The efficacy and safety of adding PD-1 blockade to induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) for locoregionally advanced nasopharyngeal carcinoma: an observational, propensity score-matched analysis.

BACKGROUND: Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC  plus cisplatin CCRT ) for LANPC patients. METHODS: From January 2020 to November 2022, 347 patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0) were included. Of the 347 patients, 268 patients were treated with standard treatment (IC-CCRT), and 79 received PD-1 blockade plus IC-CCRT (PD-1 group). For the PD-1 group, PD-1 blockade was given intravenously once every 3 weeks for up to 9 cycles (3 induction and 6 adjuvant). The primary endpoint was disease-free survival (DFS) (i.e. freedom from local/regional/distant failure or death). The propensity score matching (PSM) with the ratio of 1:2 was performed to control confounding factors. RESULTS: After PSM analysis, 150 patients receiving standard treatment and 75 patients receiving additional PD-1 blockade remained in the current analysis. After three cycles of IC, the PD-1 group had significantly higher rates of complete response (defined as disappearance of all target lesions; 24% vs. 9%; P = 0.006) and complete biological response (defined as undetectable cell-free Epstein-Barr virus DNA, cfEBV DNA; 79% vs. 65%; P = 0.046) than that in the standard group. And the incidence of grade 3-4 toxicity during IC was 47% in the PD-1 group and 41% in the standard group, with no significant difference (P = 0.396). During follow-up period, additional PD-1 blockade to standard treatment improved 3-year DFS from 84 to 95%, with marginal statistical significance (HR, 0.28; 95%CI, 0.06-1.19; P = 0.064). CONCLUSION: Additiaonl PD-1 blockade to gemcitabine and cisplatin IC and adjuvant treatment results in significant improvement in tumor regression, cfEBV DNA clearance, superior DFS, and comparable toxicity profiles in high-risk LANPC patients.

m6A modification promotes EMT and metastasis of castration-resistant prostate cancer by upregulating NFIB.

The widespread use of androgen receptor (AR) signaling inhibitors has led to an increased incidence of AR-negative castration-resistant prostate cancer (CRPC), limiting effective treatment and patient survival. A more comprehensive understanding of the molecular mechanisms supporting AR-negative CRPC could reveal therapeutic vulnerabilities to improve treatment. This study showed that the transcription factor nuclear factor I/B (NFIB) was upregulated in AR-negative CRPC patient tumors and cell lines and was positively associated with an epithelial-to-mesenchymal transition (EMT) phenotype. Loss of NFIB inhibited EMT and reduced migration of CRPC cells. NFIB directly bound to gene promoters and regulated the transcription of EMT-related factors E-cadherin and vimentin, independently of other typical EMT-related transcriptional factors. In vivo data further supported the positive role of NFIB in the metastasis of AR-negative CRPC cells. Moreover, N6-methyladenosine (m6A) modification induced NFIB upregulation in AR-negative CRPC. Mechanistically, the m6A levels of mRNA, including NFIB and its E3 ubiquitin ligase TRIM8, were increased in AR-negative CRPC cells. Elevated m6A methylation of NFIB mRNA recruited YTHDF2 to increase mRNA stability and protein expression. Inversely, the m6A modification of TRIM8 mRNA, induced by ALKBH5 downregulation, decreased its translation and expression, which further promoted NFIB protein stability. Overall, this study reveals that upregulation of NFIB, mediated by m6A modification, triggers EMT and metastasis in AR-negative CRPC. Targeting the m6A/NFIB axis is a potential prevention and treatment strategy for AR-negative CRPC metastasis.

Protection of Barrier Function in Cultured Human Corneal Epithelial Cells by Semaphorin 4D.

PURPOSE: Corneal epithelial barrier function is important to maintain corneal homeostasis and is impaired by inflammation. We aimed to investigate the localization of semaphorin 4D (Sema4D) in the cornea, and its effects on the barrier function of cultured corneal epithelial cells. METHODS: The expressions of semaphorin4 D and its receptor in the murine cornea were examined by immunoblot, immunofluorescent staining and confocal microscopy observations. Human corneal epithelial (HCE) cells stimulated by TNF-α or IL-1ß were cultured with or without Sema4D. Cell viability was examined by CCK8, cell migration was evaluated by scratch wound assay, and barrier function was assessed by transepithelial electrical resistance (TEER) and Dextran-FITC permeability assay. The expression of tight junction proteins in HCE cells was examined by immunoblot, immunofluorescent staining and qRT-PCR. RESULTS: We demonstrated that the protein of Sema4D and its receptor, plexin-B1, was expressed in murine cornea. Sema4D induced an increase in the TEER and a decrease in the permeability of HCE cells. It also induced the expression of tight junction protein ZO-1, occludin and claudin-1 in HCE cells. Furthermore, under stimulation of TNF-α or IL-1ß, Sema4D treatment could inhibit the decreased TEER and the elevated permeability of HCE cells. CONCLUSIONS: Sema4D is located distinctly in corneal epithelial cells and promoted their barrier function by increasing the expression of tight junction proteins. Sema4D may act as a preventive for maintaining corneal epithelial barrier function during ocular inflammation.

Concurrent chemoradiotherapy with or without neoadjuvant chemotherapy in pediatric patients with stage III-IVa nasopharyngeal carcinoma: a real-world propensity score-matched cohort study.

OBJECTIVES: To compare neoadjuvant chemotherapy (NAC) plus concurrent chemoradiotherapy (CCRT) to CCRT alone in children and adolescents (age ≤ 18 years) with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC, stage III-IVA). MATERIALS AND METHODS: 195 CA-LANPC patients who were treated through CCRT with or without NAC between 2008 and 2018 were enrolled in this study. A matched cohort composed of CCRT patients and NAC-CCRT patients was generated by propensity score matching (PSM) at a 1:2 ratio. Survival outcomes and toxicities were compared between the CCRT group and NAC-CCRT group. RESULTS: Of the 195 patients, 158 (81%) received NAC plus CCRT, and 37 (19%) received CCRT alone. The NAC-CCRT group had higher EBV DNA levels (≥ 4000 copy/mL), more advanced TNM stage (stage IV disease), and lower incidence of a high radiation dose (> 6600 cGy) than the CCRT group. To avoid bias in treatment selection within retrospectively analysis, 34 patients from the CCRT group were matched with 68 patients from the NAC-CCRT group. In the matched cohort, the 5-year DMFS rate was 94.0% in the NAC-CCRT group versus 82.4% in the CCRT group, with marginal statistical significance (HR = 0.31; 95%CI 0.09-1.10; P = 0.055). During treatment, the accumulate incidence of severe acute toxicities (65.8% vs 45.9%; P = 0.037) in the NAC-CCRT group was higher than the CCRT group. However, the CCRT group had significantly higher accumulate incidence of severe late toxicities (30.3% vs 16.8%; P = 0.041) than the NAC-CCRT group. CONCLUSIONS: Addition of NAC to CCRT tended to improve long-term DMFS in CA-LANPC patients with acceptable toxicity. However, relative randomized clinical trial is still needed in the future.

Quantitative immunohistochemistry (IHC) analysis of biomarker combinations for human esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous carcinoma (ESCC) is one of the most common cancers in developing countries. However, currently there are no specific biomarkers for ESCC. This study evaluated the expression of proliferating cell nuclear antigen (PCNA), tumor suppressor protein p53, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) as biomarkers for ESCC. METHODS: This study included 60 clinical cases (30 ESCC and 30 non-ESCC cases that were confirmed pathologically). The expression of PCNA, p53, EGFR, and VEGF were investigated using a quantitative computerized immunohistochemistry (IHC) method. The expression level of each protein was indicated by a H-score from the quantitative analysis. Receiver operating characteristic curve (ROC) and area under curve (AUC) analyses were performed. The sensitivity and specificity of each individual protein and combinations of the proteins were calculated. RESULTS: The H-score analysis indicated that expressions of EGFR, PCNA, and VEGF were statistically significantly higher in ESCC than non-ESCC patients; however, p53 was not. The panels of combinations of these proteins were more sensitive than that of any single protein. In the triplicate combination, the AUC prediction probability increased to 0.86, while the single protein AUC prediction probabilities were 0.74 (EGFR), 0.80 (PCNA), and 0.70 (VEGF). CONCLUSIONS: The high expression of PCNA, EGFR, and VEGF suggests that they are potential biomarkers for ESCC. The combination of these biomarkers may provide targets for molecular therapy and molecular imaging.

Concomitant corticosteroid nasal spray plus antihistamine (oral or local spray) for the symptomatic management of allergic rhinitis.

The purpose of this study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the symptomatic management of corticosteroid nasal spray plus antihistamine (oral or local spray) with that of either therapy given alone, or placebo in patients with allergic rhinitis (AR). The PRISMA guidelines for meta-analysis reporting were followed. Total nasal symptom scores and individual nasal symptom scores were pooled after assessing heterogeneity among studies. The pooled estimates were expressed as weighted mean differences (WMD) between treatments. A total of ten studies fulfilled eligibility. Three trials studied the combination therapy of corticosteroid nasal spray and oral antihistamine. Pooled results of two trials failed to show significant difference on total nasal symptoms between combination therapy and intranasal corticosteroid alone (WMD = -0.20, 95 % CI -0.38 to -0.01, P = 0.04). The qualitative analysis showed that combination therapy has greater efficacy than oral antihistamines alone or placebo in improving symptoms. Seven trials investigated corticosteroid nasal spray plus antihistamine nasal spray. The cumulative meta-analysis of six RCTs revealed that combination therapy was superior to solo intranasal corticosteroid (WMD = -1.16, 95 % CI -1.49 to -0.83, P < 0.00001), solo intranasal antihistamine (WMD = -1.73, 95 % CI -2.08 to -1.38, P < 0.00001), and placebo (WMD = -2.81, 95 % CI -3.16 to -2.47, P < 0.00001) in improving total nasal symptom scores. Intranasal corticosteroid plus oral antihistamine have similar efficacy to intranasal corticosteroid alone, greater efficacy than oral antihistamines alone or placebo in reducing nasal symptoms for AR patients. Intranasal corticosteroid plus intranasal antihistamine are significantly superior to either therapy given alone, or placebo.

[Expression of focal adhesion kinase in cardiac myocytes of hypertrophic ventricle].

OBJECTIVES: To investigate the role of focal adhesion kinase (FAK) in the pathogenesis of cardiac hypertrophy induced by hypertension. METHODS: Using immunofluorescent labeling, confocal microscopy and Western blotting, the expression and subcellular localization of FAK in the cardiac myocytes of left ventricle were determined in 2, 6, 12, and 18 month-old rats with spontaneously hypertensive heart failure (SHHF) along with age-matched control Wistar-Kyoto (WKY) rats. RESULTS: There was no significant difference of FAK expression between 2 month-old SHHF and WKY rats (50.5+/-6.9 vs. 49.8+/-5.0, n=6, P>0.05). In contrast with the control groups, the expression of FAK significantly increased in 6, 12 and 18 month-old SHHF rats (130.6+/-3.0 vs. 47.3+/-1.3, 144.7+/-5.4 vs. 46.4+/-3.1, 141.4+/-9.8 vs. 48.5+/-2.2, each groups n=6, P<0.05) with FAK protein primarily cumulated in the intercalated disks and nuclei. CONCLUSIONS: FAK may play a role in the cell signaling transduction leading to cardiac hypertrophy, presumably through regulations of hypertrophic gene transcription and RNA processing.