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Translational Oncology Jul 2024Regorafenib was approved by the US Food and Drug Administration (FDA) for hepatocellular carcinoma (HCC) patients showing progress on sorafenib treatment. However, there...
BACKGROUND AND PURPOSE
Regorafenib was approved by the US Food and Drug Administration (FDA) for hepatocellular carcinoma (HCC) patients showing progress on sorafenib treatment. However, there is an inevitably high rate of drug resistance associated with regorafenib, which reduces its effectiveness in clinical treatment. Thus, there is an urgent need to find a potential way to solve the problem of regorafenib resistance. The metabolite of disulfiram complexed with copper, the Diethyldithiocarbamate-copper complex (CuET), has been found to be an effective anticancer drug candidate. In the present study, we aimed to evaluate the effect of CuET on regorafenib resistance in HCC and uncover the associated mechanism.
EXPERIMENTAL APPROACH
Regorafenib-resistant HCC strains were constructed by applying an increasing concentration gradient. This study employed a comprehensive range of methodologies, including the cell counting kit-8 (CCK-8) assay, colony formation assay, cell cycle analysis, wound healing assay, Transwell assay, tumor xenograft model, and immunohistochemical analysis. These methods were utilized to investigate the antitumor activity of CuET, assess the combined effect of regorafenib and CuET, and elucidate the molecular mechanism underlying CuET-mediated regorafenib resistance.
KEY RESULTS
The inhibitory effect of regorafenib on cell survival, proliferation and migration was decreased in regorafenib-resistant MHCC-97H (MHCC-97H/REGO) cells compared with parental cells. CuET demonstrated significant inhibitory effects on cell survival, proliferation, and migration of various HCC cell lines. CuET restored the sensitivity of MHCC-97H/REGO HCC cells to regorafenib in vitro and in vivo. Mechanistically, CuET reverses regorafenib resistance in HCC by suppressing epithelial-mesenchymal transition (EMT) through inhibition of the ERK signaling pathway.
CONCLUSION AND IMPLICATIONS
Taken together, the results of this study demonstrated that CuET inhibited the activation of the ERK signaling pathway, leading to the suppression of the epithelial-mesenchymal transition (EMT) and subsequently reversing regorafenib resistance in HCC both in vivo and in vitro. This study provides a new idea and potential strategy to improve the treatment of regorafenib-resistant HCC.
PubMed: 38954975
DOI: 10.1016/j.tranon.2024.102040 -
Translational Oncology Jul 2024Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor characterized by initial sensitivity to chemotherapy, followed by the development of drug resistance....
OBJECTIVE
Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor characterized by initial sensitivity to chemotherapy, followed by the development of drug resistance. The underlying mechanisms of resistance in SCLC have not been fully elucidated. Aldo-keto reductase family 1 member C3 (AKR1C3), is known to be associated with chemoradiotherapy resistance in diverse tumors. We aim to evaluate the prognostic significance and immune characteristics of AKR1C3 and investigate its potential role in promoting drug resistance in SCLC.
METHODS
81 postoperative SCLC tissues were used to analyze AKR1C3 prognostic value and immune features. The tissue microarrays were employed to validate the clinical significance of AKR1C3 in SCLC. The effects of AKR1C3 on SCLC cell proliferation, migration, apoptosis and tumor angiogenesis were detected by CCK-8, wound healing assay, transwell assay, flow cytometry and tube formation assay.
RESULTS
AKR1C3 demonstrated the highest expression level compared to other AKR1C family genes, and multivariate cox regression analysis identified it as an independent prognostic factor for SCLC. High AKR1C3 expression patients who underwent chemoradiotherapy experienced significantly shorter overall survival (OS). Furthermore, AKR1C3 was involved in the regulation of the tumor immune microenvironment in SCLC. Silencing of AKR1C3 led to the inhibition of cell proliferation and migration, while simultaneously promoting apoptosis and reducing epithelial-mesenchymal transition (EMT) in SCLC.
CONCLUSION
AKR1C3 promotes cell growth and metastasis, leading to drug resistance through inducing EMT and angiogenesis in SCLC.
PubMed: 38954974
DOI: 10.1016/j.tranon.2024.102027 -
International Journal of Surgery Case... Jun 2024Mantle cell lymphoma is a rare type of non-Hodgkin's lymphoma which accounts for 5 % of all cases. Patients present with an advanced form of the disease. We present...
INTRODUCTION AND IMPORTANCE
Mantle cell lymphoma is a rare type of non-Hodgkin's lymphoma which accounts for 5 % of all cases. Patients present with an advanced form of the disease. We present here a case of ileocolic intussusception secondary to mantle cell lymphoma which was revealed by abdominal pain and vomiting that was treated by surgical resection followed by chemotherapy.
CASE PRESENTATION
This report illustrates the case of a 34-year-old male who presented with abdominal pain and vomiting. Imageology demonstrated an ileocolic intussusception which was treated with hemicolectomy followed by chemotherapy. Histopathology confirmed the diagnosis of Mantle cell lymphoma.
CLINICAL DISCUSSION
Mantel cell lymphoma is a rare type of B-cell cancer. Patients are generally diagnosed with an advanced stage of the disease. Ileocolic intussusception is an uncommon presentation. Surgery is the pillar of the treatment. Resection depends on the extent and location of the lesion. Postoperative chemotherapy is crucial and it increases survival rate.
CONCLUSION
Mantle cell lymphoma is a rare subgroup of B-cell lymphomas. Ileocolic intussusception is a complicated form of the disease. Surgery combined with chemotherapy is the mainstay of the treatment. Diagnosis is confirmed by histological analysis of the surgical specimen.
PubMed: 38954973
DOI: 10.1016/j.ijscr.2024.109963 -
International Journal of Surgery Case... Jun 2024Traumatic pelvic fractures are complex injuries often associated with significant morbidity and mortality. Among the complications of pelvic trauma, rupture of the...
INTRODUCTION AND IMPORTANCE
Traumatic pelvic fractures are complex injuries often associated with significant morbidity and mortality. Among the complications of pelvic trauma, rupture of the ovarian vein represents a rare yet potentially life-threatening event. Prompt recognition and appropriate management are essential to mitigate the risk of hemorrhage and associated complications.
CASE PRESENTATION
We present a case of a 70-year-old woman who sustained a traumatic pelvic fracture following a skiing accident, resulting in rupture of the left ovarian vein. The patient came with the ambulance in the emergency room with lower abdominal tenderness, pelvic pain, but no signs of hemorrhagic shock. Imaging studies confirmed the diagnosis of a pelvic fracture with venous leakage of the left ovarian vein.
CLINICAL DISCUSSION
This review synthesizes recent insights into the diagnosis, management, and complications associated with pelvic fractures, with an emphasis on optimizing patient outcomes through a multidisciplinary approach. The analysis incorporates findings from key studies, including those by Wong and Bucknill, Ma Y et al., and Tullington and Blecker, which advocate for the use of advanced diagnostic tools like CT scans and systematic evaluation processes. These studies underline the necessity of precise classification systems such as the Tile classification to guide treatment and predict outcomes.
CONCLUSION
Management of traumatic pelvic fractures with associated vascular injuries requires a multidisciplinary approach involving trauma surgeons, interventional radiologists, and critical care specialists. Early recognition, accurate diagnosis, and timely intervention are paramount in optimizing outcomes and reducing the risk of mortality. This case underscores the importance of prompt intervention and highlights the challenges associated with traumatic pelvic fractures and rupture of the ovarian vein. Further research is warranted to enhance our understanding of optimal management strategies and improve outcomes for patients with these complex injuries.
PubMed: 38954965
DOI: 10.1016/j.ijscr.2024.109894 -
The Oncologist Jul 2024With the widespread use of next-generation sequencing (NGS) for solid tumors, mesenchymal-to-epithelial transition factor (MET) rearrangement/fusion has been confirmed...
With the widespread use of next-generation sequencing (NGS) for solid tumors, mesenchymal-to-epithelial transition factor (MET) rearrangement/fusion has been confirmed in multiple cancer types. MET amplification and MET exon 14 skipping mutations induce protein autophosphorylation; however, the pathogenic mechanism and drug sensitivity of MET fusion remain unclear. The following report describes the clinical case of a patient diagnosed with squamous lung cancer bearing a TFG-MET gene fusion. In vitro assays demonstrated MET phosphorylation and oncogenic capacity due to the TFG-MET rearrangement, both of which were inhibited by crizotinib treatment. The patient was treated with crizotinib, which resulted in sustained partial remission for more than 17 months. Collectively, cellular analyses and our case report emphasize the potential of MET fusion as a predictive biomarker for personalized target therapy for solid tumors.
PubMed: 38954846
DOI: 10.1093/oncolo/oyae166 -
Interdisciplinary Cardiovascular and... Jul 2024Composite end-points are common primary outcomes in clinical trials. Their main benefit of utilizing a composite outcome is increasing the number of primary outcome...
Composite end-points are common primary outcomes in clinical trials. Their main benefit of utilizing a composite outcome is increasing the number of primary outcome events meaning fewer participants are required to deliver an adequately powered trial. By combining multiple important end-points in the primary outcome rather than having to select only one, composite end-points potentially make clinically meaningful benefits easier to detect and avoid ranking outcomes hierarchically. However there are a number of important considerations when designing and interpreting clinical trials that utilize composite end-points. In this Statistical Primer, issues with composite end-points such as competing events, halo effect, risk of bias, time to event limitations and the win ratio are discussed in the context of real world clinical trials.
PubMed: 38954830
DOI: 10.1093/icvts/ivae126 -
JMIR Research Protocols Jul 2024The aging population and increased disability prevalence in Spain have heightened the demand for long-term care. Informal caregiving, primarily performed by women, plays...
BACKGROUND
The aging population and increased disability prevalence in Spain have heightened the demand for long-term care. Informal caregiving, primarily performed by women, plays a crucial role in this scenario. This protocol outlines the CUIDAR-SE study, focusing on the gender-specific impact of informal caregiving on health and quality of life among caregivers in Andalusia and the Basque Country from 2013 to 2024.
OBJECTIVE
This study aims to analyze the gender differences in health and quality of life indicators of informal caregivers residing in 2 Spanish autonomous communities (Granada, Andalusia, and Gipuzkoa; Basque Country) and their evolution over time, in relation to the characteristics of caregivers, the caregiving situation, and support received.
METHODS
The CUIDAR-SE study uses a longitudinal, multicenter design across 3 phases, tracking health and quality of life indicators among informal caregivers. Using a questionnaire adapted to the Spanish context that uses validated scales and multilevel analysis, the research captures changes in caregivers' experiences amid societal crises, notably the 2008 economic crisis and the COVID-19 pandemic. A multistage randomized cluster sampling technique is used to minimize study design effects.
RESULTS
Funding for the CUIDAR-SE study was in 3 phases starting in January 2013, 2017, and 2021, spanning a 10-year period. Data collection commenced in 2013 and continued annually, except for 2016 and 2020 due to financial and pandemic-related challenges. As of March 2024, a total of 1294 participants have been enrolled, with data collection ongoing for 2023. Initial data analysis focused on gender disparities in caregiver health, quality of life, burden, perceived needs, and received support, with results from phase I published. Currently, analysis is ongoing for phases II and III, as well as longitudinal analysis across all phases.
CONCLUSIONS
This protocol aims to provide comprehensive insights into caregiving dynamics and caregivers' experiences over time, as well as understand the role of caregiving on gender inequality in health, considering regional variations. Despite limitations in participant recruitment, focusing on registered caregivers, the study offers a detailed exploration of the health impacts of caregiving in Spain. The incorporation of a gender perspective and the examination of diverse contextual factors enrich the study's depth, contributing significantly to the discourse on caregiving health complexities in Spain.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
DERR1-10.2196/58440.
Topics: Humans; Caregivers; Quality of Life; Spain; Male; Female; Longitudinal Studies; Sex Factors; Middle Aged; Aged; Surveys and Questionnaires; COVID-19; Health Status Disparities; Adult
PubMed: 38954809
DOI: 10.2196/58440 -
JMIR Dermatology Jul 2024Dermatology is an ideal specialty for artificial intelligence (AI)-driven image recognition to improve diagnostic accuracy and patient care. Lack of dermatologists in... (Observational Study)
Observational Study
BACKGROUND
Dermatology is an ideal specialty for artificial intelligence (AI)-driven image recognition to improve diagnostic accuracy and patient care. Lack of dermatologists in many parts of the world and the high frequency of cutaneous disorders and malignancies highlight the increasing need for AI-aided diagnosis. Although AI-based applications for the identification of dermatological conditions are widely available, research assessing their reliability and accuracy is lacking.
OBJECTIVE
The aim of this study was to analyze the efficacy of the Aysa AI app as a preliminary diagnostic tool for various dermatological conditions in a semiurban town in India.
METHODS
This observational cross-sectional study included patients over the age of 2 years who visited the dermatology clinic. Images of lesions from individuals with various skin disorders were uploaded to the app after obtaining informed consent. The app was used to make a patient profile, identify lesion morphology, plot the location on a human model, and answer questions regarding duration and symptoms. The app presented eight differential diagnoses, which were compared with the clinical diagnosis. The model's performance was evaluated using sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and F-score. Comparison of categorical variables was performed with the χ test and statistical significance was considered at P<.05.
RESULTS
A total of 700 patients were part of the study. A wide variety of skin conditions were grouped into 12 categories. The AI model had a mean top-1 sensitivity of 71% (95% CI 61.5%-74.3%), top-3 sensitivity of 86.1% (95% CI 83.4%-88.6%), and all-8 sensitivity of 95.1% (95% CI 93.3%-96.6%). The top-1 sensitivities for diagnosis of skin infestations, disorders of keratinization, other inflammatory conditions, and bacterial infections were 85.7%, 85.7%, 82.7%, and 81.8%, respectively. In the case of photodermatoses and malignant tumors, the top-1 sensitivities were 33.3% and 10%, respectively. Each category had a strong correlation between the clinical diagnosis and the probable diagnoses (P<.001).
CONCLUSIONS
The Aysa app showed promising results in identifying most dermatoses.
Topics: Humans; Cross-Sectional Studies; Artificial Intelligence; Skin Diseases; Male; Female; Mobile Applications; Adult; Middle Aged; Sensitivity and Specificity; Reproducibility of Results; India; Adolescent; Dermatology; Aged; Young Adult; Diagnosis, Differential; Child
PubMed: 38954807
DOI: 10.2196/48811 -
JMIR Formative Research Jul 2024Emerging evidence indicates that individuals with type 2 diabetes (T2D) are more prone to mental health issues than the general population; however, there is a...
BACKGROUND
Emerging evidence indicates that individuals with type 2 diabetes (T2D) are more prone to mental health issues than the general population; however, there is a significant lack of data concerning the mental health burden in Chinese Americans with T2D.
OBJECTIVE
The aim of this study was to explore the comorbid mental health status, health-seeking behaviors, and mental service utilization among Chinese Americans with T2D.
METHODS
A cross-sectional telephone survey was performed among 74 Chinese Americans with T2D in New York City. We used standardized questionnaires to assess mental health status and to gather data on mental health-seeking behaviors and service utilization. Descriptive statistics were applied for data analysis.
RESULTS
A total of 74 Chinese Americans with T2D completed the survey. Most participants (mean age 56, SD 10 years) identified as female (42/74, 57%), were born outside the United States (73/74, 99%), and had limited English proficiency (71/74, 96%). Despite nearly half of the participants (34/74, 46%) reporting at least one mental health concern (elevated stress, depressive symptoms, and/or anxiety), only 3% (2/74) were currently using mental health services. Common reasons for not seeking care included no perceived need, lack of information about Chinese-speaking providers, cost, and time constraints. The cultural and language competence of the provider was ranked as the top factor related to seeking mental health care.
CONCLUSIONS
Chinese Americans with T2D experience relatively high comorbid mental health concerns yet have low service utilization. Clinicians may consider team-based care to incorporate mental health screening and identify strategies to provide culturally and linguistically concordant mental health services to engage Chinese Americans with T2D.
PubMed: 38954806
DOI: 10.2196/59121 -
Neurology(R) Neuroimmunology &... Sep 2024Neutrophils, underestimated in multiple sclerosis (MS), are gaining increased attention for their significant functions in patients with MS and the experimental...
BACKGROUND AND OBJECTIVES
Neutrophils, underestimated in multiple sclerosis (MS), are gaining increased attention for their significant functions in patients with MS and the experimental autoimmune encephalomyelitis (EAE) animal model. However, the precise role of neutrophils in cervical lymph nodes (CLNs), the primary CNS-draining lymph nodes where the autoimmune response is initiated during the progression of EAE, remains poorly understood.
METHODS
Applying single-cell RNA sequencing (scRNA-seq), we constructed a comprehensive immune cell atlas of CLNs during development of EAE. Through this atlas, we concentrated on and uncovered the transcriptional landscape, phenotypic and functional heterogeneity of neutrophils, and their crosstalk with immune cells within CLNs in the neuroinflammatory processes in EAE.
RESULTS
Notably, we observed a substantial increase in the neutrophil population in EAE mice, with a particular emphasis on the significant rise within the CLNs. Neutrophils in CLNs were categorized into 3 subtypes, and we explored the specific roles and developmental trajectories of each distinct neutrophil subtype. Neutrophils were found to engage in extensive interactions with other immune cells, playing crucial roles in T-cell activation. Moreover, our findings highlighted the strong migratory ability of neutrophils to CLNs, partly regulated by triggering the receptor expressed on myeloid cells 1 (TREM-1). Inhibiting TREM1 with LR12 prevents neutrophil migration both in vivo and in vitro. In addition, in patients with MS, we confirmed an increase in peripheral neutrophils with an upregulation of TREM-1.
DISCUSSION
Our research provides a comprehensive and precise single-cell atlas of CLNs in EAE, highlighting the role of neutrophils in regulating the periphery immune response. In addition, TREM-1 emerged as an essential regulator of neutrophil migration to CLNs, holding promise as a potential therapeutic target in MS.
Topics: Encephalomyelitis, Autoimmune, Experimental; Neutrophils; Animals; Triggering Receptor Expressed on Myeloid Cells-1; Mice; Single-Cell Analysis; Mice, Inbred C57BL; Female; Sequence Analysis, RNA; Lymph Nodes
PubMed: 38954781
DOI: 10.1212/NXI.0000000000200278