RESUMEN

BACKGROUND: Nirsevimab is an extended half-life monoclonal antibody (mAb) licensed for the prevention of respiratory syncytial virus (RSV)-associated lower respiratory tract disease in neonates, infants and medically vulnerable children. We characterized RSV isolates recovered from participants enrolled in MEDLEY: a randomized, palivizumab-controlled phase 2/3 trial of nirsevimab in infants born preterm and/or with congenital heart disease or chronic lung disease of prematurity. METHODS: Participants were assessed in two RSV seasons (Season 1 and 2). Season 1 participants were randomized (2:1) to receive a single dose of nirsevimab (50 mg if weight <5 kg or 100 mg if weight ≥5 kg in Season 1; 200 mg in Season 2) followed by four monthly doses of placebo, or five once-monthly doses of palivizumab (15 mg/kg weight per dose). Season 2 participants continued nirsevimab and placebo (nirsevimab/nirsevimab) or were re-randomized (1:1) to switch to nirsevimab (palivizumab/nirsevimab) or continue palivizumab (palivizumab/palivizumab). Cases of RSV infection were identified by central testing of nasal swabs from participants seeking medical attention for respiratory illnesses. Nirsevimab and palivizumab binding site substitutions were assessed via microneutralization assay. RESULTS: Twenty-five cases of confirmed RSV infection were observed during the trial and sequenced: 12 in nirsevimab recipients and 10 in palivizumab recipients during Season 1, and 1 case in each Season 2 group. Molecular sequencing of RSV A (n = 14) isolates detected no nirsevimab binding site substitutions, and 3 palivizumab neutralization-resistant substitutions (Lys272Met, Lys272Thr, Ser275Leu). The nirsevimab binding site Ile206Met:Gln209Arg and Ile206Met:Gln209Arg:Ser211Asn substitutions were the only anti-RSV mAb binding site substitutions detected among RSV B isolates (n = 11). Nirsevimab neutralized all nirsevimab and palivizumab binding site substitutions in RSV A and B isolates recovered from MEDLEY participants. CONCLUSION: No binding site substitution detected during MEDLEY affected RSV susceptibility to nirsevimab neutralization.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Antivirales , Palivizumab , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Humanos , Palivizumab/uso terapéutico , Palivizumab/administración & dosificación , Infecciones por Virus Sincitial Respiratorio/prevención & control , Lactante , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Método Doble Ciego , Masculino , Virus Sincitial Respiratorio Humano/inmunología , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Virus Sincitial Respiratorio Humano/genética , Femenino , Recién Nacido , Anticuerpos Antivirales/inmunología , Preescolar , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre

RESUMEN

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangre , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento/métodos

RESUMEN

Oxidative stress (OS) is a key factor in the generation of various pathophysiological conditions. Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a major transcriptional regulator of antioxidant reactions. Heme oxygenase-1 (HO-1), a gene regulated by Nrf2, is one of the most critical cytoprotective molecules. In recent years, Nrf2/HO-1 has received widespread attention as a major regulatory pathway for intracellular defense against oxidative stress. It is considered as a potential target for the treatment of inflammatory bowel disease (IBD). This review highlights the mechanism of action and therapeutic significance of Nrf2/HO-1 in IBD and IBD complications (intestinal fibrosis and colorectal cancer (CRC)), as well as the potential of phytochemicals targeting Nrf2/HO-1 in the treatment of IBD. The results suggest that the therapeutic effects of Nrf2/HO-1 on IBD mainly involve the following aspects: (1) Controlling of oxidative stress to reduce intestinal inflammation and injury; (2) Regulation of intestinal flora to repair the intestinal mucosal barrier; and (3) Prevention of ferroptosis in intestinal epithelial cells. However, due to the complex role of Nrf2/HO-1, a more nuanced understanding of the exact mechanisms involved in Nrf2/HO-1 is the way forward for the treatment of IBD in the future.

RESUMEN

Adriamycin (ADR) is widely used against breast cancer, but subsequent resistance always occurs. YAP, a downstream protein of angiomotin (AMOT), importantly contributes to ADR resistance, whereas the mechanism is largely unknown. MCF-7 cells and MDA-MB-231 cells were used to establish ADR-resistant cell. Then, mRNA and protein expressions of AMOT and YAP expressions were determined. After AMOT transfection alone or in combination with YAP, the sensitivity of the cells to ADR were evaluated in vitro by examining cell proliferation, apoptosis, and cell cycle, as well as in vivo by examining tumor growth. Additionally, the expressions of proteins in YAP pathway were determined in AMOT-overexpressing cells. In the ADR-resistant cells, the expression of AMOT was decreased while YAP was increased, respectively, and the nucleus localization of YAP was increased at the same time. After AMOT overexpression, these were inhibited, whereas the cell sensitivity to ADR was enhanced. However, the AMOT-induced changes were significantly suppressed by YAP knockdown. The consistent results in vivo showed that AMOT enhanced the inhibition of ADR on tumor growth, and inhibited YAP signaling, evidenced by decreased levels of YAP, CycD1, and p-ERK. Our data revealed that decreased AMOT contributed to ADR resistance in breast cancer cells, which was importantly negatively mediated YAP. These observations provide a potential therapy against breast cancer with ADR resistance.

Asunto(s)

Angiomotinas , Apoptosis , Neoplasias de la Mama , Proliferación Celular , Doxorrubicina , Resistencia a Antineoplásicos , Ratones Desnudos , Proteínas Señalizadoras YAP , Humanos , Doxorrubicina/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Células MCF-7 , Proteínas Señalizadoras YAP/metabolismo , Animales , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ratones Endogámicos BALB C , Antibióticos Antineoplásicos/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas de Microfilamentos/metabolismo , Proteínas de Microfilamentos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ciclo Celular/efectos de los fármacos

RESUMEN

Objective: To identify the gut bacteria associated with chemotherapeutic outcomes, t characterized the gut microbiota in patients with esophageal squamous cell carcinoma (ESCC) in this prospective study. Design: Thirty-one patients with ESCC were enrolled. Chemotherapy was performed with paclitaxel and cisplatin (TP). Fecal samples were collected before and after treatment and analyzed using 16S rRNA sequencing. Results: The species with differences in baseline abundance between partial response (PR) and non-PR groups was identified as Bacteroides plebeius (P = 0.043). The baseline abundance of B. plebeius was higher in the responder (R, PR + stable disease (SD)) group (P = 0.045) than in the non-responder (NR). The abundance of B. ovatus was identified as a predictor for distinguishing patients with PR from those without PR (sensitivity, 83.3 %; specificity, 69.6 %). The abundance of B. plebeius was positively associated with the response to PR + SD (R) in predicting responders in the receiver operating characteristic (ROC) curve analysis (area under the ROC curve = 0.865, P = 0.041). The abundance of B. plebeius and B.uniform was a predictor of grade (G) 3-4 chemotherapy toxicities. The sensitivity and specificity of the established multi-analyte microbial predictive model demonstrated a better predictive ability than a single parameter (B. uniform or B. plebeius). Conclusion: The abundance of gut microbiota B. plebeius and B. ovatus are associated with the efficacy of TP chemotherapy in patients with ESCC. The abundance of B. plebeius and B.uniform may related to the toxicity of TP chemotherapy.

RESUMEN

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Ginsenoside may be an ideal agent for UC treatment. However, its efficacy and safety are unknown. We aim to conduct a systematic evaluation to assess the effects and potential mechanisms of ginsenosides in animal models of UC. METHODS: Six electronic databases will be searched (PubMed, Embase, Web of Science, China Knowledge Network (CNKI), China Science and Technology Journal Database (CQVIP), and Wanfang Data Knowledge). SYRCLE list will be used to assess the quality of literature, and STATA 15.1 for data analysis. Time-dose effects analysis will be used to reveal the time-dosage response relations between ginsenosides and UC. RESULTS: Ultimately, fifteen studies involving 300 animals were included. Preliminary evidence was shown that ginsenosides could reduce Disease Activity Index (DAI) scores, weight loss, histological colitis score (HCS), spleen weight, Malondialdehyde (MDA), Myeloperoxidase (MPO) activity, interleukin-1ß (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and increase colon length (CL), myeloperoxidase (GSH), interleukin 4 (IL-4), interleukin 10 (IL-10), Zonula Occludens-1 (ZO-1) and occludin. Results of time-dose interval analysis indicated that ginsenosides at a dosage of 5-200 mg/kg with an intervention time of 7-28 days were relatively effective. CONCLUSIONS: Preclinical evidence suggests that ginsenoside is a novel treatment for UC. And the mechanisms of ginsenosides in treating UC may involve anti-inflammatory, antioxidant, barrier protection, intestinal flora regulation, and immune regulation. Although, due to the high heterogeneity, further large-scale and high-quality preclinical studies are needed to examine the protection of ginsenosides against UC.

RESUMEN

OBJECTIVE: To analyze the efficacy and adverse effects of anti-PD-1 immune checkpoint inhibitors aimed at nasopharyngeal carcinoma (NPC). METHODS: During the first stage of the study, using 40 patients with stage III/IVa NPC treated with anti-PD-1 immune checkpoint inhibitors in combination with chemoradiotherapy as a first-line treatment (observation group) and 70 patients with NPC treated with chemoradiotherapy alone (control group). In the second stage of the study, 88 patients with NPC treated with immune checkpoint inhibitors were grouped according to the number of lines of immunotherapy, the number of times, and the types of application. RESULTS: Observation of the short-term effects in the first stage indicated that the objective response rate (ORR) of the observation group and the control group against primary foci of NPC was 75.0% versus 40.0%; the mortality rate of the observation group was much lower than that of the control group. The overall first-line treatment evaluation of the observation vs. control groups were as follows: ORR (67.5% vs. 38.6%); median PFS (17.52 vs. 17.21 months); and median OS (18.68 vs. 18.14 months), respectively (p < 0.05). The second stage of the study had an ORR of 53.4%, and the efficacy of immunotherapy was related to staging, timing, and frequency. CONCLUSION: Anti-PD-1 immune checkpoint inhibitors combined with chemoradiotherapy as the first-line treatment for nasopharyngeal carcinoma may improve patient outcomes significantly. Timing, frequency, and the type of immunotherapy exerted an effect on the efficacy of immunotherapy. Adverse effects that occurred during treatment were tolerable and controllable.

Asunto(s)

Quimioradioterapia , Inhibidores de Puntos de Control Inmunológico , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Receptor de Muerte Celular Programada 1 , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/mortalidad , Adulto , Anciano , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estadificación de Neoplasias , Resultado del Tratamiento , Adulto Joven

RESUMEN

Ulcerative colitis (UC), a subtype of inflammatory bowel disease, manifests with symptoms such as abdominal pain, diarrhea, and mucopurulent, bloody stools. The pathogenesis of UC is not fully understood. At present, the incidence of UC has increased significantly around the world. Conventional therapeutic arsenals are relatively limited, with often poor efficacy and many adverse effects. In contrast, traditional Chinese medicine (TCM) holds promise due to their notable effectiveness, reduced recurrence rates, and minimal side effects. In recent years, significant progress has been made in the basic research on TCM for UC treatment. It has been found that the inhibition of ferroptosis through the intervention of TCM can significantly promote intestinal mucosal healing and reverse UC. The mechanism of action involves multiple targets and pathways. Aim of the review: This review summarizes the experimental studies on the targeted regulation of ferroptosis by TCM and its impact on UC in recent years, aiming to provide theoretical basis for the prevention, treatment, and further drug development for UC. Results: Ferroptosis disrupts antioxidant mechanisms in intestinal epithelial cells, damages the intestinal mucosa, and participates in the pathological process of UC. TCM acts on various pathways such as Nrf2/HO-1 and GSH/GPX4, blocking the pathological progression of ferroptosis in intestinal epithelial cells, inhibiting pathological damage to the intestinal mucosa, and thereby alleviating UC. Conclusion: The diverse array of TCM single herbs, extracts and herbal formulas facilitates selective and innovative research and development of new TCM methods for targeting UC treatment. Although progress has been made in studying TCM compound formulas, single herbs, and extracts, there are still many issues in clinical and basic experimental designs, necessitating further in-depth scientific exploration and research.

RESUMEN

Objective: To investigate the correlation between programmed death ligand 1(PD-L1), tumor mutation burden (TMB) and the short-term efficacy and clinical characteristics of anti-PD-1 immune checkpoint inhibitor combination chemotherapy in NSCLC patients. The efficacy of the prediction model was evaluated. Methods: A total of 220 NSCLC patients receiving first-line treatment with anti-PD-1 immune checkpoint inhibitor combined with chemotherapy were retrospectively collected. The primary endpoint was short-term efficacy ORR. The correlation between short-term efficacy, PD-L1, TMB, and clinical characteristics using χ2 test or t-test was evaluated. Screen the independent prognostic factors using univariate and multivariate logistic regression analyses, and construct a nomogram prediction model using the "rms" package in R software. Using receiver operating characteristic (ROC) curve analysis to evaluate the independent Prognostic factors and the prediction model. Using decision curve analysis (DCA) to verify the superiority of the prediction model. Results: The mean values of PD-L1, TMB, neutrophils, lymphocytes, neutrophil-to-lymphocyte ratio, and albumin were the highest in the ORR group, PD-L1 expression and TMB correlated with epidermal growth factor receptor expression. Multivariate analyses showed that PD-L1, TMB, and neutrophil were independent prognostic factors for ORR. The area under the ROC curve (AUC) values of the ROC constructed based on these three indicators were 0.7104, 0.7139, and 0.7131, respectively. The AUC value under the ROC of the nomogram model was 0.813. The DCA of the model showed that all three indicators used together to build the prediction model of the net return were higher than those of the single indicator prediction model. Conclusion: PD-L1, TMB, and neutrophils are independent prognostic factors for short-term efficacy. The nomogram prediction model constructed using these three indicators can further improve predictive efficacy of ICIs in patients with NSCLC.

RESUMEN

Although PD-1 inhibitors have revolutionized the treatment paradigm of non-small cell lung cancer (NSCLC), their efficacy in treating NSCLC has remained unsatisfactory. Targeting cancer-associated fibroblasts (CAFs) is a potential approach for improving the immunotherapy response. Multitarget antiangiogenic tyrosine kinase receptor inhibitors (TKIs) can enhance the efficacy of PD-1 inhibitors in NSCLC patients. However, the effects and mechanisms of antiangiogenic TKIs on CAFs have not been elucidated. In this study, we first compared anlotinib with other antiangiogenic TKIs and confirmed the superior efficacy of anlotinib. Furthermore, we established NSCLC-associated CAF models and found that anlotinib impaired CAF viability and migration capacity and contributed to CAF apoptosis and cell cycle arrest in the G2/M phase. Moreover, anlotinib treatment attenuated the capacity of CAFs to recruit lung cancer cells and macrophages. Experiments in animal models suggested that anlotinib could enhance the efficacy of anti-PD1 therapy in NSCLC and affect CAF proliferation and apoptosis. Anlotinib increased the abundance of tumor-infiltrating CD8 + T cells, and PD-1 inhibitor-induced cytotoxicity to tumor cells was achieved through the transformation of the tumor microenvironment (TME) caused by anlotinib, which may partly explain the synergistic antitumor effect of anlotinib and PD-1 inhibitors. Mechanistically, anlotinib affects CAF apoptosis and cell viability at least in part by inhibiting the AKT pathway. In conclusion, our study suggested that anlotinib could regulate the TME, inhibit the AKT pathway and promote CAF apoptosis, providing new insights into the antitumor effect of anlotinib and improving the efficacy of immunotherapy.

Asunto(s)

Adenocarcinoma del Pulmón , Apoptosis , Indoles , Neoplasias Pulmonares , Receptor de Muerte Celular Programada 1 , Proteínas Proto-Oncogénicas c-akt , Quinolinas , Quinolinas/farmacología , Quinolinas/uso terapéutico , Animales , Indoles/farmacología , Indoles/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Ratones , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Ratones Endogámicos BALB C , Sinergismo Farmacológico

RESUMEN

In this research, interactions between α-lactalbumin (ALA) and three protopanaxadiol ginsenosides [20(S)-Rg3, 20(S)-Rh2, and 20(S)-PPD] were compared to explore the effects of similar ligand on structure and cytotoxicity of ALA. Multi-spectroscopy revealed the binding between ALA and ginsenoside changed the conformation of ALA, which related to different structures and solubility of ligands. Scanning electron microscope illustrated that all ALA-ginsenoside complexes exhibited denser structures via hydrophobic interactions. Additionally, the cytotoxic experiments confirmed that the cytotoxicity of ginsenoside was enhanced after binding with ALA. Molecular docking showed all three ginsenosides were bound to the sulcus depression region of ALA via hydrogen bonding and hydrophobic interaction. Furthermore, molecular dynamics simulation elucidated the precise binding sites and pertinent system properties. Among all three composite systems, 20(S)-Rh2 had optimal binding affinity. These findings enhanced understanding of the synergistic utilization of ALA and ginsenosides as functional ingredients in food, medicine, and cosmetics.

Asunto(s)

Ginsenósidos , Sapogeninas , Ginsenósidos/farmacología , Ginsenósidos/química , Lactalbúmina , Simulación del Acoplamiento Molecular , Sapogeninas/química , Sapogeninas/farmacología

RESUMEN

Background: Co-occurrence of breast cancer and non-Hodgkin's lymphoma is a rare condition with diagnostic and therapeutic challenges. The coexistence of follicular lymphoma (FL) and triple-negative breast cancer (TNBC) has not been described previously. Case Presentation: A 46-year-old woman, already suffering a history of untreated, advanced-stage, high tumor burden FL, was admitted for a rapidly progressing right breast mass. Ultrasonography showed an 8.3 × 3.6 × 4.1 cm fungating mass in the right breast with enlarged lymph nodes (LNs) in bilateral axillae. PET-CT demonstrated increased 18F- FDG activity in right breast mass, LNs on both sides of the diaphragm, enlarged spleen, and bone marrow. Biopsy of the right breast mass revealed TNBC. The patient underwent neoadjuvant therapy with R-CHOP and achieved partial response of breast tumor. However, TNBC progressed after three cycles of R-CHOP. According to the next-generation sequencing (NGS) assay on breast mass showing a homologous recombination repair (HRR) deficiency (HRD) score of 72, the neoadjuvant regimen was changed to rituximab plus nab-paclitaxel and cisplatin (R-TP) and resulted in significant tumor regression. The patient then underwent right mastectomy with an axillary LN dissection. After the surgery, she was regularly monitored and given adjuvant therapy with R-TP and radiotherapy. Conclusion: The coexistence of FL and HRD-positive TNBC poses diagnostic and treatment challenges. Well-founded neoadjuvant strategy based on multidisciplinary team (MDT) discussion and NGS warranted a good outcome in this case.

RESUMEN

Adenine base editors (ABEs) are genome-editing tools that have been harnessed to introduce precise A•T to G•C conversion. The discovery of split genes revealed that all introns contain two highly conserved dinucleotides, canonical "AG" (acceptor) and "GT" (donor) splice sites. ABE can directly edit splice acceptor sites of the adenine (A) base, leading to aberrant gene splicing, which may be further adopted to remodel splicing. However, spliced isoforms triggered with ABE have not been well explored. To address it, we initially generated a cell line harboring C-terminal enhanced GFP (eGFP)-tagged ß-actin (ACTB), in which the eGFP signal can track endogenous ß-actin expression. Expectedly, after the editing of splice acceptor sites, we observed a dramatical decrease in the percentage of eGFP-positive cells and generation of splicing products with the noncanonical splice site. Furthermore, we manipulated Peroxidasin in mouse embryos with ABE, in which a noncanonical acceptor was activated to remodel splicing, successfully generating a mouse disease model of anophthalmia and severely malformed microphthalmia. Collectively, we demonstrate that ABE-mediated splicing remodeling can activate a noncanonical acceptor to manipulate human and mouse genomes, which will facilitate the investigation of basic and translational medicine studies.

Asunto(s)

Adenina , Sitios de Empalme de ARN , Animales , Humanos , Ratones , Actinas/genética , Secuencia de Bases , Edición Génica , Intrones , Empalme del ARN , Células HEK293

RESUMEN

BACKGROUND: There are no standard third-line treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC). Trametinib in combination with hydroxychloroquine (HCQ) or CDK4/6 inhibitors for pancreatic adenocarcinoma showed promising efficacy in preclinical studies. However, the regimens have not been well examined in patients with mPDAC. METHODS: Patients with mPDAC who received the combination of trametinib and HCQ or CDK4/6 inhibitors as third- or later-line therapy were reviewed. The efficacy and prognosis were further analyzed. RESULTS: A total of 13 mPDAC patients were enrolled, of whom 8 and 5 patients were treated with trametinib plus HCQ or a CDK4/6 inhibitor (palbociclib or abemaciclib), respectively. All enrolled patients had either KRAS G12D or G12V mutations and had received a median of 3 prior lines of therapy (range, 2-6). The median trametinib treatment duration was 1.4 months. Of the 10 patients with measurable disease, only 1 patient achieved stable disease, and the remaining patients had progressive disease. Moreover, in patients treated with trametinib plus HCQ and a CDK4/6 inhibitor, the median progression-free survival was 2.0 and 2.8 months, respectively, and the median overall survival was 4.2 and 4.7 months, respectively. Moreover, 5 (50%) patients experienced grade 3-4 adverse events in 10 patients with available safety data. CONCLUSIONS: The combination of trametinib and HCQ or CDK4/6 inhibitors may not be an effective later-line treatment for mPDAC, and the current preliminary findings need to be confirmed by other studies with larger sample sizes.

Asunto(s)

Adenocarcinoma , Antineoplásicos , Hidroxicloroquina , Neoplasias Pancreáticas , Inhibidores de Proteínas Quinasas , Humanos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quimioterapia Combinada , Hidroxicloroquina/administración & dosificación , Hidroxicloroquina/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Pancreáticas

RESUMEN

BACKGROUND: Therapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response. Here, we comprehensively assess the molecular characterization of EHCC with clinical implications. METHODS: Whole-exome sequencing (WES) on 37 tissue samples of EHCC were performed to evaluate genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS: Mutation of KRAS (16%) was significantly correlated to poor OS. ERBB2 mutation was associated with improved OS. ERBB2, KRAS, and ARID1A were three potentially actionable targets. TMB ≥10 mutations per megabase was detected in 13 (35.1%) cases. Six patients (16.2%) with MSIsensor scores ≥10 were found. In multivariate Cox analysis, patients with MSIsensor sore exceed a certain threshold (MSIsensor score ≥0.36, value approximately above the 20th percentile as thresholds) showed a significant association with the improved OS (HR = 0.16; 95% CI: 0.056-0.46, p < 0.001), as well as patients with both TMB ≥3.47 mutations per megabase (value approximately above the 20th percentile) and MSIsensor score ≥0.36. CONCLUSIONS: TMB and MSI are potential biomarkers associated with better prognosis for EHCC patients. Furthermore, our study highlights important genetic alteration and potential therapeutic targets in EHCC.

Asunto(s)

Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Inhibidores de Puntos de Control Inmunológico , Proteínas Proto-Oncogénicas p21(ras)/genética , Pronóstico , Colangiocarcinoma/genética , Mutación , Biomarcadores de Tumor/genética , Inestabilidad de Microsatélites , Conductos Biliares Intrahepáticos , Neoplasias de los Conductos Biliares/genética

RESUMEN

OBJECTIVE: Gemcitabine plus nab-paclitaxel (GnP) is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC). S-1, an oral fluoropyrimidine derivative, as compared with gemcitabine, is non-inferior in terms of overall survival (OS) and is associated with lower hematologic toxicity. Accordingly, S-1 is a convenient oral alternative treatment for advanced PDAC. This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1 (GS) vs. GnP as first-line chemotherapy for advanced PDAC. METHODS: Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated. RESULTS: A total of 300 patients were assessed, of whom 84 received GS and 216 received GnP. The chemotherapy completion rate was higher with GS than GnP (50.0% vs. 30.3%, P = 0.0028). The objective response rate (ORR) was slightly higher (14.3% vs. 9.7%, P = 0.35), and the median OS was significantly longer (17.9 months vs. 13.3 months, P = 0.0078), in the GS group than the GnP group. However, the median progression-free survival (PFS) did not significantly differ between groups. Leukopenia risk was significantly lower in the GS group than the GnP group (14.9% vs. 28.1%, P = 0.049). CONCLUSIONS: As first-line chemotherapy for advanced PDAC, the GS regimen led to a significantly longer OS than the GnP regimen. The PFS, ORR, and incidence of severe adverse events were comparable between the GS and GnP groups.

Asunto(s)

Adenocarcinoma , Gemcitabina , Humanos , Desoxicitidina/efectos adversos , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Paclitaxel , Neoplasias Pancreáticas

RESUMEN

BACKGROUND: The adoption of molecular profiling in non-small cell lung cancers (NSCLC) have promoted the discoveries of novel anaplastic lymphoma kinase (ALK) mutation patterns including rare intergenic rearrangements. It is always meaningful to report the structure of these fusions and their responses to ALK-inhibitors for future reference. Reports of cerebral ischemic strokes caused by atrial metastases through lymphohematogeneous spread are scarce. CASE PRESENTATION: A 35-year-old woman with no history of astherosclerosis presented with sudden onset of diplopia and facial palsy. Brain MRI scan discovered multiple infarcts around cortical and subcortical areas supplied by bilateral middle cerebral arteries, the occlusions of which were confirmed by angiography. Echocardiogram revealed intracavity appendages in atriums. The histology following valve debridement displayed endocardial metastases from lung cancer on mitral and trucuspid valves. PET/CT found right lower lobe primary tumor and mediastinal lymphadenopathies. The histology of primary lung tumor suggested adenocarcinoma and a DNA-based next-generation sequencing (NGS) test uncovered an intergenic (FAM49A, RAD51AP2)-ALK (intergenic: A14) rearrangement. Further RNA-based NGS uncovered a novel SLC34A2-ALK (exon 1: exon 15) fusion. Strokes recurred after valve surgery and vegetations reappeared on the mitral valve. Alectinib 600 mg bid was administered based on molecular finding and achieved remarkable tumor regression. Neurologic symptoms were largely relieved. No new infarctions or cerebral metastases has ever been found since. CONCLUSIONS: We report a novel SLC34A2-ALK rearrangement responding well to alectinib in a very interesting case of peripheral lung adenocarcinoma presenting with recurrent cerebral ischemic strokes due to endocardial metastases.

Asunto(s)

Fibrilación Atrial , Carcinoma de Pulmón de Células no Pequeñas , Accidente Cerebrovascular Isquémico , Neoplasias Pulmonares , Accidente Cerebrovascular , Femenino , Humanos , Adulto , Quinasa de Linfoma Anaplásico/genética , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Tomografía Computarizada por Tomografía de Emisión de Positrones , Recurrencia Local de Neoplasia , Carcinoma de Pulmón de Células no Pequeñas/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb

RESUMEN

INTRODUCTION: Depression is considered a prodromal state of Alzheimer's disease (AD), yet the underlying mechanism(s) by which depression increases the risk of AD are not known. METHODS: Single-nucleotide polymorphism (SNP) analysis was used to determine the CALHM2 variants in AD patients. Cellular and molecular experiments were conducted to investigate the function of CALHM2 V136G mutation. We generated a new genetically engineered Calhm2 V136G mouse model and performed behavioral tests with these mice. RESULTS: CALHM2 V136G mutation (rs232660) is significantly associated with AD. V136G mutation resulted in loss of the CALHM2 ATP-release function in astrocytes and impaired synaptic plasticity. Mice homozygous for the Calhm2 V136G allele displayed depressive-like behaviors that were rescued by administration of exogenous ATP. Moreover, Calhm2 V136G mutation predisposed mice to cognitive decline in old age. DISCUSSION: CALHM2 dysfunction is a biologically relevant mechanism that may contribute to the observed clinical correlation between depression and AD.

RESUMEN

BACKGROUND: Patients with advanced pancreatic ductal adenocarcinoma (PDAC) need timely medical assistance since the emergence of complications due to the disease and antitumor treatment. Studies have confirmed that instant messaging can improve the quality of life and compliance of cancer patients. However, the prognostic role of instant doctor-patient communication based on instant messaging applications in PDAC has not been studied. METHODS: Patients with PDAC who received first-line chemotherapy at Peking Union Medical College Hospital between January 2015 and October 2022 were reviewed. We categorized patients into two groups according to whether they received WeChat-based instant doctor-patient communication, and the prognosis and toxicity data between the two groups were compared. RESULTS: A total of 431 PDAC patients were enrolled, of whom 163 had long-term instant communication with their doctors based on WeChat, and 268 did not receive WeChat-based instant communication. There was no significant correlation between WeChat-based communication and first-line chemotherapy overall response rate (14.1% vs. 8.6%, p = 0.074), incidence of grade ≥ 3 adverse events (66.9% vs. 65.7%, p = 0.814) or overall survival (14.7 vs. 13.9 months, p = 0.170) in all enrolled patients. However, patients who received WeChat-based instant communication had a higher completion rate of first-line chemotherapy (42.0% vs. 30.7%, p = 0.023). Consistently, in the patients who developed grade ≥ 3 adverse events (n = 231), those who received WeChat-based instant communication had significantly longer overall survival (17.3 vs. 15.3 months, p = 0.018), even after adjustment for biases. CONCLUSIONS: WeChat-based instant doctor-patient communication demonstrated no superiority in improving the efficacy of chemotherapy or preventing chemotherapy toxicity in PDAC patients, but it may contribute to improving the completion rate of chemotherapy and the prognosis in patients who experienced severe adverse events. IMPLICATIONS FOR CANCER SURVIVORS: Instant doctor‒patient communication may help to timely and appropriately deal with adverse events and prolong the survival time of patients with PDAC, supporting the promotion of mobile technology in clinical practice.

RESUMEN

High altitude exposure leads to various cognitive impairments. The cerebral vasculature system plays an integral role in hypoxia-induced cognitive defects by reducing oxygen and nutrition supply to the brain. RNA N6-methyladenosine (m6A) is susceptible to modification and regulates gene expression in response to environmental changes, including hypoxia. However, the biological significance of m6A in endothelial cell performance under hypoxic conditions is unknown. Using m6A-seq, RNA immunoprcipitation-seq, and transcriptomic co-analysis, the molecular mechanism of vascular system remodeling under acute hypoxia is investigated. A novel m6A reader protein, proline-rich coiled-coil 2B (PRRC2B), exists in endothelial cells. PRRC2B knockdown promoted hypoxia-induced endothelial cell migration by regulating alternative splicing of the alpha 1 chain of collagen type XII in an m6A-dependent manner and the decay of matrix metallopeptidase domain 14 and ADAM metallopeptidase domain 19 mRNA in an m6A-independent manner. In addition, conditional knockout of PRRC2B in endothelial cells promotes hypoxia-induced vascular remodeling and cerebral blood flow redistribution, thus alleviating hypoxia-induced cognitive decline. Therefore, PRRC2B is integral in the hypoxia-induced vascular remodeling process as a novel RNA-binding protein. These findings provide a new potential therapeutic target for hypoxia-induced cognitive decline.

Asunto(s)

Células Endoteliales , Remodelación Vascular , Ratones , Animales , ARN , Hipoxia , Metaloproteasas