Eliciting Older Cancer Patients' Preferences for Follow-Up Care to Inform a Primary Healthcare Follow-Up Model in China: A Discrete Choice Experiment.

BACKGROUND AND OBJECTIVES: Increasing longevity and advances in treatment have increased the cancer burden in the elderly, resulting in complex follow-up care needs; however, in China, little is known about the follow-up care preferences of these patients. This study quantified older cancer patients' preferences for follow-up care and examined the trade-offs they are willing to make to accept an alternative follow-up model. METHODS: A discrete choice experiment was conducted among inpatients aged over 60 years with breast, prostate, or colorectal cancer, at two large tertiary hospitals in Nantong, China. Preference weights for follow-up care were estimated using mixed logit analysis. Subgroup analysis and latent class analysis were used to explore preference heterogeneity. RESULTS: Complete results were obtained from 422 patients (144 with breast cancer, 133 with prostate cancer, 145 with colorectal cancer), with a mean age of 70.81 years. Older cancer patients stated a preference for follow-up by specialists over primary healthcare (PHC) providers ( ß = -1.18, 95% confidence interval -1.40 to -0.97). The provider of follow-up care services was the most valued attribute among patients with breast cancer (relative importance [RI] 37.17%), while remote contact services were prioritized by patients with prostate (RI 43.50%) and colorectal cancer (RI 33.01%). The uptake rate of an alternative care model integrating PHC increased compared with the baseline setting when patients were provided with preferred services (continuity of care, individualized care plans, and remote contact services). CONCLUSION: To encourage older cancer patients to use PHC-integrated follow-up care, alternative follow-up care models need to be based on patients' preferences before introducing them as a routine option.

Unveiling the methionine cycle: a key metabolic signature and NR4A2 as a methionine-responsive oncogene in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with notable metabolic reprogramming, yet the pivotal metabolic feature driving ESCC progression remains elusive. Here, we show that methionine cycle exhibits robust activation in ESCC and is reversely associated with patient survival. ESCC cells readily harness exogenous methionine to generate S-adenosyl-methionine (SAM), thus promoting cell proliferation. Mechanistically, methionine augments METTL3-mediated RNA m6A methylation through SAM and revises gene expression. Integrative omics analysis highlights the potent influence of methionine/SAM on NR4A2 expression in a tumor-specific manner, mediated by the IGF2BP2-dependent stabilization of methylated NR4A2 mRNA. We demonstrate that NR4A2 facilitates ESCC growth and negatively impacts patient survival. We further identify celecoxib as an effective inhibitor of NR4A2, offering promise as a new anti-ESCC agent. In summary, our findings underscore the active methionine cycle as a critical metabolic characteristic in ESCC, and pinpoint NR4A2 as a novel methionine-responsive oncogene, thereby presenting a compelling target potentially superior to methionine restriction.

Gut microbes combined with metabolomics reveal the protective effects of Qijia Rougan decoction against CCl4-induced hepatic fibrosis.

Background: The occurrence and development of Hepatic fibrosis (HF) are closely related to the gut microbial composition and alterations in host metabolism. Qijia Rougan decoction (QJ) is a traditional Chinese medicine compound utilized clinically for the treatment of HF with remarkable clinical efficacy. However, its effect on the gut microbiota and metabolite alterations is unknown. Therefore, our objective was to examine the impact of QJ on the gut microbiota and metabolism in Carbon tetrachloride (CCl4)-induced HF. Methods: 40% CCl4 was used to induce HF, followed by QJ administration for 6 weeks. Serum biochemical analyses, histopathology, immunohistochemistry, RT-PCR, 16S rRNA gene sequencing, and non-targeted metabolomics techniques were employed in this study to investigate the interventional effects of QJ on a CCl4-induced HF model in rats. Results: This study demonstrated that QJ could effectively ameliorate CCl4-induced hepatic inflammation and fibrosis. Moreover, QJ upregulated the expression of intestinal tight junction proteins (TJPs) and notably altered the abundance of some gut microbes, for example, 10 genera closely associated with HF-related indicators and TJPs. In addition, metabolomics found 37 key metabolites responded to QJ treatment and strongly associated with HF-related indices and TJPs. Furthermore, a tight relation between 10 genera and 37 metabolites was found post correlation analysis. Among them, Turicibacter, Faecalibaculum, Prevotellaceae UCG 001, and unclassified Peptococcaceae may serve as the core gut microbes of QJ that inhibit HF. Conclusion: These results suggest that QJ ameliorates hepatic inflammation and fibrosis, which may be achieved by improving intestinal tight junctions and modulating gut microbiota composition as well as modulating host metabolism.

Clinical effect analysis of different treatment schemes for children with ulnar and radial double fractures.

Objective: The objective of the study is to evaluate the safety and efficacy of three different treatment methods for pediatric ulnar and radial double fractures. Methods: 120 children with ulnar and radial double fractures were included in the study. According to the different treatment plans, children were divided into three groups: manual reduction, splint external fixation, double elastic intramedullary fixation, and double plate fixation. Surgical indicators, radiological results, clinical efficacy, and complications were evaluated and compared among the groups. Results: The average hospital stay and operation time were significantly longer in the double plate internal fixation group compared to the other two groups. The double elastic intramedullary nailing group showed a higher fracture healing rate at 3 months compared to the other groups. There were no significant differences in clinical efficacy among the three groups. Complications were observed in all groups but did not show significant statistical differences. Conclusion: Double elastic intramedullary nailing fixation demonstrated favorable outcomes in terms of surgical indicators and fracture healing rates for pediatric ulnar and radial double fractures.

Objetivo: Evaluar la seguridad y eficacia de tres métodos de tratamiento diferentes para las fracturas dobles cubital y radial pediátricas. Métodos: Se incluyeron en el estudio 120 niños con fracturas dobles de cúbito y radio. Según los diferentes planes de tratamiento, los niños se dividieron en tres grupos: reducción manual, fijación externa con férula, fijación intramedular doble elástica y fijación con doble placa. Se evaluaron y compararon entre los grupos indicadores quirúrgicos, resultados radiológicos, eficacia clínica y complicaciones. Resultados: La estancia hospitalaria promedio y el tiempo de operación fueron significativamente más prolongados en el grupo de fijación interna con doble placa en comparación con los otros dos grupos. El grupo de clavo intramedular elástico doble mostró una mayor tasa de curación de la fractura a los 3 meses en comparación con los otros grupos. No hubo diferencias significativas en la eficacia clínica entre los tres grupos. Se observaron complicaciones en todos los grupos pero no mostraron diferencias estadísticas significativas. Conclusión: La fijación con clavo intramedular elástico doble demostró resultados favorables en términos de indicadores quirúrgicos y tasas de curación de fracturas pediátricas dobles cubital y radial.

Cost-effectiveness analysis of Tislelizumab vs Sorafenib as the first-line treatment of unresectable hepatocellular carcinoma.

BACKGROUND: To evaluate the cost-effectiveness of Tislelizumab vs Sorafenib as the first-line treatment of unresectable hepatocellular carcinoma (HCC) from the perspective of the Chinese health service system. METHODS: A lifetime partitioned survival model (PSM) was developed to cost-effectively analyze Tislelizumab vs Sorafenib as the first-line treatment of unresectable HCC. The clinical and safety data were derived from a recently randomized clinical trial (RATIONALE-301). Utilities were collected from the published literature. Costs were obtained from an open-access database (http://www.yaozh.com) and previous studies. The model cycle was 21 days, according to the RATIONALE-301 study, and the simulation period was patients' lifetime. Long-term direct medical costs and quality-adjusted life-years (QALYs) were determined. The incremental cost-effectiveness ratio (ICER) was used as the evaluation index. one-way sensitivity analysis (OSWA) and probabilistic sensitivity analysis (PSA) were used to analyze the uncertainty of parameters and to adjust and verify the stability of the baseline results. RESULTS: The Tislelizumab group generated a cost of $39,746.34 and brought health benefits to 2.146 QALYs, while the cost and utility of the Sorafenib group were $26750.95 and 1.578 QALYs, respectively. The Tislelizumab group increased QALYs by 0.568, the incremental cost was $12995.39, and the ICER was $22869.64/QALY, lower than the willingness to pay threshold (WTP). OSWA results showed that the utility of progressed disease (PD), cost of Camrelizumab, and cost of Tislelizumab were the main factors affecting the ICER. PSA results showed that, within 1000 times the Monte Carlo simulation, the cost of the Tislelizumab group was lower than three times the per capita gross domestic product (GDP) of China ($37653/QALY). The cost-effectiveness acceptability curves (CEAC) revealed that when WTP was no less than $12251.00, the Tislelizumab group was the dominant scheme, and the economic advantage grew with an increasing WTP. When WTP ≥ $19000.00, the Tislelizumab group became the absolute economic advantage. CONCLUSION: Under the current economic conditions in China, the Tislelizumab therapeutic scheme is more cost-effective than the Sorafenib therapeutic scheme for treating patients with unresectable HCC.

Addressing the need for preclinical study of penile prosthesis infection: a new animal model and narrative review.

Background and Objective: Erectile dysfunction (ED) is a common condition in men, and many patients refractory to conservative treatment may undergo penile prostheses (PPs) placement. The primary concern following PP implantation is device infection. Although antibiotic and hydrophilic coatings have reduced the incidence of inflatable PP (IPP) infections, there remains room for improvement. Optimization of PP outcomes requires a practical in vivo model to better understand mechanisms of infection and to test new infection control strategies. We aimed to describe a new rabbit model which contains a functional IPP and review previously reported animal PP models. Methods: An IPP was placed into rabbit flanks and cycled for functionality testing. Rabbits were evaluated for signs of pain and distress over 14 days. Separately, narrative review methodology was utilized to search the PubMed and Scopus databases for all publications through March 21, 2023, which studied PP within an in vivo setting. Three independent reviewers ultimately selected 12 papers from 1992-2021 for inclusion. Key Content and Findings: Several animal studies highlighted the initial functionality or feasibility of devices for ED before their introduction in the clinical setting. There are several subsequent studies aimed at optimizing the type of antibiotic use or coating material using segments of PP material in an in vivo setting. However, the literature lacks a contemporary animal model containing a functional IPP. Our novel rabbit model offers a safe, practical way to implant a functioning IPP and investigate new perioperative infection prevention and treatment strategies before trials in the clinical setting. Conclusions: Animal models have played a key role in testing medical devices, including PPs, prior to their clinical introduction. Our review uncovered no modern animal studies involving placement of a functional PP. A new animal model can facilitate study of evolving microorganism profiles, novel methods to enhance antibiotic delivery, and proposed treatment options.

The power and the promise of synthetic lethality for clinical application in cancer treatment.

Synthetic lethality is a phenomenon wherein the simultaneous deficiency of two or more genes results in cell death, while the deficiency of any individual gene does not lead to cell death. In recent years, synthetic lethality has emerged as a significant topic in the field of targeted cancer therapy, with certain drugs based on this concept exhibiting promising outcomes in clinical trials. Nevertheless, the presence of tumor heterogeneity and the intricate DNA repair mechanisms pose challenges to the effective implementation of synthetic lethality. This review aims to explore the concepts, development, and ethical quandaries surrounding synthetic lethality. Additionally, it will provide an in-depth analysis of the clinical application and underlying mechanism of synthetic lethality.

The power and the promise of CAR-mediated cell immunotherapy for clinical application in pancreatic cancer.

BACKGROUND: Pancreatic cancer, referred to as the "monarch of malignancies," is a neoplastic growth mostly arising from the epithelial cells of the pancreatic duct and acinar cells. This particular neoplasm has a highly unfavorable prognosis due to its marked malignancy, inconspicuous initial manifestation, challenging early detection, rapid advancement, and limited survival duration. Cellular immunotherapy is the ex vivo culture and expansion of immune effector cells, granting them the capacity to selectively target malignant cells using specialized techniques. Subsequently, these modified cells are reintroduced into the patient's organism with the purpose of eradicating tumor cells and providing therapeutic intervention for cancer. PRESENT SITUATION: Presently, the primary cellular therapeutic modalities employed in the treatment of pancreatic cancer encompass CAR T-cell therapy, TCR T-cell therapy, NK-cell therapy, and CAR NK-cell therapy. AIM OF REVIEW: This review provides a concise overview of the mechanisms and primary targets associated with various cell therapies. Additionally, we will explore the prospective outlook of cell therapy in the context of treating pancreatic cancer.

KLK10/LIPH/PARD6B/SLC52A3 are promising molecular biomarkers for the prognosis of pancreatic cancer through a ceRNA network.

Pancreatic adenocarcinoma (PAAD) remains challenging to diagnose and treat clinically due to its difficult early diagnosis, low surgical resection rate, and high risk of postoperative recurrence and metastasis. SMAD4 is a classical mutated gene in pancreatic cancer and is lost in up to 60%-90 % of PAAD patients, and its mutation often predicts a poor prognosis and treatment resistance. In this study, based on the expression profile data in The Cancer Genome Atlas database, we identified a ceRNA network composed of 2 lncRNAs, 1 miRNA, and 4 mRNAs through differential expression analysis and survival prognosis analysis. Among them, high expression of KLK10/LIPH/PARD6B/SLC52A3 influenced the prognosis and overall survival of PAAD patients. We confirmed the high expression of these target genes in pancreatic tissue of pancreatic-specific SMAD4-deficient mice. In addition, immune infiltration analysis showed that the high expression of these target genes affects the tumor immune environment and contributes to the progression of PAAD. Abnormal overexpression of these target genes may be caused by hypermethylation. In conclusion, we found that KLK10/LIPH/PARD6B/SLC52A3 is a potential prognostic marker for PAAD based on a competing endogenous RNA-mediated mechanism and revealed the potential pathogenic mechanism by which deficient expression of SMAD4 promotes pancreatic cancer progression, which provides a new pathway and theoretical basis for targeted therapy or improved prognosis of pancreatic cancer. These data will help reveal potential therapeutic targets for pancreatic cancer and improve the prognosis of pancreatic cancer patients.

Contrast-enhanced US Evaluation of Hepatocellular Carcinoma Response to Chemoembolization: A Prospective Multicenter Trial.

Background Contrast-enhanced (CE) US has been studied for use in the detection of residual viable hepatocellular carcinoma (HCC) after locoregional therapy, but multicenter data are lacking. Purpose To compare two-dimensional (2D) and three-dimensional (3D) CE US diagnostic performance with that of CE MRI or CT, the current clinical standard, in the detection of residual viable HCC after transarterial chemoembolization (TACE) in a prospective multicenter trial. Materials and Methods Participants aged at least 21 years with US-visible HCC scheduled for TACE were consecutively enrolled at one of three participating academic medical centers from May 2016 to March 2022. Each underwent baseline 2D and 3D CE US before TACE, 2D and 3D CE US 1-2 weeks and/or 4-6 weeks after TACE, and CE MRI or CT 4-6 weeks after TACE. CE US and CE MRI or CT were evaluated by three fellowship-trained radiologists for the presence or absence of viable tumors and were compared with reference standards of pathology (18%), angiography on re-treatment after identification of residual disease at 1-2-month follow-up imaging (31%), 4-8-month CE MRI or CT (42%), or short-term (approximately 1-2 months) CE MRI or CT if clinically decompensated and estimated viability was greater than 50% at imaging (9%). Diagnostic performance criteria, including sensitivity and specificity, were obtained for each modality and time point with generalized estimating equation analysis. Results A total of 132 participants were included (mean age, 64 years ± 7 [SD], 87 male). Sensitivity of 2D CE US 4-6 weeks after TACE was 91% (95% CI: 84, 95), which was higher than that of CE MRI or CT (68%; 95% CI: 58, 76; P < .001). Sensitivity of 3D CE US 4-6 weeks after TACE was 89% (95% CI: 81, 94), which was higher than that of CE MRI or CT (P < .001), with no evidence of a difference from 2D CE US (P = .22). CE MRI or CT had 85% (95% CI: 76, 91) specificity, higher than that of 4-6-week 2D and 3D CE US (70% [95% CI: 56, 80] and 67% [95% CI: 53, 78], respectively; P = .046 and P = .023, respectively). No evidence of differences in any diagnostic criteria were observed between 1-2-week and 4-6-week 2D CE US (P > .21). Conclusion The 2D and 3D CE US examinations 4-6 weeks after TACE revealed higher sensitivity in the detection of residual HCC than CE MRI or CT, albeit with lower specificity. Importantly, CE US performance was independent of follow-up time. Clinical trial registration no. NCT02764801 © RSNA, 2023 Supplemental material is available for this article.

Identification of sentinel lymph nodes in esophageal cancer patients using contrast-enhanced EUS with peritumoral injections.

Objectives: The objective of this pilot study was to compare the performance of contrast-enhanced EUS (CE-EUS)-guided fine-needle aspiration (FNA) with EUS-FNA for lymph node (LN) staging in esophageal cancer. Methods: Thirty-seven subjects with esophageal cancer undergoing EUS staging were enrolled, and 30 completed this institutional review board-approved study. A Prosound F75 US system (Hitachi Medical Systems, Tokyo, Japan) with harmonic contrast imaging software and GF-UCT180 curvilinear endoscope (Olympus, Tokyo, Japan) was utilized. All LNs identified by standard EUS were first noted. Sonazoid (dose: 1 mL; GE Healthcare, Oslo, Norway) was administered peritumorally, and all enhanced LNs were recorded. Fine-needle aspiration was performed on LNs considered suspicious by EUS alone, as well as LNs enhanced on CE-EUS. Performance of each modality was compared using FNA cytology as reference standard. Results: A total of 132 LNs were detected with EUS, of which 59 showed enhancement on CE-EUS. Fifty-three LNs underwent FNA, and 22 LNs were determined to be malignant. Among the latter, 10 were considered suspicious by EUS, whereas the other 12 LNs underwent FNA only because of CE-EUS enhancement. Contrast-enhanced EUS showed enhancement in 19 of the 22 malignant LNs. The rate of metastatic node identification from EUS was 45% (10/22), and it was 86% (19/22; P = 0.008) for CE-EUS. Eight subjects (8/30 [27% of study total]) had nodal status upgraded by the addition of CE-EUS, which influenced LN staging and clinical management. Conclusions: Fine-needle aspiration of LNs identified by CE-EUS may increase metastasis positive rate by ruling out LNs not associated with the tumor drainage pattern. In addition, CE-EUS seems to identify more metastatic LNs that would not be biopsied under the standard EUS criteria.

Surmounting Cancer Drug Resistance: New Perspective on RNA-Binding Proteins.

RNA-binding proteins (RBPs), being pivotal elements in both physiological and pathological processes, possess the ability to directly impact RNA, thereby exerting a profound influence on cellular life. Furthermore, the dysregulation of RBPs not only induces alterations in the expression levels of genes associated with cancer but also impairs the occurrence of post-transcriptional regulatory mechanisms. Consequently, these circumstances can give rise to aberrations in cellular processes, ultimately resulting in alterations within the proteome. An aberrant proteome can disrupt the equilibrium between oncogenes and tumor suppressor genes, promoting cancer progression. Given their significant role in modulating gene expression and post-transcriptional regulation, directing therapeutic interventions towards RBPs represents a viable strategy for combating drug resistance in cancer treatment. RBPs possess significant potential as diagnostic and prognostic markers for diverse cancer types. Gaining comprehensive insights into the structure and functionality of RBPs, along with delving deeper into the molecular mechanisms underlying RBPs in tumor drug resistance, can enhance cancer treatment strategies and augment the prognostic outcomes for individuals afflicted with cancer.

Mendelian randomization analysis identified tumor necrosis factor as being associated with severe COVID-19.

Background: Observational studies have shown that anti-tumor necrosis factor (TNF) therapy may be beneficial for patients with coronavirus disease 2019 (COVID-19). Nevertheless, because of the methodological restrictions of traditional observational studies, it is a challenge to make causal inferences. This study involved a two-sample Mendelian randomization analysis to investigate the causal link between nine TNFs and COVID-19 severity using publicly released genome-wide association study summary statistics. Methods: Summary statistics for nine TNFs (21,758 cases) were obtained from a large-scale genome-wide association study. Correlation data between single-nucleotide polymorphisms and severe COVID-19 (18,152 cases vs. 1,145,546 controls) were collected from the COVID-19 host genetics initiative. The causal estimate was calculated by inverse variance-weighted (IVW), MR-Egger, and weighted median methods. Sensitivity tests were conducted to assess the validity of the causal relationship. Results: Genetically predicted TNF receptor superfamily member 6 (FAS) positively correlated with the severity of COVID-19 (IVW, odds ratio = 1.10, 95% confidence interval = 1.01-1.19, p = 0.026), whereas TNF receptor superfamily member 5 (CD40) was protective against severe COVID-19 (IVW, odds ratio = 0.92, 95% confidence interval = 0.87-0.97, p = 0.002). Conclusion: Genetic evidence from this study supports that the increased expression of FAS is associated with the risk of severe COVID-19 and that CD40 may have a potential protective effect against COVID-19.

Anatomy Versus Physiology: Is Breast Lymphatic Drainage to the Internal Thoracic (Internal Mammary) Lymphatic System Clinically Relevant?

Approximately 15%-25% of breast lymphatic drainage passes through the internal thoracic (internal mammary) lymphatic system, draining the inner quadrants of the breast. This study aimed to use lymphosonography to identify sentinel lymph nodes (SLNs) in the axillary and internal thoracic lymphatic systems in patients with breast cancer. Seventy-nine patients received subcutaneous ultrasound contrast agent injections around the tumor. Lymphosonography was used to identify SLNs. In 14 of the 79 patients (17.7%), the tumor was located in the inner quadrant of the breast. Lymphosonography identified 217 SLNs in 79 patients, averaging 2.7 SLNs per patient. The 217 identified SLNs in the 79 patients were located in the axillary lymphatic system; none were located in the internal thoracic (internal mammary) lymphatic system, although it was expected in two to four patients (i.e., 4-11 SLNs). These results implied that SLNs associated with breast cancer are predominantly located in the axillary lymphatic system.

Genetic predisposition to subjective well-being, depression, and suicide in relation to COVID-19 susceptibility and severity.

BACKGROUND: Epidemiological studies have reported associations between subjective well-being (SWB), depression, and suicide with COVID-19 illness, but the causality has not been established. We performed a two-sample Mendelian randomization (MR) analysis to investigate the causal link between SWB, depression, suicide and COVID-19 susceptibility and severity. METHODS: Summary statistics for SWB (298,420 cases), depression (113,769 cases) and suicide (52,208 cases) were obtained from three large-scale GWAS. Data on the associations between the Single Nucleotide Polymorphisms (SNPs) and COVID-19 (159,840 cases), hospitalized COVID-19 (44,986 cases), and severe COVID-19 (18,152 cases) were collected from the COVID-19 host genetics initiative. The causal estimate was calculated by the Inverse Variance Weighted, MR Egger and Weighted Median methods. Sensitivity tests were used to evaluate the validity of the causal relationship. RESULTS: Our results showed that genetically predicted SWB (OR = 0.98, 95 % CI: 0.86-1.10, P = 0.69), depression (OR = 0.76, 95 % CI: 0.54-1.06, P = 0.11), and suicide (OR = 0.99, 95 % CI: 0.96-1.02, P = 0.56) were not causally related to COVID-19 susceptibility. Similarly, we did not find a potential causal relationship between SWB, depression, suicide and COVID-19 severity. CONCLUSIONS: This indicated that positive or negative emotions would not make COVID-19 better or worse, and strategies that attempted to use positive emotions to improve COVID-19 symptoms may be useless. Improving knowledge about the SARS-CoV-2 and timely medical intervention to reduce panic during a pandemic is one of the effective measures to deal with the current decrease in well-being and increase in depression and suicide rates.

Whole-exome and targeted gene sequencing of large-cell lung carcinoma reveals recurrent mutations in the PI3K pathway.

BACKGROUND: Large cell lung carcinoma (LCLC) is an exceptionally aggressive disease with a poor prognosis. At present, little is known about the molecular pathology of LCLC. METHODS: Ultra-deep sequencing of cancer-related genes and exome sequencing were used to detect the LCLC mutational in 118 tumor-normal pairs. The cell function test was employed to confirm the potential carcinogenic mutation of PI3K pathway. RESULTS: The mutation pattern is determined by the predominance of A > C mutations. Genes with a significant non-silent mutation frequency (FDR) < 0.05) include TP53 (47.5%), EGFR (13.6%) and PTEN (12.1%). Moreover, PI3K signaling (including EGFR, FGRG4, ITGA1, ITGA5, and ITGA2B) is the most mutated pathway, influencing 61.9% (73/118) of the LCLC samples. The cell function test confirmed that the potential carcinogenic mutation of PI3K pathway had a more malignant cell function phenotype. Multivariate analysis further revealed that patients with the PI3K signaling pathway mutations have a poor prognosis (P = 0.007). CONCLUSIONS: These results initially identified frequent mutation of PI3K signaling pathways in LCLC and indicate potential targets for the treatment of this fatal type of LCLC.

The alleviative effect of Calendula officinalis L. extract against Parkinson's disease-like pathology in zebrafish via the involvement of autophagy activation.

Introduction: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. However, effective preventative or therapeutic agents for PD remain largely limited. Marigold Calendula officinalis L. (CoL) has been reported to possess a wide range of biological activities, but its neuroprotective activity including anti-neurodegenerative diseases is unclear. Here, we aim to investigate whether the extract of CoL (ECoL) has therapeutic activity on PD. Methods: We identified the chemical composition of flavonoid, an important active ingredient in ECoL, by a targeted HPLC-Q-TOF-MS analysis. Subsequently, we evaluated the anti-PD effect of ECoL by using zebrafish PD model induced by 1-methyl-4-phenyl-1-1,2,3,6-tetrahydropyridine (MPTP). After ECoL+MPTP co-treatments, the changes of dopaminergic neurons, neural vasculature, nervous system, and locomotor activity were examined, respectively. The expressions of genes related to neurodevelopment and autophagy were detected by RT-qPCR. Further, the interaction between autophagy regulators and ECoL flavonoids was predicted using molecular docking method. Results: As a result, 5 kinds of flavonoid were identified in ECoL, consisting of 121 flavones and flavonols, 32 flavanones, 22 isoflavonoids, 11 chalcones and dihydrochalcones, and 17 anthocyanins. ECoL significantly ameliorated the loss of dopaminergic neurons and neural vasculature, restored the injury of nervous system, and remarkably reversed the abnormal expressions of neurodevelopment-related genes. Besides, ECoL notably inhibited the locomotor impairment in MPTP-induced PD-like zebrafish. The underlying anti-PD effect of ECoL may be implicated in activating autophagy, as ECoL significantly upregulated the expressions of genes related to autophagy, which contributes to the degradation of α-synuclein aggregation and dysfunctional mitochondria. Molecular docking simulation showed the stable interaction between autophagy regulators (Pink, Ulk2, Atg7, and Lc3b) and 10 main compounds of flavonoid in ECoL, further affirming the involvement of autophagy activation by ECoL in anti-PD action. Conclusion: Our results suggested that ECoL has the anti-PD effect, and ECoL might be a promising therapeutic candidate for PD treatment.

Efficacy and safety of proton pump inhibitors and H2 receptor antagonists in the initial non­eradication treatment of duodenal ulcer: A network meta­analysis.

The present network meta-analysis aimed to enhance the corresponding evidence with respect to the efficacy and safety of pharmaceuticals treatments. Frequentist network meta-analysis was used. Medical literature up to November 2022 was searched for randomized clinical trials assessing the efficacy and safety of these pharmaceuticals, either compared with each other or compared with placebo. With the exception of ranitidine (300 mg four times daily) and vonoprazan (20 mg once daily) having lower safety than placebo, the efficacy and safety of the remaining treatments were superior to placebo. Cimetidine (400 mg four times daily) and pantoprazole (40 mg once daily) were ranked first in terms of efficacy. The frequentist network meta-analysis shows that for cimetidine (except 400 mg once daily), famotidine, rabeprazole, ilaprazole, lansoprazole (except 7.5 mg once daily) and omeprazole (except 10 mg once daily or 30 mg once daily), the efficacy comparison between the different doses of each of the aforementioned pharmaceuticals did not indicate statistically significant differences. In conclusion, pantoprazole (40 mg once daily) was the best choice for the initial non-eradication treatment of patients with duodenal ulcer, and cimetidine (400 mg twice daily), omeprazole (20 mg once daily), lansoprazole (15 mg once daily), ilaprazole (5 mg once daily) and rabeprazole (10 mg once daily) could be used as the first choice. If the aforementioned pharmaceuticals cannot be prescribed, famotidine (40 mg twice daily) is recommended.

Persistent Lipid Accumulation Leads to Persistent Exacerbation of Endoplasmic Reticulum Stress and Inflammation in Progressive NASH via the IRE1α/TRAF2 Complex.

Non-alcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to other severe liver diseases, yet treatment options are limited. Endoplasmic reticulum (ER) stress is an important pathogenetic mechanism of NASH and plays a key role in tandem steatosis as well as liver inflammation. This study aims to develop a progressive NASH model through sustained lipid accumulation and to elucidate its molecular mechanism through IRE1α/TRAF2 complex. Male SD rats were fed a high-fat diet (HFD) for 4, 8, and 12 weeks to induce progressive NASH. MRNA sequencing and PPI analysis were used to screen core genes. Transmission electron microscopy, immunofluorescence staining, ELISA, qRT-PCR, and Western blotting were used at each time point to compare differences between each index of progressive NASH at 4, 8, and 12 weeks. Sustained lipid accumulation led to structural disruption of the ER, a reduction in ER number, and an increase of lipid droplet aggregation in hepatocytes. Persistent lipid accumulation led to a persistent increase in mRNA and protein expression of the IRE1α/TRAF2 complex, IKK/IκB/NF-κB signaling pathway and ASK1/JNK1 signaling pathway, and TNF-α, IL-1ß, and IL-6 also continued to increase. Persistent lipid accumulation led to a persistent exacerbation of ER stress and inflammation in progressive NASH via the IRE1α/TRAF2 complex.

Improved Tumor Control Following Radiosensitization with Ultrasound-Sensitive Oxygen Microbubbles and Tumor Mitochondrial Respiration Inhibitors in a Preclinical Model of Head and Neck Cancer.

Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of tumor mitochondrial respiration (lonidamine (LND)), which resulted in ultrasound-sensitive microbubbles loaded with O2 and LND providing prolonged oxygenation relative to oxygenated microbubbles alone. This follow-up study aimed to evaluate the therapeutic response to radiation following the administration of oxygen microbubbles combined with tumor mitochondrial respiration inhibitors in a head and neck squamous cell carcinoma (HNSCC) tumor model. The influences of different radiation dose rates and treatment combinations were also explored. The results demonstrated that the co-delivery of O2 and LND successfully sensitized HNSCC tumors to radiation, and this was also enhanced with oral metformin, significantly slowing tumor growth relative to unsensitized controls (p < 0.01). Microbubble sensitization was also shown to improve overall animal survival. Importantly, effects were found to be radiation dose-rate-dependent, reflecting the transient nature of tumor oxygenation.