CheckMate 77T (NCT04025879) demonstrated statistically significant and clinically meaningful improvement in event-free survival for perioperative NIVO added to neoadjuvant (neoadj) chemo (NIVO+chemo/NIVO) vs perioperative placebo added to neoadj chemo (chemo/PBO) in patients (pts) with resectable NSCLC. Here we report HRQoL results. Adults with untreated, resectable stage IIA-IIIB NSCLC were randomized 1:1 to NIVO 360 mg Q3W + chemo (4 cycles) followed by surgery and adjuvant (adj) NIVO 480 mg Q4W (1 y), or PBO Q3W + chemo (4 cycles) followed by surgery and adj PBO Q4W (1 y). Pt-reported outcome (PRO) measures included NSCLC-SAQ, FACT-L, EQ-5D-3L, and PROMIS Physical Function Short-Form 8c. The assessment schedule was the same in both treatment (tx) arms. Changes from baseline (BL) were analyzed using a mixed model for repeated measures. Time to definitive deterioration (TTDD) was defined as time from randomization to worsening from BL with no subsequent improvement. Completion rates for all PRO measures were mostly > 90%, except at pre- and postsurgical visits. BL scores indicated good HRQoL for pts in both tx arms. Pts generally maintained their HRQoL during tx, except at the postsurgical visit. Least squares mean change (95% CI) from BL over the on-tx period for NSCLC-SAQ was 0.26 (−0.06 to 0.58) in the NIVO+chemo/NIVO arm and 0.33 (0.02 to 0.65) in the chemo/PBO arm and ranged from −0.51 to 1.71 and −0.76 to 1.43, respectively. Pts treated with NIVO+chemo/NIVO had delayed median TTDD vs those treated with chemo/PBO (NSCLC-SAQ HR 0.66 [95% CI 0.45–0.98]; results in table). Table: 121PTTDD in all randomized ptsScaleMedian TTDDa, mo (95% CI)HR (95% CI)NIVO+chemo/NIVO n = 229Chemo/PBO n = 232NSCLC-SAQb40.0 (33.6–NR)31.1 (25.0–NR)0.66 (0.45–0.98)FACT-L LCSc32.7 (27.2–NR)27.5 (20.2–NR)0.69 (0.49–0.97)EQ-5D-3L UId31.3 (25.8–NR)26.6 (20.9–NR)0.82 (0.60–1.12)EQ-5D-3L VASeNR (36.6–NR)NR (22.8–NR)0.67 (0.47–0.96)aTTDD was assessed during tx and follow-up. RD of ≥ b+3, c−3, d−0.08, and e−7 point changes from BL. FACT-L, Functional Assessment of Cancer Therapy - Lung; LCS, Lung Cancer Subscale; NR, not reached; NSCLC-SAQ, NSCLC Symptom Assessment Questionnaire; RD, responder definition; UI, utility index; VAS, visual analogue scale. Open table in a new tab aTTDD was assessed during tx and follow-up. RD of ≥ b+3, c−3, d−0.08, and e−7 point changes from BL. FACT-L, Functional Assessment of Cancer Therapy - Lung; LCS, Lung Cancer Subscale; NR, not reached; NSCLC-SAQ, NSCLC Symptom Assessment Questionnaire; RD, responder definition; UI, utility index; VAS, visual analogue scale. In CheckMate 77T, perioperative NIVO did not adversely impact HRQoL during the tx period and reduced the risk of definitive deterioration vs chemo/PBO. These findings, along with previously reported efficacy and safety results, support perioperative NIVO as a potential tx option for pts with resectable NSCLC.
To investigate the expressions of epidermal growth factor receptor (EGFR) in primary nasopharygeal carcinoma (NPC) and lymph node metastases.Archived samples of primary NPC and paired lymph node metastases from 86 patients were examined immunohistochemically for the protein expression of EGFR.EGFR expression positivity was detected in the primary NPC and lymph node metastases at the rate of 73.3% and 60.5%, respectively, and primary and metastatic foci showed significant difference in the expression levels (P=0.001). A discrepancy of EGFR expression between the primary and metastatic foci was found in 25 patients, with a discrepancy rate of 29.1% (25/86).The difference in EGFR expression between the primary and lymph node metastastic foci of NPC needs to be evaluated when performing EGFR-targeted therapies especially in advanced NPC cases.
To investigate the significance of serum IgD quantitation in evaluation of clinical efficacy in IgD myeloma.Serum IgD and free light chain (sFLC) levels were determined by immune scatter turbidimetry with SPA plus analysis machine in 29 patients with IgD multiple myeloma (MM) achieving VGPR or better response following previous treatments. The concurrent immunofixation electrophoresis (IFE) results were also incorporated and analyzed.Increased IgD levels were detected in 1 of 12 patients achieving sCR, 2 of 5 patients achieving CR and 4 of 12 patients achieving VGPR, respectively. The median progression-free survival (PFS) was 38.5 months, 34.1 months and 15.5 months for patients achieving sCR, CR and VGPR, respectively, with a significant difference between sCR and VGPR groups (P=0.022), and between CR and VGPR groups (P=0.018). There was no difference in overall survival (OS) among sCR, CR and VGPR groups (P>0.05). The median PFS were 7.8, 33.7 and 43.9 months, respectively for the patients with both abnormal sFLC ratios and IgD levels (6 cases, Group A), with either abnormal sFLC ratios or increased IgD levels (10 cases, Group B) or with normal sFLC ratios and IgD levels (13 cases, Group C). A significant PFS benefit of Group A over Group C was found (P=0.033), and no differences in terms of OS among three groups (P>0.05).IgD levels may remain abnormal in IgD MM patients who have achieved VGPR or better response, and IgD quantitation represented a useful assay complementary to the current lab examinations. IgD quantitation assay was of significance in clinical efficacy evaluation and survival judgement, and should be incorporated into the evaluation parameters used for IgD MM in addition to sFLC and IFE assays.
Copper/zinc superoxide dismutase (Cu/Zn-SOD) plays critical roles in protecting cells and tissues against oxidative damage. Excessive copper ions (Cu2+) in water can damage the cells of aquatic organisms, leading to impaired growth and development and reduced antioxidant defenses. Many regulatory factors control the response to excess Cu2+. Among them, microRNAs (miRNAs) are important small RNAs that regulate the expression of their target genes and participate in the oxidative stress response. In the present study, we used bioinformatics and dual luciferase reporter gene analyses to demonstrate that the miR-489-3p of hybrid yellow catfish (Pelteobagrus fulvidraco♀ × P. vachelli♂) binds to the 3'-untranslated region (UTR) of its target gene, which encodes a Cu/Zn-SOD. The regulatory relationship between this miRNA and its target gene Cu/Zn-SOD was analyzed using qRT-PCR and luciferase activity assays. We also investigated the effect of the loss of miR-489-3p expression on the oxidative stress response of hybrid yellow catfish exposed to Cu2+. The Cu/Zn-SOD 3'UTR region was found to be fully complementary to positions 2-9 of the 5'-end seed region of miR-489-3p. The miR-489-3p expression levels were negatively related to Cu/Zn-SOD expression. Silencing of miR-489-3p up-regulated Cu/Zn-SOD expression in the liver and gill tissues, increased activities of SOD and catalase, and reduced the malondialdehyde content. This study is the first to demonstrate that miR-489-3p targets Cu/Zn-SOD to mediate the oxidative response to metal stress. These findings provide a theoretical basis for further studies on the response to oxidative stress caused by metals in cultured fish, and provide an experimental basis for the management of the culture environment.
// Patrick J. Killela 1,* , Christopher J. Pirozzi 1,* , Patrick Healy 2 , Zachary J. Reitman 1 , Eric Lipp 1 , B. Ahmed Rasheed 1 , Rui Yang 1 , Bill H. Diplas 1 , Zhaohui Wang 1 , Paula K. Greer 1 , Huishan Zhu 1 , Catherine Y. Wang 1 , Austin B. Carpenter 1 , Henry Friedman 1 , Allan H. Friedman 1 , Stephen T. Keir 1 , Jie He 3 , Yiping He 1 , Roger E. McLendon 1 , James E. Herndon II 2 , Hai Yan 1 and Darell D. Bigner 1 1 Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center at Duke, and Pediatric Brain Tumor Foundation Institute at Duke, Durham, NC, USA 2 Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA 3 Department of Thoracic Surgery, Cancer Institute and Hospital Chinese Academy of Medical Sciences, Beijing, 100021, China * Denotes equal contribution Correspondence: Hai Yan, email: // Keywords : TERT promoter, IDH1, IDH2, Glioma Received : January 26, 2014 Accepted : January 28, 2014 Published : January 28, 2014 Abstract Frequent mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) and the promoter of telomerase reverse transcriptase ( TERT ) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival.
The superoxide anion and the hydroxyl radical (OH.) play an important role in the radiotherapy of tumors. The superoxide dismutase (SOD) and the metallothionien (MT) are the main enzymes to clear the superoxide anion and OH. Up to now, there are few reports on the relationship between the nasopharyngeal carcinoma (NPC) and SOD or MT. This study was conducted to observe the dynamic changes of the activity of total superoxide dismutase (T-SOD) in the serum and the expression of MT in the tissue from the NPC patients treated with radiotherapy.From December 2000 to January 2002, 46 patients with NPC were selected randomly to test the activity of T-SOD in serum using xanthine oxidase method and the expression of MT in tissue using immunohistochemistry before, during, and after radiotherapy. And 26 persons without cancer were enrolled as normal control.Thirty-two patients were performed 3 times of examinations of T-SOD activity. The activity of T-SOD before radiotherapy (83.9+/-19.6 U(N)/ml) was lower than normal control (96.8+/-23.6 U(N)/ml) (P< 0.05). The activities of T-SOD in the serum samples before, during, and after the radiotherapy were 77.6+/-19.1, 87.1+/-18.6, and 96.3+/-31.6 in the NPC patients at stage I(P >0.05); 80.1+/-15.0, 78.0+/-35.4, and 110.6+/-72.0 in the NPC patients at stage IV(P >0.05); 79.8+/-18.2, 87.2+/-31.7, and 94.8+/-36.3 in the patients with complete response to radiotherapy (P >0.05); 98.5+/-18.6, 62.9+/-35.3, and 79.2+/-27.3 in the patients with part response to radiotherapy (P >0.05). Among the 32 patients, 27 patients were performed 3 times of tests of MT expression. The expression rate of MT in NPC tissues was 39.8+/-37.8% before radiotherapy, and markedly higher than the normal control 12.1+/-22.4% (P< 0.05). The expression rates of MT before, during, and after radiotherapy were 33.0+/-42.2%, 21.3+/-36.1%, and 5.0+/-10.0% in the tissues from the patients at stage I(P< 0.05); 62.2+/-40.5%, 9.2+/-12.8%, and 9.2+/-15.0% in the patients at stage IV( P< 0.05); 42.5+/-38.6%, 19.8+/-27.5%, and 10.0+/-13.9% in the patients with complete response to radiotherapy (P< 0.05); 32.3+/-37.2%, 1.43+/-2.43%, and 5.4+/-9.1% in the patients with part response to radiotherapy (P< 0.05).The test of T-SOD in serum may be helpful for the diagnosis of initial NPC. But the dynamic change of the activity of total T-SOD in radiotherapy was not obvious. The expression rates of MT in NPC tissues increased markedly before radiotherapy, and decreased obviously after radiotherapy.
Spontaneous clearance of hepatitis B virus (HBV) is frequent in adults (95%) but rare in infants (5%), emphasizing the critical role of age-related hepatic immunocompetence. However, the underlying mechanisms of hepatocyte-specific immunosurveillance and age-dependent HBV clearance remain unclear. Here, we identified PGLYRP2 as a hepatocyte-specific pattern recognition receptor with age-dependent expression, and demonstrated that phase separation of PGLYRP2 was a critical driver of spontaneous HBV clearance in hepatocytes. Mechanistically, PGLYRP2 recognized and potentially eliminated covalently closed circular DNA (cccDNA) via phase separation, coordinated by its intrinsically disordered region and HBV DNA-binding domain (PGLYRP2IDR/209-377) in the nucleus. Additionally, PGLYRP2 suppressed HBV capsid assembly by directly interacting with the viral capsid, mediated by its PGRP domain. This interaction promoted the nucleocytoplasmic translocation of PGLYRP2 and subsequent secretion of the PGLYRP2-HBV capsid complex, thereby bolstering the hepatic antiviral response. Pathogenic variants or deletions in PGLYRP2 impaired its ability to inhibit HBV replication, highlighting its essential role in hepatocyte-intrinsic immunity. These findings suggest that targeting the PGLYRP2-mediated host-virus interaction may offer a potential therapeutic strategy for the development of anti-HBV treatments, representing a promising avenue for achieving a functional cure for HBV infection.
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