bluuebunny/crossref_metadata_2025 huggingface dataset:
Deciphering the lipid–cancer nexus: comprehensive Mendelian randomization analysis of the associations between lipid profiles and digestive system cancer susceptibility
Authors: Jin Yongyan , Zhou Haiyan , Jin Xiaoli , Wang Jun
Published: June 2024

Background

Digestive system cancers represent a significant global health challenge and are attributed to a combination of demographic and lifestyle changes. Lipidomics has emerged as a pivotal area in cancer research, suggesting that alterations in lipid metabolism are closely linked to cancer development. However, the causal relationship between specific lipid profiles and digestive system cancer risk remains unclear.

Methods

Using a two-sample Mendelian randomization (MR) approach, we elucidated the causal relationships between lipidomic profiles and the risk of five types of digestive system cancer: stomach, liver, esophageal, pancreatic, and colorectal cancers. The aim of this study was to investigate the effect impact of developing lipid profiles on the risk of digestive system cancers utilizing data from public databases such as the GWAS Catalog and the UK Biobank. The inverse‒variance weighted (IVW) method and other strict MR methods were used to evaluate the potential causal links. In addition, we performed sensitivity analyses and reverse MR analyses to ensure the robustness of the results.

Results

Significant causal relationships were identified between certain lipidomic traits and the risk of developing digestive system cancers. Elevated sphingomyelin (d40:1) levels were associated with a reduced risk of developing gastric cancer (odds ratio (OR) = 0.68, P < 0.001), while elevated levels of phosphatidylcholine (16:1_20:4) increased the risk of developing esophageal cancer (OR = 1.31, P = 0.02). Conversely, phosphatidylcholine (18:2_0:0) had a protective effect against colorectal cancer (OR = 0.86, P = 0.036). The bidirectional analysis did not suggest reverse causality between cancer risk and lipid levels. Strict MR methods demonstrated the robustness of the above causal relationships.

Conclusion

Our findings underscore the significant causal relationships between specific lipidomic traits and the risk of developing various digestive system cancers, highlighting the potential of lipid profiles in informing cancer prevention and treatment strategies. These results reinforce the value of MR in unraveling complex lipid-cancer interactions, offering new avenues for research and clinical application.
Activation of the Wnt/β-catenin signalling pathway enhances exosome production by hucMSCs and improves their capability to promote diabetic wound healing
Authors: Wang Liming , Chen Jun , Song Jia , Xiang Yingyue , Yang Mengmeng , Xia Longqing , Yang Jingwen , Hou Xinguo , Chen Li , Wang Lingshu
Published: June 2024

Background

The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell transplantation, thus making exosomes promising candidates for large-scale clinical implementation and commercialization. However, exosome extraction and purification efficiencies are relatively low, and therapeutic heterogeneity is high due to differences in culture conditions and cell viability. Therefore, in this study, we investigated a priming procedure to enhance the production and therapeutic effects of exosomes from human umbilical cord mesenchymal stem cells (hucMSCs). After preconditioning hucMSCs with agonists/inhibitors that target the Wnt/β-catenin pathway, we assessed both the production of exosomes and the therapeutic efficacy of the optimized exosomes in the context of diabetic wound healing, hoping to provide a safer, more stable and more effective option for clinical application.

Results

The Wnt signalling pathway agonist CHIR99021 increased exosome production by 1.5-fold without causing obvious changes in the characteristics of the hucMSCs or the size of the exosome particles. Further studies showed that CHIR99021 promoted the production of exosomes by facilitating exocytosis. This process was partly mediated by SNAP25. To further explore whether CHIR99021 changed the cargo that was loaded into the exosomes and its therapeutic effects, we performed proteomic and transcriptomic analyses of exosomes from primed and control hucMSCs. The results showed that CHIR99021 significantly upregulated the expression of proteins that are associated with cell migration and wound healing. Animal experiments confirmed that, compared to control hucMSC-derived exosomes, CHIR99021-pretreated hucMSC-derived exosomes (CHIR-Exos) significantly accelerated wound healing in diabetic mice, enhanced local collagen deposition, promoted angiogenesis, and reduced chronic inflammation. Subsequent in vitro experiments confirmed that the CHIR-Exos promoted wound healing by facilitating cell migration, inhibiting oxidative stress-induced apoptosis, and preventing cell cycle arrest.

Conclusions

The Wnt agonist CHIR99021 significantly increased exosome secretion by hucMSCs, which was partly mediated by SNAP25. Notably, CHIR99021 treatment also significantly increased the exosomal levels of proteins that are associated with wound healing and cell migration, resulting in enhanced acceleration of wound healing. All of these results suggested that pretreatment of hucMSCs with CHIR99021 not only promoted exosome production but also improved the exosome therapeutic efficacy, thus providing a promising option for large-scale clinical implementation and commercialization.

Graphical Abstract
High-temperature PTT/CDT coordination nanoplatform realizing exacerbated hypoxia for enhancing hypoxia-activated chemotherapy to overcome tumor drug resistance
Authors: Chang Peng , Guo Yingying , Chen Dan , Li Ke , Wang Wei , Yang Zhihua , Ma Jingwen , Zeng Yun , Zhan Wenhua , Zhan Yonghua
Published: June 2024

Background

Hypoxia-activated prodrugs present new opportunities for safe and effective tumor drug resistance therapy due to their high selectivity for hypoxic cells. However, the uneven distribution of oxygen in solid tumor and insufficient hypoxia in the tumor microenvironment greatly limit its therapeutic efficacy.

Results

In this paper, a novel AQ4N-Mn(II)@PDA coordination nanoplatform was designed and functionalized with GMBP1 to target drug-resistant tumor cells. Its excellent photothermal conversion efficiency could achieve local high-temperature photothermal therapy in tumors, which could not only effectively exacerbate tumor hypoxia and thus improve the efficacy of hypoxia-activated chemotherapy of AQ4N but also significantly accelerate Mn2+-mediated Fenton-like activity to enhance chemodynamic therapy. Moreover, real-time monitoring of blood oxygen saturation through photoacoustic imaging could reflect the hypoxic status of tumors during treatment. Furthermore, synergistic treatment effectively inhibited tumor growth and improved the survival rate of mice bearing orthotopic drug-resistant tumors.

Conclusions

This study not only provided a new idea for PTT combined with hypoxia-activated chemotherapy and CDT for drug-resistant tumors but also explored a vital theory for real-time monitoring of hypoxia during treatment.
Traumatic brain injury alters the effects of class II invariant peptide (CLIP) antagonism on chronic meningeal CLIP + B cells, neuropathology, and neurobehavioral impairment in 5xFAD mice
Authors: Iannucci Jaclyn , Dominy Reagan , Bandopadhyay Shreya , Arthur E. Madison , Noarbe Brenda , Jullienne Amandine , Krkasharyan Margret , Tobin Richard P. , Pereverzev Aleksandr , Beevers Samantha , Venkatasamy Lavanya , Souza Karienn A. , Jupiter Daniel C. , Dabney Alan , Obenaus Andre , Newell-Rogers M. Karen , Shapiro Lee A.
Published: June 2024

Background

Traumatic brain injury (TBI) is a significant risk factor for Alzheimer’s disease (AD), and accumulating evidence supports a role for adaptive immune B and T cells in both TBI and AD pathogenesis. We previously identified B cell and major histocompatibility complex class II (MHCII)-associated invariant chain peptide (CLIP)-positive B cell expansion after TBI. We also showed that antagonizing CLIP binding to the antigen presenting groove of MHCII after TBI acutely reduced CLIP + splenic B cells and was neuroprotective. The current study investigated the chronic effects of antagonizing CLIP in the 5xFAD Alzheimer’s mouse model, with and without TBI.

Methods

12-week-old male wild type (WT) and 5xFAD mice were administered either CLIP antagonist peptide (CAP) or vehicle, once at 30 min after either sham or a lateral fluid percussion injury (FPI). Analyses included flow cytometric analysis of immune cells in dural meninges and spleen, histopathological analysis of the brain, magnetic resonance diffusion tensor imaging, cerebrovascular analysis, and assessment of motor and neurobehavioral function over the ensuing 6 months.

Results

9-month-old 5xFAD mice had significantly more CLIP + B cells in the meninges compared to age-matched WT mice. A one-time treatment with CAP significantly reduced this population in 5xFAD mice. Importantly, CAP also improved some of the immune, histopathological, and neurobehavioral impairments in 5xFAD mice over the ensuing six months. Although FPI did not further elevate meningeal CLIP + B cells, it did negate the ability of CAP to reduce meningeal CLIP + B cells in the 5xFAD mice. FPI at 3 months of age exacerbated some aspects of AD pathology in 5xFAD mice, including further reducing hippocampal neurogenesis, increasing plaque deposition in CA3, altering microgliosis, and disrupting the cerebrovascular structure. CAP treatment after injury ameliorated some but not all of these FPI effects.
Cumulative exposure to AHA Life's Essential 8 is associated with nonalcoholic fatty liver disease: a large cohort study
Authors: Yaqin Wang , Shuwen Deng , Ting Yuan , Xiaoling Zhu , Yuling Deng , Lei Liu , Changfa Wang
Published: June 2024

Background and Aim

We aimed to explore the associations of baseline and cumulative cardiovascular health with nonalcoholic fatty liver disease (NAFLD) development and regression using the new Life’s Essential 8 score.

Methods

From a health screening database, participants who underwent at least 4 health examinations between 2012 and 2022 were recruited and categorized into two cohorts: (a) the NAFLD development cohort with no history of NAFLD prior to Exam 4 and (b) the NAFLD regression cohort with diagnosed NAFLD prior to Exam 4. The LE8 score was calculated from each component. The outcomes were defined as newly incident NAFLD or regression of existing NAFLD from Exam 4 to the end of follow-up.

Results

In the NAFLD development cohort, of 21,844 participants, 3,510 experienced incident NAFLD over a median follow-up of 2.3 years. Compared with the lowest quartile of cumulative LE8, individuals in the highest quartile conferred statistically significant 76% lower odds (hazard ratio [HR] 0.24, 95% confidence interval [CI], 0.21–0.28) of NAFLD incidence, and corresponding values for baseline LE8 were 42% (HR 0.58, 95% CI 0.53–0.65). In the NAFLD regression cohort, of 6,566 participants, 469 experienced NAFLD regression over a median follow-up of 2.4 years. Subjects with the highest quartile of cumulative LE8 had 2.03-fold (95% CI, 1.51–2.74) higher odds of NAFLD regression, and corresponding values for baseline LE8 were 1.61-fold (95% CI, 1.24–2.10).

Conclusion

Cumulative ideal cardiovascular health exposure is associated with reduced NAFLD development and increased NAFLD regression. Improving and preserving health behaviors and factors should be emphasized as an important part of NAFLD prevention and intervention strategies.

Graphical Abstract
Delayed hemothorax following blunt thoracic trauma: a case report
Authors: Álvarez-Ortega Astrid Carolina , Aranda-Hoyos Alcibíades , Posso-Nuñez Jose Alejandro , García-González Carlos Alejandro , Puyana Juan Carlos , Sánchez-Ortiz Álvaro Ignacio , Velásquez-Galvis Mauricio
Published: June 2024

Background

Late hemothorax is a rare complication of blunt chest trauma. The longest reported time interval between the traumatic event and the development of hemothorax is 44 days.

Case presentation

An elderly patient with right-sided rib fractures from chest trauma, managed initially with closed thoracostomy, presented with a delayed hemothorax that occurred 60 days after initial management, necessitating conservative and then surgical intervention due to the patient’s frail condition and associated complications.

Conclusions

This case emphasizes the clinical challenge and significance of delayed hemothorax in chest trauma, highlighting the need for vigilance and potential surgical correction in complex presentations, especially in the elderly.
The correlation between KRAS and TP53 gene mutations and early growth of pulmonary nodules
Authors: Zhao Bin , Li Bin , Guo Haoxin , Zhao Qingtao , Zhang Xiaopeng , Zhao Huanfen , Xue Wenfei , Li Wei , Duan Guochen , Xu Shun
Published: June 2024

Purpose

The purpose of this study is to investigate whether gene mutations can lead to the growth of malignant pulmonary nodules.

Methods

Retrospective analysis was conducted on patients with pulmonary nodules at Hebei Provincial People’s Hospital, collecting basic clinical information such as gender, age, BMI, and hematological indicators. According to the inclusion and exclusion criteria, 85 patients with malignant pulmonary nodules were selected for screening, and gene mutation testing was performed on all patient tissues to explore the relationship between gene mutations and the growth of malignant pulmonary nodules.

Results

There is a correlation between KRAS and TP53 gene mutations and the growth of pulmonary nodules (P < 0.05), while there is a correlation between KRAS and TP53 gene mutations and the growth of pulmonary nodules in the subgroup of invasive malignant pulmonary nodules (P < 0.05).

Conclusion

Mutations in the TP53 gene can lead to the growth of malignant pulmonary nodules and are correlated with the degree of invasion of malignant pulmonary nodules.
Methadone in combination with magnesium, ketamine, lidocaine, and dexmedetomidine improves postoperative outcomes after coronary artery bypass grafting: an observational multicentre study
Authors: Weinberg Laurence , Johnston Samuel , Fletcher Luke , Caragata Rebecca , Hazard Riley H. , Le Peter , Karp Jadon , Carp Bradly , Sean Yip Sui Wah , Walpole Dominic , Shearer Nicholas , Neal-Williams Tom , Nicolae Robert , Armellini Angelica , Matalanis George , Seevanayagam Siven , Bellomo Rinaldo , Makar Timothy , Pillai Param , Warrillow Stephen , Ansari Ziauddin , Koshy Anoop N. , Lee Dong-Kyu , Yii Michael
Published: June 2024

Background

An optimal pharmacological strategy for fast-track cardiac anesthesia (FTCA) is unclear. This study evaluated the effectiveness and safety of an FTCA program using methadone and non-opioid adjuvant infusions (magnesium, ketamine, lidocaine, and dexmedetomidine) in patients undergoing coronary artery bypass grafting.

Methods

This retrospective, multicenter observational study was conducted across private and public teaching sectors. We studied patients managed by a fast-track protocol or via usual care according to clinician preference. The primary outcome was the total mechanical ventilation time in hours adjusted for hospital, body mass index, category of surgical urgency, cardiopulmonary bypass time and EuroSCORE II. Secondary outcomes included successful extubation within four postoperative hours, postoperative pain scores, postoperative opioid requirements, and the development of postoperative complications.

Results

We included 87 patients in the fast-track group and 88 patients in the usual care group. Fast-track patients had a 35% reduction in total ventilation hours compared with usual care patients (p = 0.007). Thirty-five (40.2%) fast-track patients were extubated within four hours compared to 10 (11.4%) usual-care patients (odds ratio: 5.2 [95% CI: 2.39–11.08; p < 0.001]). Over 24 h, fast-track patients had less severe pain (p < 0.001) and required less intravenous morphine equivalent (22.00 mg [15.75:32.50] vs. 38.75 mg [20.50:81.75]; p < 0.001). There were no significant differences observed in postoperative complications or length of hospital stay between the groups.

Conclusion

Implementing an FTCA protocol using methadone, dexmedetomidine, magnesium, ketamine, lignocaine, and remifentanil together with protocolized weaning from a mechanical ventilation protocol is associated with significantly reduced time to tracheal extubation, improved postoperative analgesia, and reduced opioid use without any adverse safety events. A prospective randomized trial is warranted to further investigate the combined effects of these medications in reducing complications and length of stay in FTCA.

Trials registration

The study protocol was registered in the Australian New Zealand Clinical Trials Registry (https://www.anzctr.org.au/ACTRN12623000060640.aspx, retrospectively registered on 17/01/2023).
Shikonin blocks CAF-induced TNBC metastasis by suppressing mitochondrial biogenesis through GSK-3β/NEDD4-1 mediated phosphorylation-dependent degradation of PGC-1α
Authors: Fan Shuangqin , Yan Xiaomin , Hu Xiaoxia , Liu Xing , Zhao Shijie , Zhang Yue , Zhou Xiaofeng , Shen Xiangchun , Qi Qi , Chen Yan
Published: June 2024

Background

Triple-negative breast cancer (TNBC) is characterized by its high metastatic potential, which results in poor patient survival. Cancer-associated fibroblasts (CAFs) are crucial in facilitating TNBC metastasis via induction of mitochondrial biogenesis. However, how to inhibit CAF-conferred mitochondrial biogenesis is still needed to explore.

Methods

We investigated metastasis using wound healing and cell invasion assays, 3D-culture, anoikis detection, and NOD/SCID mice. Mitochondrial biogenesis was detected by MitoTracker green FM staining, quantification of mitochondrial DNA levels, and blue-native polyacrylamide gel electrophoresis. The expression, transcription, and phosphorylation of peroxisome-proliferator activated receptor coactivator 1α (PGC-1α) were detected by western blotting, chromatin immunoprecipitation, dual-luciferase reporter assay, quantitative polymerase chain reaction, immunoprecipitation, and liquid chromatography-tandem mass spectrometry. The prognostic role of PGC-1α in TNBC was evaluated using the Kaplan–Meier plotter database and clinical breast cancer tissue samples.

Results

We demonstrated that PGC-1α indicated lymph node metastasis, tumor thrombus formation, and poor survival in TNBC patients, and it was induced by CAFs, which functioned as an inducer of mitochondrial biogenesis and metastasis in TNBC. Shikonin impeded the CAF-induced PGC-1α expression, nuclear localization, and interaction with estrogen-related receptor alpha (ERRα), thereby inhibiting PGC-1α/ERRα-targeted mitochondrial genes. Mechanistically, the downregulation of PGC-1α was mediated by synthase kinase 3β-induced phosphorylation of PGC-1α at Thr295, which associated with neural precursor cell expressed developmentally downregulated 4e1 recognition and subsequent degradation by ubiquitin proteolysis. Mutation of PGC-1α at Thr295 negated the suppressive effects of shikonin on CAF-stimulated TNBC mitochondrial biogenesis and metastasis in vitro and in vivo.

Conclusions

Our findings indicate that PGC-1α is a viable target for blocking TNBC metastasis by disrupting mitochondrial biogenesis, and that shikonin merits potential for treatment of TNBC metastasis as an inhibitor of mitochondrial biogenesis through targeting PGC-1α.
Revision of the sophorolipid biosynthetic pathway in Starmerella bombicola based on new insights in the substrate profile of its lactone esterase
Authors: Diao Zhoujian , Roelants Sophie L. K. W. , Luyten Goedele , Goeman Jan , Vandenberghe Isabel , Van Driessche Gonzalez , De Maeseneire Sofie L. , Soetaert Wim K. , Devreese Bart
Published: June 2024

Background

Sophorolipids (SLs) are a class of natural, biodegradable surfactants that found their way as ingredients for environment friendly cleaning products, cosmetics and nanotechnological applications. Large-scale production relies on fermentations using the yeastStarmerella bombicolathat naturally produces high titers of SLs from renewable resources. The resulting product is typically an extracellular mixture of acidic and lactonic congeners. Previously, we identified an esterase, termedStarmerella bombicolalactone esterase (SBLE), believed to act as an extracellular reverse lactonase to directly use acidic SLs as substrate.

Results

We here show based on newly available pure substrates, HPLC and mass spectrometric analysis, that the actual substrates of SBLE are in fact bola SLs, revealing that SBLE actually catalyzes an intramolecular transesterification reaction. Bola SLs contain a second sophorose attached to the fatty acyl group that acts as a leaving group during lactonization.

Conclusions

The biosynthetic function by which theStarmerella bombicola‘lactone esterase’ converts acidic SLs into lactonic SLs should be revised to a ‘transesterase’ where bola SL are the true intermediate. This insights paves the way for alternative engineering strategies to develop designer surfactants.
Test-retest reliability and validity of vagally-mediated heart rate variability to monitor internal training load in older adults: a within-subjects (repeated-measures) randomized study
Authors: Manser Patrick , de Bruin Eling D.
Published: June 2024

Background

Vagally-mediated heart rate variability (vm-HRV) shows promise as a biomarker of internal training load (ITL) during exergame-based training or motor-cognitive training in general. This study evaluated the test-retest reliability of vm-HRV during exergaming in healthy older adults (HOA) and its validity to monitor ITL.

Methods

A within-subjects (repeated-measures) randomized study was conducted that included baseline assessments and 4 measurement sessions. Participants played 5 exergames at 3 standardized levels of external task demands (i.e., “easy”, “challenging”, and “excessive”) in random order for 90 s. Test-retest reliability was assessed on the basis of repeated-measures analyses of variance (ANOVA), intraclass correlation coefficients (ICC3,1), standard errors of measurement (SEM), and smallest detectable differences (SDD). Validity was determined by examining the effect of game level on vm-HRV in the ANOVA.

Results

Fourty-three HOA (67.0 ± 7.0 years; 58.1% females (25 females, 18 males); body mass index = 23.7 ± 3.0 kg·m−2) were included. Mean R-R time intervals (mRR) and parasympathetic nervous system tone index (PNS-Index) exhibited mostly good to excellent relative test-retest reliability with no systematic error. Mean SEM% and SDD% were 36.4% and 100.7% for mRR, and 44.6% and 123.7% for PNS-Index, respectively. Significant differences in mRR and PNS-Index were observed between standardized levels of external task demands, with mostly large effect sizes (mean r = 0.847). These results persisted irrespective of the type of neurocognitive domain trained and when only motoric and cognitive demands were manipulated while physical intensity was kept constant. The remaining vm-HRV parameters showed inconsistent or poor reliability and validity.

Conclusion

Only mRR and PNS-Index demonstrated reliable measurement and served as valid biomarkers for ITL during exergaming at a group level. Nonetheless, the presence of large SEMs hampers the detection of individual changes over time and suggests insufficient precision of these measurements at the individual level. Future research should further investigate the reliability and validity of vm-HRV with a specific focus on comparing different measurement methodologies and exercise conditions, particularly focusing on ultra-short-term HRV measurements, and investigate the potential implications (i.e., superiority to other markers of ITL or monitoring strategies?) of using vm-HRV as a biomarker of ITL.
PANX1-mediated ATP release confers FAM3A’s suppression effects on hepatic gluconeogenesis and lipogenesis
Authors: Hu Cheng-Qing , Hou Tao , Xiang Rui , Li Xin , Li Jing , Wang Tian-Tian , Liu Wen-Jun , Hou Song , Wang Di , Zhao Qing-He , Yu Xiao-Xing , Xu Ming , Liu Xing-Kai , Chi Yu-Jing , Yang Ji-Chun
Published: June 2024

Background

Extracellular adenosine triphosphate (ATP) is an important signal molecule. In previous studies, intensive research had revealed the crucial roles of family with sequence similarity 3 member A (FAM3A) in controlling hepatic glucolipid metabolism, islet β cell function, adipocyte differentiation, blood pressure, and other biological and pathophysiological processes. Although mitochondrial protein FAM3A plays crucial roles in the regulation of glucolipid metabolism via stimulating ATP release to activate P2 receptor pathways, its mechanism in promoting ATP release in hepatocytes remains unrevealed.

Methods

db/db, high-fat diet (HFD)-fed, and global pannexin 1 (PANX1) knockout mice, as well as liver sections of individuals, were used in this study. Adenoviruses and adeno-associated viruses were utilized for in vivo gene overexpression or inhibition. To evaluate the metabolic status in mice, oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT), insulin tolerance test (ITT), and magnetic resonance imaging (MRI) were conducted. Protein–protein interactions were determined by coimmunoprecipitation with mass spectrometry (MS) assays.

Results

In livers of individuals and mice with steatosis, the expression of ATP-permeable channel PANX1 was increased (P < 0.01). Hepatic PANX1 overexpression ameliorated the dysregulated glucolipid metabolism in obese mice. Mice with hepatic PANX1 knockdown or global PANX1 knockout exhibited disturbed glucolipid metabolism. Restoration of hepatic PANX1 rescued the metabolic disorders of PANX1-deficient mice (P < 0.05). Mechanistically, ATP release is mediated by the PANX1-activated protein kinase B-forkhead box protein O1 (Akt-FOXO1) pathway to inhibit gluconeogenesis via P2Y receptors in hepatocytes. PANX1-mediated ATP release also activated calmodulin (CaM) (P < 0.01), which interacted with c-Jun N-terminal kinase (JNK) to inhibit its activity, thereby deactivating the transcription factor activator protein-1 (AP1) and repressing fatty acid synthase (FAS) expression and lipid synthesis (P < 0.05). FAM3A stimulated the expression of PANX1 via heat shock factor 1 (HSF1) in hepatocytes (P < 0.05). Notably, FAM3A overexpression failed to promote ATP release, inhibit the expression of gluconeogenic and lipogenic genes, and suppress gluconeogenesis and lipid deposition in PANX1-deficient hepatocytes and livers.

Conclusions

PANX1-mediated release of ATP plays a crucial role in maintaining hepatic glucolipid homeostasis, and it confers FAM3A’s suppressive effects on hepatic gluconeogenesis and lipogenesis.
Integrating phylogenetic, phylogeographic, and morphometric analyses to reveal cryptic lineages within the genus Asaccus (Reptilia: Squamata: Phyllodactylidae) in Iran
Authors: Kamali Kamran , Nazarizadeh Masoud , Fatemizadeh Faezeh , Salmabadi Saeed , Hung Chih–Ming , Kaboli Mohammad
Published: June 2024

The Middle Eastern endemic genus Asaccus comprises Southwest Asian leaf-toed geckos. To date, this genus includes 19 species of leaf-toed geckos (seven in Arabia and 12 in the Zagros Mountains). Despite a recent study on the taxonomy and phylogeny of Asaccus species in Iran, controversies still remain surrounding the phylogeny and phylogeography of the genus. Here, we used an integrative approach to determine the phylogeny and phylogeography of Asaccus species using two mitochondrial genes (12 S and Cyt b), and one nuclear gene (c-mos). Our results uncovered 22 distinct lineages, demonstrating a significant cryptic diversity that challenges the current morphological classifications of these species. Phylogenetic analyses reinforce the monophyly of the Asaccus group, positioning A. montanus as a basal lineage, which supports a deep evolutionary divergence dating back to the Late Oligocene, approximately 27.94 million years ago. This genetic diversity also highlights the impact of historical climatic and geographical changes on species diversification. The findings advocate for an integrative approach combining both molecular and morphological data to resolve species identities accurately, thereby enhancing conservation strategies to protect these genetically distinct lineages.
Proactive patient safety: enhancing hospital readiness through simulation-based clinical systems testing and healthcare failure mode and effect analysis
Authors: Hazwani Tarek , Hamam Heba , Caswell Angela , Madkhaly Azza , Al Saif Saif , Al Hassan Zahra , Al Sweilem Reem , Arabi Asma
Published: June 2024

Background

Recognizing and identifying latent safety threats (LSTs) before patient care commences is crucial, aiding leaders in ensuring hospital readiness and extending its impact beyond patient safety alone. This study evaluated the effectiveness of a combination of Simulation-based Clinical Systems Testing (SbCST) with Healthcare Failure Mode and Effect Analysis (HFMEA) with regard to mitigating LSTs within a newly constructed hospital.

Methods

Three phases of the combined SbCST and HFMEA approach were implemented across all hospital settings. The scenarios tested system functionalities, team responses, and resource availability. The threats thus identified were categorized into system-related issues, human issues, and resource issues, after which they were prioritized and addressed using mitigation strategies. Reassessment confirmed the effectiveness of these strategies before hospital commissioning.

Results

More than 76% of the LSTs were mitigated through the combined approach. System-related issues, such as nonfunctional communication devices and faulty elevators, were addressed by leadership. Human issues such as miscommunication and nonadherence to hospital policy led to improvements in interprofessional communication and teamwork. Resource issues, including missing equipment and risks of oxygen explosion, were addressed through procurement, maintenance, and staff training for equipment preparation.

Conclusion

The SbCST and HFMEA were highly effective with regard to proactively identifying and mitigating LSTs across all aspects of hospital preparedness. This systematic and comprehensive approach offers a valuable tool for enhancing patient safety in new healthcare facilities, thereby potentially setting a new standard for proactive hazard identification and risk management in the context of healthcare construction and commissioning.
A case of gallbladder hemangioma detected in a patient with jaundice and suspected Klatskin tumor: case report and review of the literature
Authors: Karahan F. , Atay A. , Ekinci N. , Dilek O. N.
Published: June 2024

Background and objective

The diagnosis and treatment of benign tumors of the gallbladder and bile ducts are difficult due to their anatomical relationships with neighboring vital organs. Hemangiomas are non-epithelial benign tumors of the gallbladder. The gallbladder is an extremely rare localization for cavernous hemangiomas. To date, 7 cases of cavernous gallbladder hemangioma have been reported in the literature. Although it is seen very rarely, the main problem is that it mimics malignant lesions. Pre-operative diagnosis of gallbladder hemangiomas is difficult. Ultrasound (US), computed tomography (CT) magnetic resonance imaging(MRI), endoscopic ultrasound (EUS), and angiography are helpful in differential diagnosis.

Here, we aimed to present our case, which is the first case of cavernous gallbladder hemangioma and obstructive jaundice in the literature.

Case presentation

A 49-year-old female patient was admitted with the complaint of pain in the right upper quadrant of her abdomen. Bilirubin levels were high due to obstructive jaundice. Abdominal CT and MRI showed an appearance in favor of hemangioma in the gallbladder. There was an increase in bile duct wall thickness on MRCP, and it was evaluated as suspicious for malignant neoplasia. The patient was operated on, and extrahepatic bile duct resection + Roux-en-Y hepaticojejunostomy procedure was performed. As a result of histopathology, hemangioma was detected in the gallbladder. There was no malignancy in the bile ducts.

Conclusion

It should be kept in mind that the mass detected in the gallbladder in a patient with jaundice who is suspected of having a bile duct tumor may also be a hemangioma.
Translation, cross-cultural adaptation, and psychometric evaluation of the brief illness perception questionnaire into Yoruba language among persons with chronic low back pain
Authors: Fatoye Francis , Daramola Olusegun Joshua , Oyewole Olufemi Oyeleye , Falade Olatomiwa , Gebrye Tadesse , Idowu Opeyemi , Fatoye Clara , Mbada Chidozie
Published: June 2024

Background

Illness perception may influence the coping behaviors of patients. There is a lack of tools to measure this construct among Yoruba speakers. Therefore, we translate, cross-culturally adapt and determine the reliability and the validity of the Yoruba version of the Brief Illness Perception Questionnaire (BIPQ-Y).

Methods

The translation and cross-cultural adaptation process was according to Beaton criteria. The psychometric testing of the BIPQ-Y was carried out among 28 consenting patients with low back pain attending a university teaching hospital, while only 10 of them participated in the reliability test. The convergent and discriminant validity of the BIPQ-Y was carried out using the Fear Avoidance Belief Questionnaire and Quadruple Visual Analogue scale. Confirmatory factor analysis was to assess construct validity.

Results

The mean age of the respondents was 47 ± 15.3 years. The concurrent validity of the BIPQ-Y was excellent (r = 0.996) for the total score of BIPQ-Y while the internal consistency was moderate (α = 0.52). The test–retest of BIPQ-Y yielded excellent results with item intra-class correlation coefficient (ICC) ranging between 0.833 and 0.973 and an overall ICC of 0.889. For the confirmatory analysis of the BIPQ-Y, the factor loading for the eight items ranged from − 0.071 to 0.799 and the composite reliability was good with a score of 0.68.

Conclusion

The BIPQ-Y demonstrated excellent psychometric properties that are satisfactory with standards, and it is recommended for assessing illness perceptions of patients with chronic low back pain among the Yoruba-speaking populations.
Is “green” ammonia a misnomer? Unpacking the green label from a food-water-energy nexus perspective in water-scarce regions
Authors: Simha Prithvi , van der Merwe Gert
Published: June 2024

The term ‘green ammonia’ can be misleading. For fertilisers to merit a green label, the industry must adopt a planetary boundaries framework that includes reducing carbon emissions and circular management of nutrients. It should seek to achieve net reductions in reactive nitrogen and phosphorus fluxes to terrestrial and marine ecosystems.
Investigation of missense mutation-related type 1 diabetes mellitus through integrating genomic databases and bioinformatic approach
Authors: Pakha Dyonisa Nasirochmi , Yudhani Ratih Dewi , Irham Lalu Muhammad
Published: June 2024

Though genes are already known to be responsible for type 1 diabetes mellitus (T1DM), the knowledge of missense mutation of that disease gene has still to be under covered. A genomic database and a bioinformatics-based approach are integrated in the present study in order to address this issue. Initially, nine variants associated with T1DM were retrieved from the GWAS catalogue. Different genomic algorithms such as PolyPhen2.0, SNPs and GTEx analyser programs were used to study the structural and functional effects of these mutations. Subsequently, SNPnexus was also employed to understand the effect of these mutations on the function of the expressed protein. Nine missense variants of T1DM were identified using the GWAS catalogue database. Among these nine SNPs, three were predicted to be related to the progression of T1DM disease by affecting the protein level. TYK2 gene variants with SNP rs34536443 were thought to have a probably damaging effect. Meanwhile, both COL4A3 and IFIH1 genes with SNPs rs55703767 and rs35667974, respectively, might alter protein function through a possibly damaging prediction. Among the variants of the three genes, the TYK2 gene with SNP rs34536443 had the strongest contribution in affecting the development of T1DM, with a score of 0.999. We sincerely hope that the results could be of immense importance in understanding the genetic basis of T1DM.
Phase I trial of aurora kinase A (AURKA) inhibitor VIC-1911 plus osimertinib for TKI-resistant, EGFR-mutant non-small cell lung cancer (NSCLC).
Authors: Zhao Shen , Zhao Hongyun , Zhang Li , Sun Yuping , Zhuang Wu , Dong Xiaorong , Zhou Jianying , Li Mingjun , Li Xiaoyan , xi yuqin , Zhang Jintao , Xu Wen , Li Ao , Chen Qianrong , Paradiso Linda J. , Myers Thomas J. , Zhang Lei
Published: June 2024

8077

Background: ARUKA has been implicated in the emergence of resistance to osimertinib. VIC-1911 is a highly selective ARUKA inhibitor that has minimal activity in EGFR-mutant (mt) cell lines as a monotherapy. Preclinical data show synergy of VIC-1911 with osimertinib across in vitro and in vivo osimertinib-resistant models. Sustained tumor control after drug withdrawal is observed in both osimertinib-naïve and -resistant xenograft models. This trial evaluated the safety and efficacy of VIC-1911 plus osimertinib in patients with TKI-resistant, EGFRmt NSCLC (NCT05489731). Methods: This is a phase I trial with a 3+3 dose escalation stage and a dose expansion stage. Eligible patients should have advanced NSCLC with EGFR 19del/L858R and failure after ≥1 lines of EGFR-TKIs. Patients enrolled into the dose escalation stage were treated with VIC-1911 150mg or 200mg BID intermittently (4 days on, 3 days off) plus osimertinib 80 mg QD consecutively. Patients enrolled into the dose expansion stage were treated with VIC-1911 at the recommended phase 2 dose (RP2D) plus osimertinib 80 mg QD. Toxicity was assessed by the NCI CTCAE V5. Efficacy was evaluated per RECIST v1.1. Results: As of 18 December 2023, a total of 24 patients were treated. Median lines of prior treatment were 3 (range,1-8). Seven patients were enrolled during the dose escalation stage (150mg = 4, 200mg = 3). No DLT was observed and 200mg was selected as the RP2D. The most common AEs related to VIC-1911 at RP2D were diarrhea (52.3%), leucopenia (38.1%), neutropenia (33.3%), and thrombocytopenia (28.6%). Efficacy was evaluable in 23 patients. Among them, 10 patients were osimertinib-naïve (T790M-negative = 8,T790M-positive = 2) and 13 were osimertinib-resistant. For osimertinib-naïve patients, confirmed objective response rate (ORR) was 50% (5PRs, T790M-negative = 4, T790M-positive = 1) and disease control rate (DCR) was 80% (3SDs). For osimertinib-resistant patients, ORR was 0% and DCR was 53.8% (7SDs). Among patients with disease control, 66.7% (10/15) stayed on treatment as of data cutoff. The median follow-up duration was 5.5 months. Median duration of response (DOR) was not reached. The 6-month (6m) DOR rate was 50%. Median progression-free survival (PFS) was not reached and 4.3months for osimertinib- naïve and -resistant patients, respectively. The 6m PFS rate was 70.0% and 38.5%, respectively. Updated DOR and PFS data will be presented. Conclusions: VIC-1911 in combination of osimertinib is well-tolerated in previously-treated EGFRmt NSCLC. The combination demonstrates sustained antitumor activity, which indicates the potential of AURKA blockade in delaying the emergence of resistance to osimertinib. Clinical trial information: NCT05489731 .
EGFR-TKI as neoadjuvant treatment in patients with NSCLC with EGFR sensitive mutation: A retrospective real-world analysis.
Authors: Liu Sangtian , Liang Wenhua , He Jianxing
Published: June 2024

8081

Background: This study aimed to evaluate the efficacy and outcome of Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as preoperative neoadjuvant treatment in patients with NSCLC and EGFR sensitive mutation. Methods: A retrospective analysis was conducted. Patients with resectable stage I-III NSCLCs and received neoadjuvant treatment with any generation of EGFR-TKI before surgical resection were enrolled. The primary endpoint were major pathological response (MPR) and objective response rate (ORR), the second endpoints included diseases down staging, surgical outcomes, disease-free survival (DFS) and overall survival (OS). Results: A total of 58 patients were enrolled. Female accounted for 62.1% and most of them (77.6%) were never-smoker. Forty-five (77.6%) patients received the first generation of EGFR-TKI and 11 received the third. The median duration of EGFR-TKI before surgery was 3.6 months (0.7-19.5m). Nine (15.5%) patients achieved MPR and one patient (1.71%) achieved pathological complete response (pCR). The ORR was 60.3% (35/58) according to RECIST v1.1. Eighteen patients achieved TNM downstaging with T downstaging occurred in 44.8% of patients and N downstaging was about 32.8%. Majority of patients (96.6%) underwent thoracoscopic surgery and the rate of R0 resection was 82.8% (48/58). The DFS and OS of the whole cohort was 25.7months and not reached respectively. Patients with MPR had statistically improved outcomes than those without. What noticeable was that patients with tumor regression grade 3 (13/58) (residual viable tumor cells counts for 10% to 50%) also demonstrated a significant benefit from EGFR-TKI preoperative treatment than those with TRG4 or 5 (residual viable tumor cells>50%) (p = 0.01). We define patients with TRG1 to TRG3 as deep pathological regression (DPR) and the rest as non-DPR, and the DPR cohort showed significantly prolonged DFS than those with non-DPR (median DFS, 60.9 vs 16.7 months; HR, 0.29 (95%CI: 0.11-0.74), p = 0.006), the data of OS was not mature. Subgroup analysis validated DPR was an independent predictive factor for DFS. Conclusions: EGFR-TKI as neoadjuvant therapy had good effect on tumor pathological regression and disease downstaging, DPR patients were more likely to achieve long-term disease-free survival. Patients with NDPR should be closely followed up and appropriate adjuvant therapy was necessary after surgery due to the high risk of reccurence.
Health-related quality of life (HRQoL) with tepotinib in patients with MET exon 14 (METex14) skipping non-small cell lung cancer (NSCLC) with brain, liver, adrenal, or bone metastases in the phase II VISION trial.
Authors: Reinmuth Niels , Mazieres Julien , Popat Sanjay , Paz-Ares Luis G. , Hook Emma S , Hatswell Anthony , Vlassak Soetkin , Johne Andreas , Vioix Helene , Paik Paul K.
Published: June 2024

8575

Background: Tepotinib, a highly selective MET inhibitor, showed robust and durable activity in patients with METex14 skipping NSCLC in the VISION trial (NCT02864992) (1). Systemic and intracranial activity was seen in patients with brain metastases. Secondary endpoints in the overall population showed stability in overall HRQoL, dyspnea and chest pain, with clinically meaningful improvement in cough. We analyzed HRQoL in patients with brain, liver, adrenal or bone metastases. Methods: Eligible patients (including patients with brain metastases if asymptomatic or neurologically stable on a stable steroid dose) received oral tepotinib 500 mg (450 mg active moiety) once daily. HRQoL was assessed at baseline and during follow-up using the EORTC QLQ-C30 Global Health Score (GHS), EQ-5D-5L visual analog scale (VAS), and EORTC QLQ-LC13 cough, dyspnea, and chest pain scores. Subgroup analyses evaluated patients with brain, liver, adrenal or bone metastases at baseline per independent review (data cut-off: November 20, 2022). Mean change from baseline across all visits was evaluated by linear mixed model regression in patients with baseline and ≥1 post-baseline score. Results: Of 313 enrolled patients, change from baseline in HRQoL was evaluable in 52 patients with brain (16.6%), 56 with liver (17.9%), 54 with adrenal (17.3%), and 86 with bone metastases (27.5%). At baseline, mean ± standard error (SE) EORTC QLQ-C30 GHS was worst in patients with bone metastases (49.90 ± 2.03), followed by patients with adrenal (51.85 ± 2.51), liver (58.33 ± 2.77), or brain metastases (59.94 ± 2.53). A similar pattern was observed for baseline EQ-5D-5L VAS (bone: 60.42 ± 1.94; adrenal: 63.06 ± 2.45; liver: 65.30 ± 2.46; brain: 66.75 ± 2.57). During tepotinib treatment, overall HRQoL (i.e. EORTC QLQ-C30 GHS and EQ-5D-5L VAS) remained stable in patients with brain, liver, adrenal or bone metastases (Table). Symptom scores in these patients showed trends for improvement in cough, with stability in dyspnea and chest pain. Conclusions: In the VISION trial in METex14 skipping NSCLC, patients with brain, liver, adrenal or bone metastases maintained overall HRQoL during tepotinib treatment, with trends for improvement in cough, consistent with results for the overall population. 1. Mazieres et al. JAMA Oncol 2023;9:1260–66. Clinical trial information: NCT02864992 . [Table: see text]
KRAS mutation subtypes responded differently to combination immunotherapy via disturbing myeloid-derived suppressor cells in non-small cell lung cancer.
Authors: Gong Caifeng , Yang Xu , Zhang Jinsong , Wan Rui , Zhong Jia , Wang Zhijie , Wang Jie
Published: June 2024

8635

Background: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy has shown high efficacy in non-small cell lung cancer (NSCLC) patients, but further exploration of the predictive biomarkers is needed. KRAS is the most common driver oncogene in patients with NSCLC. However, the influence of different KRAS mutation subtypes on immunotherapy response remains controversial. We aimed to evaluate the value of KRAS mutation subtypes for predicting response to immunotherapy in NSCLC patients and to further analyze the related tumor immune microenvironment (TiME) phenotypes. Methods: In this retrospective study, clinical data were extracted from the medical records of patients with advanced NSCLC treated with ICIs and whose available molecular analysis included KRAS mutation information between January 2017 and December 2022. NSCLC tissue samples were collected for TiME analysis. Differences in immune cell subsets between different groups were analyzed using the Mann‒Whitney U test. Clinical characteristics, ICI treatment efficacy, progression-free survival (PFS), and overall survival (OS) were analyzed using multivariate Cox models. Results: A total of 1913 eligible KRAS-mutated NSCLC patients were screened, and 137 patients who received systemic immunotherapy were enrolled (108 males vs 29 females), with a median age of 62 (range, 39-84) years. Among them, 126 (92.0%) patients had adenocarcinoma, 99 (72.3%) patients were systemic therapy naïve, and 124 (90.5%) patients received combined immunotherapy. Among the patients with KRAS mutations, 48 (35.0%) had G12C, 20 (14.6%) had G12V, 27 (19.7%) had G12D and 42 (30.7%) had other subtypes. PFS was significantly longer in the G12C subgroup than in the other mutation subgroup (median PFS: 11.3 vs 6.8 months, P = 0.001). The median PFS times in the G12C/G12V subgroup and the other groups were 11.1 months and 6.5 months, respectively ( P= 0.0005). Multivariate analysis of the immunotherapy cohort revealed that G12C/G12V was an independent predictor of PFS ( P = 0.003, hazard ratio (HR): 2.021, 95% CI: 1.265-3.227). Further TiME analysis suggested that the infiltration of myeloid-derived suppressor cells (MDSCs, CD33+CD11b+) in the tumor and stromal areas in the G12C/G12V subgroup was significantly lower than that in the other subgroup (tumor area, P= 0.045; stroma area, P= 0.015). However, no significant difference in PD-L1 expression was found between the G12C/G12V group and the other groups. Conclusions: KRAS G12C and G12V were associated with favorable combined ICI treatment efficacy in patients with NSCLC. Patients with G12C or G12V mutations had longer PFS and lower infiltration of MDSCs. KRAS mutation subtypes are potential predictive biomarkers disturbed by MDSCs for combination therapy in NSCLC patients.