Anti-angiogenic effects of Hypericin-photodynamic therapy in combination with Celebrex in the treatment of human nasopharyngeal carcinoma

Photodynamic therapy (PDT) is being investigated as an alternative treatment modality in cancer treatment. It has been shown to induce tumor hypoxia and upregulation of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF). The objective of this study was to improve in vivo tumor growth control of nasopharyngeal carcinoma (NPC), treated at a subcurative dosage by using a combination of Hypericin-PDT and COX-2 inhibitor, Celebrex (CX). The effect of an initial CX dose at 6- and 24-h post-PDT was investigated simultaneously. It was observed that hypoxic NPC/CNE2 cells upregulate both COX-2 and VEGF A genes in vitro. In vivo studies, down-regulation of COX-2 and hypoxia inducible factor-1alpha (HIF-1alpha) genes at 24-h post-PDT and bulk tumor ablation at 48-h post-PDT was observed. However, 24-28 days later regrowth was observed. In a combination treatment, 1st CX dose at 6-h post-PDT had the highest tumor control in which tumors were 相似文献   

Photodynamic therapy induced Fas-mediated apoptosis in human carcinoma cells

Photodynamic therapy (PDT) is a clinical approach that utilizes light-activated drugs for the treatment of a variety of pathologic conditions. Human poorly (CNE2) and moderately differentiated (TW0-1) human nasopharyngeal carcinoma (NPC) cells undergo rapid apoptosis when treated with PDT sensitized with Hypocrellin A (HA) and Hypocrellin B (HB). It has been shown that these compounds have a strong photodynamic effect on tumors and viruses. The initiating events of PDT sensitized HA and HB-induced apoptosis are poorly defined. In the current study, we sought to determine whether Fas/FasL upregulation and involvement of mitochondrial events are an early event in HA and HB-treated PDT induced apoptosis. Loss of mitochondrial transmembrane potential, release of cytochrome c, involvement of caspases-8 and -3 and the status caspase-3 specific substrate PARP, were evaluated in PDT treated tumor cells. Photoactivation of HA and HB enhanced both CD95/CD95L expression and induced CD95-signaling dependent cell death in all tumor cell lines studied. CD95/ CD95L expression appeared within 2 h following light activation and appeared to be a primary event in PDT induced apoptosis. Furthermore, these results indicate that release of mitochondrial cytochrome c into the cytoplasm is a secondary event following the activation of initiator caspase-8 preceding caspase-3 activation, cleavage of PARP and DNA fragmentation. Cytochrome c appeared in the cytosol within 2-3 h post PDT. Cleavage of PARP was observed at 3-4 h following PDT and caspase-3 specific inhibitor DEVD-CHO and broad-spectrum caspases inhibitor z-VAD-fmk blocked caspase-3 activation and PARP cleavage suggesting that caspase-3 plays an important role in HA and HB-induced apoptosis.     

Decoding glaucoma module premium edition

Background:Traditional methods for neuroretinal rim width measurement in spectral domain optical coherence tomography (SD-OCT) employs the Bruch‘s membrane opening (BMO) as the anatomical border of the rim, referenced to a BMO horizontal reference plane, termed as “Bruch’s Membrane Opening-Horizontal Rim Width” (BMO-HRW). BMO-HRW is defined as the distance between BMO and internal limiting membrane (ILM) on the horizontal plane. In contrast, the Spectralis OCT (Heidelberg Engineering, Germany) employs a new parameter called “Bruch’s Membrane Opening–Minimum Rim Width” (BMO-MRW) with Glaucoma Module Premium Edition (GMPE). GMPE provides a novel objective method of optic nerve head (ONH) analysis using BMO, but the neuroretinal rim assessment is performed from the BMO to the nearest point on the ILM, rather than on the horizontal reference plane. It is the BMO-MRW and is defined as the minimum distance between the BMO and ILM in the ONH.Purpose:In this video, anatomy of the ONH and GMPE is decoded from a neophyte user’s point of view, as to why BMO-MRW is more important than the traditional BMO-HRW for glaucoma evaluation.Synopsis:The GMPE concepts are depicted in a novel dynamic (Clinical vs OCT Vs Histology) screenplay, detailing the below focal points with 2D & 3D animations: True Margin of ONH, Bruch’s Membrane (BM), Histology Vs OCT, BMO, Bruch’s Membrane Opening-Minimum Rim Width, Bruch’s Membrane Opening-Minimum Rim Width Versus Bruch’s Membrane Opening-Horizontal Rim Width, Alpha, Beta, Gamma Zone of ONH in OCT, Anatomic Positioning System, Impact of Fovea Bruch’s Membrane Opening Centre Axis.Highlights:This video also highlights, how with the advent of Anatomic Positioning System, scans were able to align relative to the individual’s Fovea-to-BMO-center (FoBMOC) axis at every follow-up, for accurately detecting changes, as small as 1 micron in BMO-MRW, thus creating a new world in diagnosing glaucoma and detecting glaucomatous progression with precision.Video link: https://youtu.be/6RqF5guAziw     

Clinical outcomes and immune phenotypes associated with STK11 co-occurring mutations in non-small cell lung cancer

BackgroundSTK11 mutation in non-small cell lung cancer (NSCLC) is associated with worse survival as well as primary resistance to PD-1/PD-L1 targeting immunotherapy. We hypothesize that co-occurring mutations and tumor mutation burden (TMB) may impact response to therapy and prognosis.MethodsForty-one patients with STK11-mutated NSCLC seen in our Thoracic oncology clinic with available next-generation sequencing tumor data were included in the analysis. Data from the Cancer Genome Atlas (TCGA) was used for survival and immune gene expression analysis. Overall and progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared using a log-rank test.ResultsIn the 41 patients included, common co-occurring alterations with STK11 were KRAS (54%), TP53 (44%), CDKN2A (37%) and KEAP1 (27%). Overall 17 patients received locoregional therapy with surgery or radiation with median OS of 8.6 years and there was no significant difference in clinical outcomes with KRAS and TP53 co-occurring mutations. Response to both chemotherapy and immunotherapy was poor across all co-occurring mutations. However, TP53 co-mutation was associated with improved clinical benefit with immunotherapy. Patients with higher TMB had longer PFS with immunotherapy. In TCGA survival analysis, tumors with STK11 mutation with or without KRAS co-mutation were associated with worse survival (P<0.05) but tumors with STK11/TP53 co-mutation did not have worst survival compared to STK11 wild type tumors. Moreover, co-occurring mutations had significant effect on intratumoral immune status with both STK11 alone and STK11/KRAS co-mutated tumors showing more enrichment for wound healing immune subtype while STK11/TP53 co-mutated tumors showed more enrichment for IFN-g immune subtype.ConclusionsOur retrospective analysis in patients with STK11-mutated NSCLC found that both TMB and co-occurring mutations may be predictors for response to immunotherapy with worse outcomes in patients with low TMB or KRAS co-mutation and improved outcomes with TP53 co-mutation. Patients with STK11-mutated NSCLC also demonstrate chemotherapy resistance but have similar outcomes with localized treatment compared to STK11 wild type tumors. Moreover, co-mutations with KRAS or TP53 significantly alter tumor immune landscape of STK11-mutated tumors and therefore response to immunotherapy.     

Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial

Context  Standard therapy for hot flashes has been hormone replacement with estradiol or progestational agents, but recent data suggest that antidepressants inhibiting serotonin reuptake may also be effective. Objective  To evaluate a selective serotonin reuptake inhibitor (paroxetine controlled release [CR]) in treating the vasomotor symptoms displayed by a general cross-section of menopausal women. Design and Setting  Randomized, double-blind, placebo-controlled, parallel group study conducted across 17 US sites, including urban, suburban, and rural clinics. Patients  A total of 165 menopausal women aged 18 years or older experiencing at least 2 to 3 daily hot flashes and must have discontinued any hormone replacement therapy for at least 6 weeks. Women were excluded if they had any signs of active cancer or were undergoing chemotherapy or radiation therapy. Intervention  After a 1-week placebo run-in phase, study participants were randomized to receive placebo or receive 12.5 mg/d or 25.0 mg/d of paroxetine CR (in a 1:1:1 ratio) for 6 weeks. Main Outcome Measures  Mean change from baseline to week 6 in the daily hot flash composite score (frequency x severity). Results  Fifty-six participants were randomly assigned to receive placebo and 51 to receive 12.5 mg/d and 58 to receive 25.0 mg/d of paroxetine CR. The mean reductions in the hot flash frequency composite score from baseline to week 6 were statistically significantly greater for those receiving paroxetine CR than for those receiving placebo. By week 6, the mean daily hot flash frequency went from 7.1 to 3.8 (mean reduction, 3.3) for those in the 12.5-mg/d and from 6.4 to 3.2 (mean reduction, 3.2) for those in the 25-mg/d paroxetine CR groups and from 6.6 to 4.8 (mean reduction, 1.8) for those in the placebo group. Mean placebo-adjusted reduction in hot flash composite scores were -4.7 (95% confidence interval, - 8.1 to -1.3; P = .007) comparing 12.5-mg/d paroxetine CR with placebo; and -3.6 (95% confidence interval, -6.8 to -0.4; P = .03) comparing 25.0-mg/d paroxetine CR with placebo. This corresponded to median reductions of 62.2% for those in the 12.5-mg/d and 64.6% for those in the 25.0-mg/d paroxetine CR groups compared with 37.8% for those in the placebo group. Conclusion  Paroxetine CR may be an effective and acceptable alternative to hormone replacement and other therapies in treating menopausal hot flash symptoms.      

Utility of pulse oximetry in diagnosing pneumonia in nursing home residents

BACKGROUND: The differential diagnosis of acute infection in elderly nursing home patients is often difficult. This study evaluated pulse oximetry in pneumonia in this population. METHODS: A case-control study was performed in a veteran's nursing home involving 2 analyses: (1) pneumonia patients (case subjects) were compared with patients with nonpulmonary infections (control subjects) at time of acute infection; (2) differences in paired values measured at time of infection versus a noninfected baseline were compared for pneumonia patients and control subjects. Vital signs including pulse oximetry were obtained routinely (at least monthly) and with acute illness. RESULTS: Oxygen saturations were lower in 45 pneumonia patients than in 22 patients with acute nonpulmonary infections (P < 0.001). An oxygen saturation < 94 gave a sensitivity for pneumonia of 80%, specificity of 91%, and positive predictive value of 95%. The drop in oxygen saturation from the last baseline value was greater in pneumonia patients than in control subjects (P < 0.001). The sensitivity of an oxygen saturation drop >3% from baseline for pneumonia was 73% with specificity and positive predictive values of 100%. CONCLUSIONS: Pulse oximetry may be very helpful in evaluating acutely infected nursing home residents. The present study suggests that in acutely infected nursing home patients, a decrease in oxygen saturation of >3% from baseline, as well as a single oxygen saturation of <94, should suggest pneumonia. A decrease from baseline of <4% or a single oxygen saturation of 94 or higher suggests that pneumonia is unlikely.