into the complex interactions between different lipid pathways in activation of pro‐resolving responses contributing to the reestablishment of homeostasis in the aftermath of acute inflammation.
“If You Plant That Seed, It Will Grow”: A Qualitative Study to Improve Linkage to Care Among Patients With Methamphetamine Use Disorder in Emergency Department Settings
Authors: Rinehart Deborah J. , Duarte Karina G. , Gilbert Aiden , Al-Tayyib Alia , Camfield Katherine , Simpson Scott A.
Published: May 2024

Objectives

Methamphetamine addiction is a serious and difficult-to-treat disorder. Existing treatment options are limited, and patient perspectives on effective strategies are lacking. Emergency departments (EDs) may be a critical entry point for individuals with methamphetamine use disorder (MUD) to be identified and linked to treatment. We aimed to understand patients’ perspectives regarding their methamphetamine use and related ED experiences and how to improve linkage to substance treatment.

Methods

Between July and November 2022, semistructured qualitative interviews were conducted with adult patients with MUD in an urban safety-net healthcare setting in Denver, Colorado. Interviews were recorded, summarized, and analyzed using the Rapid Assessment Process.

Results

During the interviews, 18 patients shared their experiences. Participants described feeling stigmatized and experiencing a lack of communication from ED staff during their visit. Additionally, participants shared the perception that ED staff often did not take their health concerns seriously once substance use was identified. Participants were uncertain about overdose risk and felt that their psychiatric symptoms complicated treatment. Referrals to treatment were lacking, and participants supported a care navigation intervention that incorporates elements of contingency management. Participants also shared the importance of ED staff recognizing their social needs and being empathetic, trauma-informed, and flexible to meet patients where they are regardless of their readiness to seek treatment.

Conclusions

Treatment options and entry points for individuals with MUD are currently limited. The patient perspectives described here are helpful in developing services to support, engage, and link individuals to MUD services after discharge from ED services.
RAD51 Expression as a Biomarker to Predict Efficacy of Platinum-Based Chemotherapy and PD-L1 Blockade for Muscle-Invasive Bladder Cancer
Authors: Li Bingyu , Jin Kaifeng , Liu Zhaopei , Su Xiaohe , Xu Ziyue , Liu Ge , Xu Jingtong , Chang Yuan , Wang Yiwei , Zhu Yu , Xu Le , Wang Zewei , Liu Hailong , Zhang Weijuan
Published: May 2024

RAD51, a key recombinase that catalyzes homologous recombination (HR), is commonly overexpressed in multiple cancers. It is curial for DNA damage repair (DDR) to maintain genomic integrity which could further determine the therapeutic response. Herein, we attempt to explore the clinical value of RAD51 in therapeutic guidance in muscle-invasive bladder cancer (MIBC). In this retrospective study, a total of 823 patients with MIBC were included. Zhongshan hospital (ZSHS) cohort (n=134) and The Cancer Genome Atlas-Bladder Cancer (TCGA-BLCA) cohort (n=391) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n=298) was utilized to interrogate the predictive efficacy of RAD51 status to programmed cell death ligand-1 (PD-L1) blockade. In addition, the association of RAD51 with genomic instability and tumor immune contexture was investigated. Patients with RAD51 overexpression were more likely to benefit from both platinum-based chemotherapy and immunotherapy rather than RAD51-low patients. The TMBhighPD-L1highRAD51high subgroup possessed the best clinical benefits from PD-L1 blockade. RAD51-high tumors featured by genomic instability were correlated to highly inflamed and immunogenic contexture with activated immunotherapeutic pathway in MIBC. RAD51 could serve as a prognosticator for treatment response to platinum-based chemotherapy and PD-L1 inhibitor in MIBC patients. Besides, it could also improve the predictive efficacy of TMB and PD-L1.
Bupropion-disguised chest pain presenting in a middle-aged male: a case report and review of literature
Authors: Ahmed Hasaan , Ismayl Mahmoud , Palicherla Anirudh , Selim Mohammad , Aboeata Ahmed
Published: May 2024

Introduction and importance:

Chest pain is one of the most prevalent complaints amongst individuals presenting in healthcare settings, encompassing a broad spectrum of etiologies. Work-up for chest pain often focuses on excluding life-threatening conditions before the consideration of atypical causes.

Case presentation:

A 47-year-old male with a past medical history of tobacco use and depression presented with persistent left-sided chest pain. Vitals on arrival were notable for mild hypertension. Two consecutive high-sensitivity troponins were unremarkable. The electrocardiogram showed sinus rhythm with no ischemic changes. Due to the atypical presentation of chest pain, the patient’s home medications were reviewed, and his bupropion was discontinued due to concern for medication-induced chest pain. The patient was discharged and presented 2 days for follow-up endorsing complete resolution of his chest pain.

Clinical discussion:

Prior investigations have shown bupropion to be associated with chest pain, with resolution noted after discontinuation. The etiology of chest pain is likely sympathomimetic, as bupropion has been shown to exhibit positive inotropic effects on myocardial tissue, propagated by catecholamine release.

Conclusion:

Patients taking bupropion may present with atypical chest pain. Medication discontinuation may be beneficial in alleviating symptoms.
Temporal bone mucocele with extension to mastoid in a 60-year-old male: a case report and literature review
Authors: Shah Ujjwal Kumar , Muskan Vitasta , Dahal Alok , Malla Justin Jung , Lamichhane Samiksha , Shah Krishnandan
Published: May 2024

Introduction:

Mucoceles, characterized by cystic lesions with sterile mucus accumulation, mostly occur in the paranasal but rarely affect the temporal-mastoid bone. The pathogenesis involves obstruction of natural drainage or cyst enlargement. Here, the authors present a rare case of temporal-mastoid mucocele with temporal hypertrophy.

Case presentation:

A 60-year-old male presented with progressive painless right temporal region swelling associated with diminished hearing, headache, fever and ear symptoms. Audiometry indicated a profound hearing loss in the right ear. Computed tomography (CT) of the right temporal bone and MRI brain revealed a large, destructive lesion involving the right temporal mastoid suggesting temporal-mastoid mucocele. Surgical excision of the mucocele and mastoid exploration were performed. Postoperative recovery was uneventful, with significant improvement in symptoms.

Clinical discussion:

Temporal bone mucoceles are rare, with few cases reported in the literature. Their etiology remains unclear, although chronic otitis media may be associated in some cases. Clinical presentations may vary, ranging from asymptomatic to symptoms such as serous otitis media, retroauricular edema, or cholesteatoma. Expansion of the mucocele cavity can lead to bone erosion or remodeling, potentially causing hearing loss. Differentials should include cholesteatoma, histiocytosis, and cholesterol granuloma. Imaging such as temporal bone CT and MRI are crucial for diagnosing, with characteristic findings on T2W images helping in differentiation. Surgical treatment, such as mastoidectomy with marsupialization or complete lesion removal, is indicated to prevent complications and reduce the risk of recurrence.

Conclusion:

This study reports a unique case of concomitant temporal-mastoid mucocele with involvement of organs of hearing with temporal bone hypertrophy.
Primary gastrointestinal stromal tumor of the liver: a case report
Authors: Pham Anh Tuan , Pham Anh The , Truong Cuong Manh , Nguyen Thang Huu , Trinh Phuong Huy
Published: May 2024

Introduction and importance:

Primary gastrointestinal stromal tumors of the liver are exceedingly rare entities, presenting diagnostic and therapeutic challenges. The authors present a case of a 64-year-old male with a primary gastrointestinal stromal tumor (GIST) of the liver, emphasizing the importance of comprehensive diagnostic evaluation and multidisciplinary management in such uncommon cases.

Case presentation:

The patient presented with persistent hypochondriac pain, leading to the discovery of a hepatic mass. Diagnostic work-ups, including imaging studies and biopsy, confirmed the diagnosis of primary GIST in the liver. Following thorough multidisciplinary consultation, the patient underwent right anterior segmentectomy of the liver, performed by our experienced surgeon. Postoperative pathology confirmed the diagnosis of GIST, and the patient was advised to use adjuvant imatinib.

Clinical discussion:

Primary GISTs of the liver pose diagnostic challenges due to their rarity and varied clinical presentations. Imaging modalities, immunohistochemistry, and molecular genotyping are crucial in accurate diagnosis and treatment planning. Surgical resection remains the cornerstone of treatment for localized GISTs, with adjuvant therapy considered based on recurrence risk factors and molecular characteristics.

Conclusion:

This case highlights the need for multidisciplinary consultation in managing primary GISTs of the liver. Accurate diagnosis, surgical expertise, and personalized adjuvant therapy are crucial for better patient outcomes. Further research is necessary to enhance our understanding of prognostic factors and treatment strategies for these rare tumors.
Stevens–Johnson syndrome associated with pancytopenia: a case report
Authors: Prasai Parikshit , Shakya Selika , Singh Avilasha , Manandhar Sarbagya , Adhikari Bibek
Published: May 2024

Introduction and importance:

Stevens–Johnson syndrome (SJS) is a rare and unusual hypersensitivity reaction to certain drugs like allopurinol, commonly used for treating gout. SJS is recognized by extensive necrosis and detachment of skin and mucus membranes. Pancytopenia, characterized by decreased levels of red blood cells, white blood cells and platelets, is an exceedingly rare occurrence in the rare disorder SJS.

Case presentation:

The authors present a 61-year-old male who exhibited symptoms of fever and rash for 5 days accompanied by pancytopenia and liver injury.

Clinical discussion:

The abdomen and bilateral lower extremities exhibited several well-defined dusky-colored hyperpigmented macular lesions. Initially, these lesions were small, tender, erythematous, and raised, later transitioning to a dark red. Multiple distinct ulcerations were present on the lips and buccal cavity. Additionally, there was denudation of the skin with bleeding observed between the toes of both legs. The causality was assessed as a definite adverse drug reaction according to the Naranjo and ALDEN algorithm. The patient received treatment consisting of intravenous steroid along with prophylactics antibiotics. The individual’s pancytopenia was resolved without requiring any blood cells or plasma or platelet concentrate transfusion.

Conclusion:

The exact pathophysiology of SJS associated with pancytopenia has not yet been fully elucidated. The authors’ study hypothesized that the cause of pancytopenia in SJS could be either the direct cytotoxicity of drugs or immune-mediated damage to the bone marrow cells. Additional studies are necessary to establish the precise pathophysiology of the condition. Moreover, our study also indicates that pancytopenia can resolve in SJS without the need for blood cells or plasma or platelet concentrate transfusion. Once more, further studies are required to establish precise management strategies for managing SJS associated with pancytopenia.
Neuroinflammation-on-a-chip for multiple sclerosis research: a narrative review
Authors: Berjaoui Christin , Kachouh Charbel , Joumaa Safaa , Hussein Ghayyad Mohammad , Abate Bekele Bisrat , Ajirenike Rita , Al Maaz Zeina , Awde Sara , Wojtara Magda , Nazir Abubakar , Uwishema Olivier
Published: May 2024

Introduction:

Multiple sclerosis (MS) is a chronic inflammatory condition that impacts the central nervous system. It is distinguished by processes like demyelination, gliosis, neuro-axonal harm, and inflammation. The prevailing theory suggests that MS originates from an immune response directed against the body’s own antigens within the central nervous system.

Aim:

The main aim of this research paper “Neuroinflammation-on-a-Chip” for studying multiple sclerosis is to enhance our comprehension of MS development, demonstrate the application of cutting-edge technology, and potentially provide valuable insights for therapeutic approaches.

Methods:

The available literature for this Narrative Review was searched on various bibliographic databases, PubMed, NCBI, and many other medical references using an individually verified, prespecified approach. Studies regarding the significance of MS and its neuroinflammatory pathogenesis in addition to the development and optimization of neuroinflammatory-on-a-chip and the advancement in innovations in this field have been reviewed in this research for a better understanding of “Neuroinflammation-on-a-chip for multiple sclerosis”. The level of evidence of the included studies was considered as per the Centre for Evidence-Based Medicine recommendations.

Results:

Several studies have indicated that the brain-chip model closely mimics cortical brain tissue compared to commonly used conventional cell culture methods like the Transwell culture system. Additionally, these studies have clearly demonstrated that further research using brain chips has the potential to enhance our understanding of the molecular mechanisms and roles of blood-brain barrier (BBB) transporters in both normal and disease conditions.

Conclusion:

Understanding neuroinflammation processes remains essential to establish new MS treatments approaches. The utilization of brain chips promises to advance our understanding of the molecular processes involving BBB transporters, both in normal and diseased states. Further research needs to be addressed in order to enhance the performance and understanding of neuroinflammation on a chip, hence aiming to provide more effective treatments for all CNS diseases.
Prevalence of sleep disorders in patients with advanced cancer: a cross-sectional study
Authors: Gyawali Siddinath , Tiwari Sagar , Sah Guru Sharan , Panthi Bishal , Upreti Apil , Pokhrel Biraj , Gyawali Bindu , Khanal Pratima , Shrestha Rakshya , Paudel Bishal
Published: May 2024

Background:

Patients with advanced cancer are more susceptible to develop sleep disorders like insomnia, restlessness, hypersomnolence, and sleep apnea due to a series of stressful events and side effects of chemotherapeutic agents. Poor sleep quality is associated with bad cancer outcomes and substandard quality of life. The authors assessed the prevalence of sleep disorders among advanced cancer patients in a tertiary center in Nepal.

Methods:

Patients with stage three and four solid malignancies were enrolled from February 2023 to July 2023 to assess their sleep status. The data were collected using the Pittsburgh Sleep Quality Index (PSQI) questionnaire, analyzed using the Statistical Package for the Social Sciences (SPSS) version 27, and subgroup exploration was done to assess the relationship of poor sleep quality with gender, marital status, malignancy type, and treatment received. An ethical clearance was obtained from the Institutional Review Committee (IRC).

Results:

The authors evaluated data from 357 patients in the study. Of them, 58.3% were female and 41.7% were male. The mean age of the patients was 51.1 years. Among total cancer patients, 56% had significant sleep disorders. A significant association was observed between the quality of sleep and gender, type of malignancy, and treatment methods (p value <0.05). A majority of the patients demonstrated increased sleep latency, struggling to fall asleep swiftly.

Conclusions:

More than half of the patients had poor sleep, which has an adverse impact on the prognosis of the disease and quality of life of cancer patients. Therefore, this aspect of cancer management requires special consideration for better quality of life and appropriate end-of-life care.
Incidental Apical Pleuroparenchymal Scarring on Computed Tomography
Authors: Toussie Danielle , Finkelstein Mark , Mendoza Dexter , Concepcion Jose , Stojanovska Jadranka , Azour Lea , Ko Jane P. , Moore William H. , Singh Ayushi , Sasson Arielle , Bhattacharji Priya , Eber Corey
Published: May 2024

Purpose:

Apical pleuroparenchymal scarring (APPS) is commonly seen on chest computed tomography (CT), though the imaging and clinical features, to the best of our knowledge, have never been studied. The purpose was to understand APPS’s typical morphologic appearance and associated clinical features.

Patients and Methods:

A random generator selected 1000 adult patients from all 21516 chest CTs performed at urban outpatient centers from January 1, 2016 to December 31, 2016. Patients with obscuring apical diseases were excluded to eliminate confounding factors. After exclusions, 780 patients (median age: 64 y; interquartile range: 56 to 72 y; 55% males) were included for analysis. Two radiologists evaluated the lung apices of each CT for the extent of abnormality in the axial plane (mild: <5 mm, moderate: 5 to 10 mm, severe: >10 mm), craniocaudal plane (extension halfway to the aortic arch, more than halfway, vs below the arch), the predominant pattern (nodular vs reticular and symmetry), and progression. Cohen kappa coefficient was used to assess radiologists’ agreement in scoring. Ordinal logistic regression was used to determine associations of clinical and imaging variables with APPS.

Results:

APPS was present on 65% (507/780) of chest CTs (54% mild axial; 80% mild craniocaudal). The predominant pattern was nodular and symmetric. Greater age, female sex, lower body mass index, greater height, and white race were associated with more extensive APPS. APPS was not found to be associated with lung cancer in this cohort.

Conclusion:

Classifying APPS by the extent of disease in the axial or craniocaudal planes, in addition to the predominant pattern, enabled statistically significant associations to be determined, which may aid in understanding the pathophysiology of apical scarring and potential associated risks.
The American Surgical Association in the 21st Century
Authors: Stain Steven C.
Published: May 2024

Writing a presidential address is an interesting exercise, and for those of you who have been fortunate enough to lead an organization, you know that not a day goes by since you become President-elect that you do not think about something that you should include, some experience with a mentor you have had that is worthy of documentation, a message you hope the audience remembers after you are finished, and the hope that it will measure up to the memorable presidential addresses that you have heard in many societies, including the American Surgical Association.
EDA2R-NIK signaling in cancer cachexia
Authors: Agca Samet , Kir Serkan
Published: May 2024

Purpose of review

Cachexia is a debilitating condition causing weight loss and skeletal muscle wasting that negatively influences treatment and survival of cancer patients. The objective of this review is to describe recent discoveries on the role of a novel signaling pathway involving ectodysplasin A2 receptor (EDA2R) and nuclear factor κB (NFκB)-inducing kinase (NIK) in muscle atrophy.

Recent findings

Studies identified tumor-induced upregulation of EDA2R expression in muscle tissues in pre-clinical cachexia models and patients with various cancers. Activation of EDA2R by its ligand promoted atrophy in cultured myotubes and muscle tissue, which depended on NIK activity. The non-canonical NFκB pathway via NIK also stimulated muscle atrophy. Mice lacking EDA2R or NIK were protected from muscle loss due to tumors. Tumor-induced cytokine oncostatin M (OSM) upregulated EDA2R expression in muscles whereas OSM receptor-deficient mice were resistant to muscle wasting.

Recent discoveries revealed a mechanism involving EDA2R-NIK signaling and OSM that drives cancer-associated muscle loss, opening up new directions for designing anti-cachexia treatments. The therapeutic potential of targeting this mechanism to prevent muscle loss should be further investigated. Future research should also explore broader implications of the EDA2R-NIK pathway in other muscle wasting diseases and overall muscle health.
A functional approach to homeostatic regulation
Authors: Arias Clemente F. , Acosta Francisco J. , Bertocchini Federica , Fernández-Arias Cristina
Published: May 2024

In this work, we present a novel modeling framework for understanding the dynamics of homeostatic regulation. Inspired by engineering control theory, this framework incorporates unique features of biological systems. First, biological variables often play physiological roles, and taking this functional context into consideration is essential to fully understand the goals and constraints of homeostatic regulation. Second, biological signals are not abstract variables, but rather material molecules that may undergo complex turnover processes of synthesis and degradation. We suggest that the particular nature of biological signals may condition the type of information they can convey, and their potential role in shaping the dynamics and the ultimate purpose of homeostatic systems. We show that the dynamic interplay between regulated variables and control signals is a key determinant of biological homeostasis, challenging the necessity and the convenience of strictly extrapolating concepts from engineering control theory in modeling the dynamics of homeostatic systems. This work provides an alternative, unified framework for studying biological regulation and identifies general principles that transcend molecular details of particular homeostatic mechanisms. We show how this approach can be naturally applied to apparently different regulatory systems, contributing to a deeper understanding of homeostasis as a fundamental process in living systems.
Low-degree decompositions of flux vectors in faces of the flux cone
Authors: Wieder Frederik , Bockmayr Alexander
Published: May 2024

Decomposing a flux vector into elementary flux modes (EFMs) is a well-known task in the constraint-based analysis of metabolic networks.

Using geometric insights into the facial structure of the flux cone, we develop a new method for decomposition. To illustrate our approach, we consider a variety of genome-scale metabolic networks from the BiGG database. We decompose the optimal solutions to flux balance analysis problems into EFMs and compare different possible decompositions. Taking into account their degree allows understanding the interplay of the different EFMs that can participate in the decomposition of a given flux vector and highlights the particular importance of low-degree decompositions.

The new method can be applied to genome-scale metabolic networks, where the whole set of EFMs is often too large to be computed in practice. The special properties of low-degree decompositions make them an interesting subject for future biological studies.
Granzyme K drives a newly-intentified pathway of complement activation
Authors: Donado Carlos A. , Jonsson A. Helena , Theisen Erin , Zhang Fan , Nathan Aparna , Rupani Karishma Vijay , Jones Dominique ,   Accelerating Medicines Partnership RA/SLE Network, Raychaudhuri Soumya , Dwyer Daniel F. , Brenner Michael B.
Published: May 2024

Granzymes are a family of serine proteases mainly expressed by CD8+T cells, natural killer cells, and innate-like lymphocytes1,2. Although their major role is thought to be the induction of cell death in virally infected and tumor cells, accumulating evidence suggests some granzymes can regulate inflammation by acting on extracellular substrates2. Recently, we found that the majority of tissue CD8+T cells in rheumatoid arthritis (RA) synovium, inflammatory bowel disease and other inflamed organs express granzyme K (GZMK)3, a tryptase-like protease with poorly defined function. Here, we show that GZMK can activate the complement cascade by cleaving C2 and C4. The nascent C4b and C2a fragments form a C3 convertase that cleaves C3, allowing further assembly of a C5 convertase that cleaves C5. The resulting convertases trigger every major event in the complement cascade, generating the anaphylatoxins C3a and C5a, the opsonins C4b and C3b, and the membrane attack complex. In RA synovium, GZMK is enriched in areas with abundant complement activation, and fibroblasts are the major producers of complement C2, C3, and C4 that serve as targets for GZMK-mediated complement activation. Our findings describe a previously unidentified pathway of complement activation that is entirely driven by lymphocyte-derived GZMK and proceeds independently of the classical, lectin, or alternative pathways. Given the widespread abundance ofGZMK-expressing T cells in tissues in chronic inflammatory diseases and infection, GZMK-mediated complement activation is likely to be an important contributor to tissue inflammation in multiple disease contexts.
Sensitivity of estimates of the effectiveness of REDD+ projects to matching specifications and moving from pixels to polygons as the unit of analysis
Authors: Guizar-Coutiño Alejandro , Coomes David , Swinfield Tom , Jones Julia P G
Published: May 2024

There is a substantial interest in the potential of carbon credits generated by Reducing Emissions from tropical Deforestation and Degradation (REDD+) and traded on the voluntary carbon market for generating the finance needed to slow forest loss. However, such credits have become marred in controversy. Recent global-scale analysis using a range of methods for estimating the counterfactual rate of deforestationex postsuggest that many REDD+ projects have overestimated their effectiveness at reducing deforestation and consequently issued more credits than can be justified. All such methods include potentially arbitrary choices which can affect the estimate of the treatment effect. In addition, using pixels as the sampling unit, as some of the studies do, can introduce biases. One study which has been widely cited in the debate (Guizar-Coutiño et al. 2022) estimated avoided deforestation using statistical matching of pixels and a single set of matching options. We estimate avoided deforestation from the same set of projects using 7-hectare plots rather than pixels to sample deforestation and explore the sensitivity of the results to matching choices (exploring 120 matched sets in total). We filtered the results on three criteria: 1) post-matching covariate balance, 2) proportion of REDD+ samples that were successfully matched, and 3) similarity of trends in deforestation rates prior to REDD+ implementation (parallel trends). While one of the 44 REDD+ projects failed these quality control process, we estimate treatment effects for the remaining 43 projects. There was a substantial correlation between our new estimates and those published in Guizar-Coutiño et al. 2022 (0.72 measured in annual percent change, and 0.9 measured in total area change) and our headline estimate of 0.22% per yr (95% CI: 0.13 to 0.34) is essentially unchanged. At a time when confidence in the voluntary carbon markets is low, we hope these results provide reassurance that ex-post counterfactual estimates of avoided deforestation are consistent, helping accelerate their widespread adoption and rebuild trust in nature-based climate solutions.
Optimal Protein Allocation Controls the Inhibition of GltA and AcnB inNeisseria gonorrhoeae
Authors: Shahreen Nabia , Chowdhury Niaz Bahar , Saha Rajib
Published: May 2024

Neisseria gonorrhea(Ngo) is a major concern for global public health due to its severe implications for reproductive health. Understanding its metabolic phenotype is crucial for comprehending its pathogenicity. Despite Ngo’s ability to encode TCA cycle proteins, GltA and AcnB, their activities are notably restricted. To investigate this phenomenon, we used the iNgo_557 metabolic model and incorporated a constraint on total cellular protein content. Our results indicate that low cellular protein content severely limits GltA and AcnB activity, leading to a shift towards acetate overflow for ATP production, which is more efficient in terms of protein usage. Surprisingly, increasing cellular protein content alleviates this restriction on GltA and AcnB and delays the onset of acetate overflow, highlighting protein allocation as a critical determinant in understanding Ngo’s metabolic phenotype. These findings underscore the significance of Ngo’s metabolic adaptation in light of optimal protein allocation, providing a blueprint to understand Ngo’s metabolic landscape.