Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents.

BACKGROUND: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority. METHODS: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations. RESULTS: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1st- (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05). CONCLUSION: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents.

Local Anesthetic Systemic Toxicity Joint Management in the Prehospital Environment: A Case Report.

Local anesthetic systemic toxicity (LAST) is a potentially life-threatening complication that may occur after local anesthetic injection. After reaching the systemic circulation, cardiovascular and central nervous system derangements may appear, with potentially fatal complications if left untreated. The pillars for LAST treatment are advanced life support measures, airway and seizure management, and a 20% lipid emulsion intravenous administration. When occurring in the prehospital setting, LAST is difficult to recognize, mostly because of its features overlapping with other acute conditions. Prompt treatment is also challenging because lipid emulsion may not be routinely carried on emergency vehicles. This article reports a case of LAST occurring in a dental ambulatory located in a remote location within the Italian Alps in which effective communication among different components of the same regional health care system (dispatch center, prehospital teams, and hospital network) led to fast lipid emulsion retrieval en route and on-site toxicity resolution. This case can inspire future operational changes, such as antidote networks available to prehospital emergency medicine crews, avoiding unnecessary deployment of antidotes on ambulances or helicopters, which is difficult to preserve without increasing management costs. However, to be established, such a network would need protocols to facilitate antidote retrieval, training focused on toxidromes recognition, and improved communication skills among different professionals involved in prehospital emergency medicine.

Profiling the patient with inflammatory bowel disease in the relationship between physical activity and partner/social network status: A post hoc patient-tailored analysis of the "BE-FIT-IBD" study.

INTRODUCTION: Normal quality of life is an ultimate target in the therapeutic approach to inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC) in the context of which regular physical activity (PA) is often a chimeric parameter that is not standardized in terms of quality/quantity. The study aimed to profile a sample of IBD patients about the relationship between PA-partner status and social network support. PATIENTS AND METHODS: A post hoc analysis of the "BE-FIT-IBD" study was set up by stratifying the data of PA with that of partner status and the support that the patient's social network (i.e., relatives, friends) provided in inciting the patient to practice regular PA. RESULTS: In the 219 patients included, there was a greater tendency for patients with stable partners to view the risk of reactivation/worsening of IBD as a barrier to conducting regular PA (p<0.0001). Single patients considered PA more as a protective factor (p=0.045). Patients without a PA-supporting social network retained IBD-related treatment as a PA barrier (p=0.016) and PA as a risk for IBD complications (p=0.01), with less confidence that PA could improve the course of IBD (p<0.001). Rectal syndrome was an IBD-related barrier more represented in patients with PA-deterring social network (p<0.0001). CONCLUSIONS: These factors are potential targets for recovering the IBD patient's adherence to regular PA.

Globe-LFMC 2.0, an enhanced and updated dataset for live fuel moisture content research.

Globe-LFMC 2.0, an updated version of Globe-LFMC, is a comprehensive dataset of over 280,000 Live Fuel Moisture Content (LFMC) measurements. These measurements were gathered through field campaigns conducted in 15 countries spanning 47 years. In contrast to its prior version, Globe-LFMC 2.0 incorporates over 120,000 additional data entries, introduces more than 800 new sampling sites, and comprises LFMC values obtained from samples collected until the calendar year 2023. Each entry within the dataset provides essential information, including date, geographical coordinates, plant species, functional type, and, where available, topographical details. Moreover, the dataset encompasses insights into the sampling and weighing procedures, as well as information about land cover type and meteorological conditions at the time and location of each sampling event. Globe-LFMC 2.0 can facilitate advanced LFMC research, supporting studies on wildfire behaviour, physiological traits, ecological dynamics, and land surface modelling, whether remote sensing-based or otherwise. This dataset represents a valuable resource for researchers exploring the diverse LFMC aspects, contributing to the broader field of environmental and ecological research.

Charting new AI education in gastroenterology: Cross-sectional evaluation of ChatGPT and perplexity AI in medical residency exam.

BACKGROUND: Conversational chatbots, fueled by large language models, spark debate over their potential in education and medical career exams. There is debate in the literature about the scientific integrity of the outputs produced by these chatbots. AIMS: This study evaluates ChatGPT 3.5 and Perplexity AI's cross-sectional performance in responding to questions from the 2023 Italian national residency admission exam (SSM23), comparing results and chatbots' concordance with previous years SSMs. METHODS: Gastroenterology-related SSM23 questions were input into ChatGPT 3.5 and Perplexity AI, evaluating their performance in correct responses and total scores. This process was repeated with questions from the three preceding years. Additionally, chatbot concordance was assessed using Cohen's method. RESULTS: In SSM23, ChatGPT 3.5 outperforms Perplexity AI with 94.11% correct responses, demonstrating consistency across years. Concordance weakened in 2023 (κ=0.203, P = 0.148), but ChatGPT consistently maintains a high standard compared to Perplexity AI. CONCLUSION: ChatGPT 3.5 and Perplexity AI exhibit promise in addressing gastroenterological queries, emphasizing potential educational roles. However, their variable performance mandates cautious use as supplementary tools alongside conventional study methods. Clear guidelines are crucial for educators to balance traditional approaches and innovative systems, enhancing educational standards.

EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong cancer plasticity. We find that ALK rearrangement is detectable in 5.1-7.5% of human LUAS, and transgenic expression of EML4-ALK drives lung adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.

May ChatGPT be a tool producing medical information for common inflammatory bowel disease patients' questions? An evidence-controlled analysis.

Artificial intelligence is increasingly entering everyday healthcare. Large language model (LLM) systems such as Chat Generative Pre-trained Transformer (ChatGPT) have become potentially accessible to everyone, including patients with inflammatory bowel diseases (IBD). However, significant ethical issues and pitfalls exist in innovative LLM tools. The hype generated by such systems may lead to unweighted patient trust in these systems. Therefore, it is necessary to understand whether LLMs (trendy ones, such as ChatGPT) can produce plausible medical information (MI) for patients. This review examined ChatGPT's potential to provide MI regarding questions commonly addressed by patients with IBD to their gastroenterologists. From the review of the outputs provided by ChatGPT, this tool showed some attractive potential while having significant limitations in updating and detailing information and providing inaccurate information in some cases. Further studies and refinement of the ChatGPT, possibly aligning the outputs with the leading medical evidence provided by reliable databases, are needed.

Inflammatory bowel diseases patients suffer from significant low levels and barriers to physical activity: The "BE-FIT-IBD" study.

BACKGROUND: The place regular physical activity (PA) should occupy in managing patients with inflammatory bowel diseases (IBD) is unclear. AIM: To assess PA levels and barriers in a southern Italian IBD population. METHODS: IBD patients with non-severe disease activity [assessed with partial Mayo score for ulcerative colitis (UC) and Harvey-Bradshaw index for Crohn's disease] were approached to receive an anonymous online questionnaire to assess PA levels using the International Physical Activity Questionnaire (IPAQ) and to assess disease activity as patient-reported outcomes 2 (PRO-2) and finally to assess habits, beliefs and barriers in conducting regular PA. Clinical, anthropometric and demographic data of patients were also collected. PA was expressed as continuous units of resting metabolic rate (Met) in min/wk. Three PA groups were identified: Inactive (< 700 Met min/wk), sufficiently active (700-2500 Met min/wk) and health enhancing PA (HEPA) (i.e., HEPA active, > 2500 Met min/wk) patients. RESULTS: Included patients (219) showed overall PA levels of 834.5 Met min/wk, with a large proportion (94, 42.9%) classified as inactive while only a minority (9, 4.1%) as health-enhancing PA. Patients without dyslipidaemia (P < 0.0001) or on biologics therapy (P = 0.022) showed better IPAQ scores in moderate activities. UC PRO-2 correlated negatively with IPAQ intense activities scores (τ = -0.156, P = 0.038). PRO-2 did not show notable sensitivity/specificity in predicting IPAQ inactivity (AUC < 0.6). IBD activity did not differ between active and inactive patients (P > 0.05). Active patients expressed the need to discuss PA with their gastroenterologist. Some barriers (e.g., diagnosis of IBD and fear of flare-ups after PA) are significantly more reported by inactive patients. CONCLUSION: A significant rate of physical inactivity was recorded in this setting. IPAQ showed good feasibility. PA should be an element of discussion in IBD visits assessed quickly with non-invasive questionnaires.

Telemedicine in inflammatory bowel diseases: A new brick in the medicine of the future?

Inflammatory bowel disease (IBD) is a chronic digestive disease that requires continuous monitoring by healthcare professionals to determine the appropriate therapy and monitor short-term and long-term complications. The progressive development of information technology has enabled healthcare personnel to deliver care services to patients remotely. Therefore, various applications of telemedicine in IBD management have evolved, including telemonitoring, teleconsulting, teleducation, telenursing, telenutrition, and telepathology. While evidence has been provided for some telemedicine applications, targeted studies are still required. This review summarises the major studies that have evaluated telemedicine and its application in the management of IBD.

Immortalization and transformation of primary cells mediated by engineered ecDNAs.

Focal gene amplifications are among the most common cancer-associated mutations, but their evolution and contribution to tumorigenesis have proven challenging to recapitulate in primary cells and model organisms. Here we describe a general approach to engineer large (>1 Mbp) focal amplifications mediated by extrachromosomal circular DNAs (ecDNAs, also known as "double minutes") in a spatiotemporally controlled manner in cancer cell lines and in primary cells derived from genetically engineered mice. With this strategy, ecDNA formation can be coupled with expression of fluorescent reporters or other selectable markers to enable the identification and tracking of ecDNA-containing cells. We demonstrate the feasibility of this approach by engineering MDM2-containing ecDNAs in near-diploid human cells, showing that GFP expression can be used to track ecDNA dynamics under physiological conditions or in the presence of specific selective pressures. We also apply this approach to generate mice harboring inducible Myc - and Mdm2 -containing ecDNAs analogous to those spontaneously occurring in human cancers. We show that the engineered ecDNAs rapidly accumulate in primary cells derived from these animals, promoting proliferation, immortalization, and transformation.

Oncogenic K-Ras suppresses global miRNA function.

K-Ras frequently acquires gain-of-function mutations (K-RasG12D being the most common) that trigger significant transcriptomic and proteomic changes to drive tumorigenesis. Nevertheless, oncogenic K-Ras-induced dysregulation of post-transcriptional regulators such as microRNAs (miRNAs) during oncogenesis is poorly understood. Here, we report that K-RasG12D promotes global suppression of miRNA activity, resulting in the upregulation of hundreds of targets. We constructed a comprehensive profile of physiological miRNA targets in mouse colonic epithelium and tumors expressing K-RasG12D using Halo-enhanced Argonaute pull-down. Combining this with parallel datasets of chromatin accessibility, transcriptome, and proteome, we uncovered that K-RasG12D suppressed the expression of Csnk1a1 and Csnk2a1, subsequently decreasing Ago2 phosphorylation at Ser825/829/832/835. Hypo-phosphorylated Ago2 increased binding to mRNAs while reducing its activity to repress miRNA targets. Our findings connect a potent regulatory mechanism of global miRNA activity to K-Ras in a pathophysiological context and provide a mechanistic link between oncogenic K-Ras and the post-transcriptional upregulation of miRNA targets.

Co-created decision-making: From co-production to value co-creation in health care.

Rare diseases are characterized by a wide diversity of signs and symptoms and vary not only from disease to disease but also from person to person, and living with a disease leads patients to peculiar experiences, without limits of time and space, as they extend to various environments and relationships of their lives. Therefore, the objective of this study is the theoretical interaction between value co-creation (VC) and the stakeholder theory (ST) with the shared decision-making (SDM) health care theory, to enable the analysis of the relationships between patients and their stakeholders in the co-creation of value for decision-making focused on the patient's quality of life. It is configured as a multi-paradigmatic proposal by enabling the analysis of multiple perspectives of different stakeholders in health care. Thus, co-created decision-making (CDM) emerges with emphasis on interactivity of the relationships. As previous studies have already highlighted the importance of holistic care, seeing the patient as a whole and not just the body, studies with CDM will be beneficial for analyses that go beyond the clinical office and doctor-patient relationships, extending to all environments and interactions that add value to the patient's treatment. It was concluded that the essence of this new theory proposed here is neither in patient-centered care nor in patient self-care, but in co-created relationships with and between stakeholders, including non-health care environments that are important to the patient, such as relationships with friends, family, other patients with the same disease, social media, public policies, and the practice of pleasurable activities.

Hericium erinaceus, a medicinal fungus with a centuries-old history: Evidence in gastrointestinal diseases.

Hericium erinaceus is an edible and medicinal mushroom commonly used in traditional Chinese medicine for centuries. Several studies have highlighted its therapeutic potential for gastrointestinal disorders such as gastritis and inflammatory bowel diseases. In addition, some components of this mushroom appear to possess strong antineoplastic capabilities against gastric and colorectal cancer. This review aims to analyse all available evidence on the digestive therapeutic potential of this fungus as well as the possible underlying molecular mechanisms.

Haemodynamic support for paediatric septic shock: a global perspective.

Septic shock is a leading cause of hospitalisation, morbidity, and mortality for children worldwide. In 2020, the paediatric Surviving Sepsis Campaign (SSC) issued evidence-based recommendations for clinicians caring for children with septic shock and sepsis-associated organ dysfunction based on the evidence available at the time. There are now more trials from multiple settings, including low-income and middle-income countries (LMICs), addressing optimal fluid choice and amount, selection and timing of vasoactive infusions, and optimal monitoring and therapeutic endpoints. In response to developments in adult critical care to trial personalised haemodynamic management algorithms, it is timely to critically reassess the current state of applying SSC guidelines in LMIC settings. In this Viewpoint, we briefly outline the challenges to improve sepsis care in LMICs and then discuss three key concepts that are relevant to management of children with septic shock around the world, especially in LMICs. These concepts include uncertainties surrounding the early recognition of paediatric septic shock, choices for initial haemodynamic support, and titration of ongoing resuscitation to therapeutic endpoints. Specifically, given the evolving understanding of clinical phenotypes, we focus on the controversies surrounding the concepts of early fluid resuscitation and vasoactive agent use, including insights gained from experience in LMICs and high-income countries. We outline the key components of sepsis management that are both globally relevant and translatable to low-resource settings, with a view to open the conversation to the large variety of treatment pathways, especially in LMICs. We emphasise the role of simple and easily available monitoring tools to apply the SSC guidelines and to tailor individualised support to the patient's cardiovascular physiology.

Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, harbors strong plasticity and is significantly associated with poor prognosis. We established an up-to-date comprehensive genomic and transcriptomic landscape of LUAS in 109 Chinese specimens and demonstrated LUAS development via adeno-to-squamous transdifferentiation. Unsupervised transcriptomic clustering and dynamic network biomarker analysis identified an inflammatory subtype as the critical transition stage during LUAS development. Dynamic dysregulation of the counteracting lineage-specific transcription factors (TFs), containing adenomatous TFs NKX2-1 and FOXA2, and squamous TFs TP63 and SOX2, finely tuned the lineage transition via promoting CXCL3/5-mediated neutrophil infiltration. Genomic clustering identified the most malignant subtype featured with STK11-inactivation, and targeting LSD1 through genetic deletion or pharmacological inhibition almost eradicated STK11-deficient lung tumors. These data collectively uncover the comprehensive molecular landscape, oncogenic driver spectrum and therapeutic vulnerability of Chinese LUAS.

Comparison of RIPASA and ALVARADO scores for risk assessment of acute appendicitis: A systematic review and meta-analysis.

BACKGROUND: In the last decades, several clinical scores have been developed and currently used to improve the diagnosis and risk management of patients with suspected acute appendicitis (AA). However, some of them exhibited different values of sensitivity and specificity. We conducted a systematic review and metanalysis of epidemiological studies, which compared RIPASA and Alvarado scores for the diagnosis of AA. METHODS: This systematic review was conducted using PubMed and Web of Science databases. Selected studies had to compare RIPASA and Alvarado scores on patients with suspected AA and reported diagnostic parameters. Summary estimates of sensitivity and specificity were calculated by the Hierarchical Summary Receiver Operating Curve (HSROC) using STATA 17 (STATA Corp, College Station, TX) and MetaDiSc (version 1.4) software. RESULTS: We included a total of 33 articles, reporting data from 35 studies. For the Alvarado score, the Hierarchical Summary Receiver Operating Curve (HSROC) model produced a summary sensitivity of 0.72 (95%CI = 0.66-0.77), and a summary specificity of 0.77 (95%CI = 0.70-0.82). For the RIPASA score, the HSROC model produced a summary sensitivity of 0.95 (95%CI = 0.92-0.97), and a summary specificity of 0.71 (95%CI = 0.60-0.80). CONCLUSION: RIPASA score has higher sensitivity, but low specificity compared to Alvarado score. Since these scoring systems showed different sensitivity and specificity parameters, it is still necessary to develop novel scores for the risk assessment of patients with suspected AA.

Interplay between K-RAS and miRNAs.

K-RAS is frequently mutated in cancers, and its overactivation can lead to oncogene-induced senescence (OIS), a barrier to cellular transformation. Feedback onto K-RAS limits its signaling to avoid senescence while achieving the appropriate level of activation that promotes proliferation and survival. Such regulation could be mediated by miRNAs, as aberrant RAS signaling and miRNA activity coexist in several cancers, with miRNAs acting both up- and downstream of K-RAS. Several miRNAs both regulate and are regulated by K-RAS, suggesting a noncoding RNA-based feedback mechanism. Functional interactions between K-RAS and the miRNA machinery have also begun to unfold. This review comprehensively surveys the state of knowledge connecting K-RAS to miRNA function and proposes a model for the regulation of K-RAS signaling by noncoding RNAs.

SARS-CoV-2 identification in an acute appendicitis case: Acute abdomen as manifestation of Multisystem Inflammatory Syndrome in a child with COVID-19.

Coronavirus disease 2019 (COVID-19) pandemic is a global health emergency. The clinical course of COVID-19 in children is mild in most of the cases, but multisystem inflammatory syndrome in children (MIS-C) is recognized as a potential life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Acute abdomen as a presentation of COVID-19 is rare, and its correlation to COVID-19 features and prognosis remains undetermined. Herein, we describe a case of appendicitis in a child with confirmed diagnosis of COVID-19 and subsequent SARS-CoV-2 identification in appendix tissue.

Rlf-Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf-Mycl-driven mouse model of SCLC. RLF-MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF-MYCL genetically engineered mouse model displayed gene expression similarities with human RLF-MYCL SCLC. Together, our studies support RLF-MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC. SIGNIFICANCE: The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF-MYCL gene fusion by developing a Rlf-Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis. This article is highlighted in the In This Issue feature, p. 2945.