Mesenchymal transition and increased therapy resistance of glioblastoma cells is related to astrocyte reactivity

Grade IV astrocytoma/glioblastoma multiforme (GBM) is essentially incurable, partly due to its heterogenous nature, demonstrated even within the glioma-initiating cell (GIC) population. Increased therapy resistance of GICs is coupled to transition into a mesenchymal (MES) cell state. The GBM MES molecular signature displays a pronounced inflammatory character and its expression vary within and between tumors. Herein, we investigate how MES transition of GBM cells relates to inflammatory responses of normal astroglia. In response to CNS insults astrocytes enter a reactive cell state and participate in directing neuroinflammation and subsequent healing processes. We found that the MES signature show strong resemblance to gene programs induced in reactive astrocytes. Likewise, astrocyte reactivity gene signatures were enriched in therapy-resistant MES-like GIC clones. Variable expression of astrocyte reactivity related genes also largely defined intratumoral GBM cell heterogeneity at the single-cell level and strongly correlated with our previously defined therapy-resistance signature (based on linked molecular and functional characterization of GIC clones). In line with this, therapy-resistant MES-like GIC secreted immunoregulatory and tissue repair related proteins characteristic of astrocyte reactivity. Moreover, sensitive GIC clones could be made reactive through long-term exposure to the proinflammatory cytokine interleukin 1 beta (IL1β). IL1β induced a slow MES transition, increased therapy resistance, and a shift in DNA methylation profile towards that of resistant clones, which confirmed a slow reprogramming process. In summary, GICs enter through MES transition a reactive-astrocyte-like cell state, connected to therapy resistance. Thus, from a biological point of view, MES GICs would preferably be called ‘reactive GICs’. The ability of GBM cells to mimic astroglial reactivity contextualizes the immunomodulatory and microenvironment reshaping abilities of GBM cells that generate a tumor-promoting milieu. This insight will be important to guide the development of future sensitizing therapies targeting treatment-resistant relapse-driving cell populations as well as enhancing the efficiency of immunotherapies in GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Berg balance scale: intrarater test-retest reliability among older people dependent in activities of daily living and living in residential care facilities

BACKGROUND AND PURPOSE: The Berg Balance Scale (BBS) is frequently used to assess balance in older people, but knowledge is lacking about the absolute reliability of BBS scores. The aim of this study was to investigate the absolute and relative intrarater test-retest reliability of data obtained with the BBS when it is used among older people who are dependent in activities of daily living and living in residential care facilities. SUBJECTS: The participants were 45 older people (36 women and 9 men) who were living in 3 residential care facilities. Their mean age was 82.3 years (SD=6.6, range=68-96), and their mean score on the Mini Mental State Examination was 17.5 (SD=6.3, range=4-30). METHODS: The BBS was assessed twice by the same assessor. The intrarater test-retest reliability assessments were made at approximately the same time of day and with 1 to 3 days in between assessments. Absolute reliability was calculated using an analysis of variance with a 95% confidence level, as suggested by Bland and Altman. Relative reliability was calculated using the intraclass correlation coefficient (ICC). RESULTS: The mean score was 30.1 points (SD=15.9, range=3-53) for the first BBS test and 30.6 points (SD=15.6, range=4-54) for the retest. The mean absolute difference between the 2 tests was 2.8 points (SD=2.7, range=0-11). The absolute reliability was calculated as being 7.7 points, and the ICC was calculated to .97. DISCUSSION AND CONCLUSION: Despite a high ICC value, the absolute reliability showed that a change of 8 BBS points is required to reveal a genuine change in function among older people who are dependent in activities of daily living and living in residential care facilities. This knowledge is important in the clinical setting when evaluating an individual's change in balance function over time in this group of older people.     

Assessing pain as a fifth vital sign in long-term care facilities: Recommendations from the field

In long-term care facilities, pain management is complex because dementia, delirium, and other reasons for residents' altered communication ability are a significant barrier to pain assessment. The purpose of this study was to explore the status of implementation of pain as a fifth vital sign in a sample of long-term care facilities. A three-round Delphi survey was used to obtain consensus from personnel in 60 long-term care facilities in NY State. Findings are presented in terms of recommendations related to pain criteria, assessment methods, frequency of pain assessment, responsibility for pain assessment, monitoring strategies, education, documentation, and pain management education. The results of this study highlight many important considerations in the treatment of pain as a fifth vital sign in long-term care facilities. Evidence-based practice will be facilitated by further research related to underexplored aspects of pain assessment and management, and further attention to care delivery systems that support continued knowledge acquisition and the implementation of best practices.     

Nitrite in saliva increases gastric mucosal blood flow and mucus thickness

Salivary nitrate from dietary or endogenous sources is reduced to nitrite by oral bacteria. In the acidic stomach, nitrite is further reduced to NO and related compounds, which have potential biological activity. We used an in vivo rat model as a bioassay to test effects of human saliva on gastric mucosal blood flow and mucus thickness. Gastric mucosal blood flow and mucus thickness were measured after topical administration of human saliva in HCl. The saliva was collected either after fasting (low in nitrite) or after ingestion of sodium nitrate (high in nitrite). In additional experiments, saliva was exchanged for sodium nitrite at different doses. Mucosal blood flow was increased after luminal application of nitrite-rich saliva, whereas fasting saliva had no effects. Also, mucus thickness increased in response to nitrite-rich saliva. The effects of nitrite-rich saliva were similar to those of topically applied sodium nitrite. Nitrite-mediated effects were associated with generation of NO and S-nitrosothiols. In addition, pretreatment with an inhibitor of guanylyl cyclase markedly inhibited nitrite-mediated effects on blood flow. We conclude that nitrite-containing human saliva given luminally increases gastric mucosal blood flow and mucus thickness in the rat. These effects are likely mediated through nonenzymatic generation of NO via activation of guanylyl cyclase. This supports a gastroprotective role of salivary nitrate/nitrite.     

NIDCD/VA hearing aid clinical trial and follow-up: coupler and real-ear measurement

A total of 190 individuals participated in a clinical visit during the Cooperative Studies Program (CSP) 418-A Long Term Follow-Up Study. Of this cohort, 158 participants were considered current hearing aid users, and 32 were non-hearing aid users. Of the current hearing aid users, 81 were still using their original 418 study devices, and 77 had acquired new hearing aids. Coupler and real ear measurements were completed on all available hearing aids. Results showed that study aids had remained relatively stable over the six years between CSP 418 and CSP 418-A. On average, these hearing aid wearers preferred use gain settings that were 6-9 dB less than current NAL-RP insertion gain targets. Mean real ear insertion gain (REIG) was comparable to the mean real ear insertion gain of the same participants in the original study, and users did not tend to increase gain as hearing decreased. Real ear saturation responses (RESR) remained unchanged. Loudness discomfort levels (LDL) obtained during 418-A were significantly lower than LDLs obtained on those same participants at both the initial and final visits in the previous study.     

Low HDL-C predicts the onset of transplant vasculopathy in pediatric cardiac recipients on pravastatin therapy

The levels and protein/lipid compositions of major lipoprotein particles of 19 pediatric cardiac transplant recipients (4-18 yr of age) were studied in this prospective, open clinical follow-up study before and at one yr of pravastatin therapy (10 mg/day). The recipients were grouped into those with (n = 6; group A) and those without (n = 13; group B) angiographically detectable vasculopathy. Twenty-one pediatric non-transplant controls were studied at baseline. At baseline, the group A recipients had 29% lower HDL-C concentrations (p = 0.031) and 29% higher apoB-100/apoA-I ratios (p = 0.034) than the group B recipients. At one yr of pravastatin, the respective figures were 29% (p = 0.013) and 33% (p = 0.005). Compared with the healthy pediatric controls, the transplant recipients had significantly higher serum TG before pravastatin [median (range): 1.3 mmol/L (0.6-3.2) vs. 0.7 mmol/L (0.3-2.4), p = 0.0002] and at one yr [1.3 mmol/L (0.5-3.5) vs. 0.7 mmol/L (0.3-2.4), p = 0.0004]. The baseline apoB-100/apoA1 ratios of the recipients were 33% higher (p = 0.005). In conclusion, low HDL-C and high apoB-100/apoA-I ratio were associated with angiographically detectable vasculopathy. Even though pravastatin effectively lowered the TC and LDL-C and improved compositional properties of LDL and HDL(2) particles, it failed to normalize the elevated TG and, in some patients, to prevent the progression of transplant vasculopathy.     

Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients

Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans.