Canine as a Comparative and Translational Model for Human Mammary Tumor / 한국유방암학회지

Despite the advances in research and treatment of human breast cancer, its incidence rate continues to increase by 0.5% per year, and the discovery of novel therapeutic strategies for specific subtypes of human breast cancer remains challenging. Traditional laboratory mouse models have contributed tremendously to human breast cancer research. However, mice do not develop tumors spontaneously; consequently, genetically engineered mouse models or patient-derived xenograft models are often relied upon for more sophisticated human breast cancer studies. Since human breast cancer develops spontaneously, there is a need for alternative, yet complementary, models that can better recapitulate the features of human breast cancer to better understand the molecular and clinical complexities of the disease in developing new therapeutic strategies. Canine mammary tumors are one such alternative model that share features with human breast cancer, including prevalence rate, subtype classification, treatment, and mutational profiles, all of which are described in this review.

Single-arm clinical trials that supported FDA accelerated approvals have modest effect sizes and were at high risk of bias.

OBJECTIVE: To describe effect sizes of single-arm clinical trials that supported AA approvals. STUDY DESIGN AND SETTING: We reviewed all the single-arm approvals granted by the FDA-AA pathway between June1992 to December2020. Two independent reviewers identified single-arm studies and extracted data from FDA Full-Medical Reviews. We performed a meta-analysis to estimate the effect sizes and compared it between studies that met post-approval FDA requirements for RCTs with those that did not. RESULTS: From the total of 254 approvals, single arm clinical trials describing effects of 54 drugs for 72 clinical indications were evaluated. The effect size estimated was OR:2.22(CI95%:1.76-2.81) [relative risk (RR) = 1.63(95CI% 1.38-1.92)]; 53% of treatments had a lower 95% CI bound crossing the null effect. Effect size did not differ between the treatments that met the FDA requirement for conducting post-approval RCTs. CONCLUSIONS AND RELEVANCE: Treatment effects observed in the FDA AA single-arm studies was modest and can be to ascribed to bias.

Effects of user experiences on continuance intention of using immersive three-dimensional virtual reality among institutionalized older adults.

AIM: To evaluate the acceptance of three-dimensional virtual reality programs and to explore the factors influencing the acceptance of the programs among the institutionalized older adults. DESIGN: A cross-sectional explanatory study. METHODS: A total of 71 residents completed the program successfully. They were invited to join a 9-week program included eight activities related to horticultural therapy in a virtual environment. Data were collected by structured questionnaires from August 2018 to February 2019. Ten association hypotheses were derived from the literature review. Partial least squares structural equation modelling was used to examine the proposed hypotheses. RESULTS: Program acceptance was defined as virtual reality practices and continuous usage intention. Frequency of practice was about 12 times during 9-week free-trial period, and the score of continuance usage intention was 13.06 (maximum value of 15). The findings indicated that virtual reality practices were significantly affected by presence and the presence was significantly affected by involvement and interactivity. Continuance usage intention was significantly affected by involvement; and involvement was significantly affected by interactivity. However, continuance usage intention was not significantly influenced by virtual reality practices. CONCLUSIONS: The findings supported that immersive three-dimensional virtual reality program was accepted by the institutionalized older adults. The acceptance, in terms of virtual reality practices and continuous usage intention, was influenced by different paths. The findings have a potential impact on the design of virtual reality technology for the care of institutionalized older adults. IMPACT: What problem did the study address? There were controversial findings about the acceptance of immersive 3D virtual reality program among older adults. What were the main findings? Interactivity advanced the sense of presence and, thus, resulted in a higher frequency of virtual reality practices. Interactivity enhanced perception of involvement, thus, contributing to an increased intention of continuous usage Where and on whom will the research have an impact? The immersive 3D virtual reality program was appropriate for older adults, even for first time users or individuals aged over 80 years. The findings revealed new insights for developing immersive 3D virtual reality programs for the older adults.

Seroprevalence of SARS-CoV-2-Specific IgG Antibodies Among Adults Living in Connecticut Between March 1 and June 1, 2020: Post-Infection Prevalence (PIP) Study

BackgroundA seroprevalence study can estimate the percentage of people with SARS-CoV-2 antibodies in the general population, however, most existing reports have used a convenience sample, which may bias their estimates. MethodsWe sought a representative sample of Connecticut residents, aged [≥]18 years and residing in non-congregate settings, who completed a survey between June 4 and June 23, 2020 and underwent serology testing for SARS-CoV-2-specific IgG antibodies between June 10 and July 29, 2020. We also oversampled non-Hispanic Black and Hispanic subpopulations. We estimated the seroprevalence of SARS-CoV-2-specific IgG antibodies and the prevalence of symptomatic illness and self-reported adherence to risk mitigation behaviors among this population. ResultsOf the 567 respondents (mean age 50 [{+/-}17] years; 53% women; 75% non-Hispanic White individuals) included at the state-level, 23 respondents tested positive for SARS-CoV-2-specific antibodies, resulting in weighted seroprevalence of 4.0 (90% confidence interval [CI] 2.0-6.0). The weighted seroprevalence for the oversampled non-Hispanic Black and Hispanic populations was 6.4% (90% CI 0.9-11.9) and 19.9% (90% CI 13.2-26.6), respectively. The majority of respondents at the state-level reported following risk mitigation behaviors: 73% avoided public places, 75% avoided gatherings of families or friends, and 97% wore a facemask, at least part of the time. ConclusionsThese estimates indicate that the vast majority of people in Connecticut lack antibodies against SARS-CoV-2 and there is variation by race/ethnicity. There is a need for continued adherence to risk mitigation behaviors among Connecticut residents to prevent resurgence of COVID-19 in this region.

High prevalence of TP53 mutations is associated with poor survival and an EMT signature in gliosarcoma patients

Gliosarcoma (GS) is a rare variant (2%) of glioblastoma (GBM) that poses clinical genomic challenges because of its poor prognosis and limited genomic information. To gain a comprehensive view of the genomic alterations in GS and to understand the molecular etiology of GS, we applied whole-exome sequencing analyses for 28 GS cases (6 blood-matched fresh-frozen tissues for the discovery set, 22 formalin-fixed paraffin-embedded tissues for the validation set) and copy-number variation microarrays for 5 blood-matched fresh-frozen tissues. TP53 mutations were more prevalent in the GS cases (20/28, 70%) compared to the GBM cases (29/90, 32%), and the GS patients with TP53 mutations showed a significantly shorter survival (multivariate Cox analysis, hazard ratio=23.9, 95% confidence interval, 2.87–199.63, P=0.003). A pathway analysis showed recurrent alterations in MAPK signaling (EGFR, RASGRF2 and TP53), phosphatidylinositol/calcium signaling (CACNA1s, PLCs and ITPRs) and focal adhesion/tight junction (PTEN and PAK3) pathways. Genomic profiling of the matched recurrent GS cases detected the occurrence of TP53 mutations in two recurrent GS cases, which suggests that TP53 mutations play a role in treatment resistance. Functionally, we found that TP53 mutations are associated with the epithelial–mesenchymal transition (EMT) process of sarcomatous components of GS. We provide the first comprehensive genome-wide genetic alternation profiling of GS, which suggests novel prognostic subgroups in GS patients based on their TP53 mutation status and provides new insight in the pathogenesis and targeted treatment of GS.

Altering endoplasmic reticulum stress in a model of blast-induced traumatic brain injury controls cellular fate and ameliorates neuropsychiatric symptoms.

Neuronal injury following blast-induced traumatic brain injury (bTBI) increases the risk for neuropsychiatric disorders, yet the pathophysiology remains poorly understood. Blood-brain-barrier (BBB) disruption, endoplasmic reticulum (ER) stress, and apoptosis have all been implicated in bTBI. Microvessel compromise is a primary effect of bTBI and is postulated to cause subcellular secondary effects such as ER stress. What remains unclear is how these secondary effects progress to personality disorders in humans exposed to head trauma. To investigate this we exposed male rats to a clinically relevant bTBI model we have recently developed. The study examined initial BBB disruption using Evan's blue (EB), ER stress mechanisms, apoptosis and impulsive-like behavior measured with elevated plus maze (EPM). Large BBB openings were observed immediately following bTBI, and persisted for at least 6 h. Data showed increased mRNA abundance of stress response genes at 3 h, with subsequent increases in the ER stress markers C/EBP homologous protein (CHOP) and growth arrest and DNA damage-inducible protein 34 (GADD34) at 24 h. Caspase-12 and Caspase-3 were both cleaved at 24 h following bTBI. The ER stress inhibitor, salubrinal (SAL), was administered (1 mg/kg i.p.) to investigate its effects on neuronal injury and impulsive-like behavior associated with bTBI. SAL reduced CHOP protein expression, and diminished Caspase-3 cleavage, suggesting apoptosis attenuation. Interestingly, SAL also ameliorated impulsive-like behavior indicative of head trauma. These results suggest SAL plays a role in apoptosis regulation and the pathology of chronic disease. These observations provide evidence that bTBI involves ER stress and that the unfolded protein response (UPR) is a promising molecular target for the attenuation of neuronal injury.

Population survey and conservation assessment of the globally threatened cheer pheasant (Catreus wallichi) in Jhelum Valley, Azad Kashmir, Pakistan.

The cheer pheasant Catreus wallichi is a globally threatened species that inhabits the western Himalayas. Though it is well established that the species is threatened and its numbers declining, updated definitive estimates are lacking, so in 2011, we conducted a survey to assess the density, population size, and threats to the species in Jhelum valley, Azad Kashmir, which holds the largest known population of cheer pheasants in Pakistan. We conducted dawn call count surveys at 17 points clustered in three survey zones of the valley, 11 of which had earlier been used for a 2002-2003 survey of the birds. Over the course of our survey, 113 birds were recorded. Mean density of cheer pheasant in the valley was estimated at 11.8 ± 6.47 pairs per km², with significant differences in terms of both counts and estimated density of cheer were significantly different across the three survey zones, with the highest in the Chinari region and the lowest, that is the area with no recorded sightings of the pheasants, in Gari Doppata. The total breeding population of cheer pheasants is estimated to be some 2 490 pairs, though this does not consider the actual area of occupancy in the study area. On the whole, more cheer pheasants were recorded in this survey than from the same points in 2002-2003, indicating some success in population growth. Unfortunately, increasing human settlement, fires, livestock grazing, hunting, and the collection of non-timber forest products continue to threaten the population of cheer in the Jhelum valley. To mitigate these potential impacts, some degree of site protection should be required for the conservation of cheer pheasants in Pakistan, and more effective monitoring of the species is clearly needed.

Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and death.

PURPOSE: Azithromycin use has been associated with increased risk of death among patients at high baseline risk, but not for younger and middle-aged adults. The Food and Drug Administration issued a public warning on azithromycin, including a statement that the risks were similar for levofloxacin. We conducted a retrospective cohort study among US veterans to test the hypothesis that taking azithromycin or levofloxacin would increase the risk of cardiovascular death and cardiac arrhythmia compared with persons taking amoxicillin. METHODS: We studied a cohort of US veterans (mean age, 56.8 years) who received an exclusive outpatient dispensation of either amoxicillin (n = 979,380), azithromycin (n = 594,792), or levofloxacin (n = 201,798) at the Department of Veterans Affairs between September 1999 and April 2012. Azithromycin was dispensed mostly for 5 days, whereas amoxicillin and levofloxacin were dispensed mostly for at least 10 days. RESULTS: During treatment days 1 to 5, patients receiving azithromycin had significantly increased risk of death (hazard ratio [HR] = 1.48; 95% CI, 1.05-2.09) and serious arrhythmia (HR = 1.77; 95% CI, 1.20-2.62) compared with patients receiving amoxicillin. On treatment days 6 to 10, risks were not statistically different. Compared with patients receiving amoxicillin, patients receiving levofloxacin for days 1 to 5 had a greater risk of death (HR = 2.49, 95% CI, 1.7-3.64) and serious cardiac arrhythmia (HR = 2.43, 95% CI, 1.56-3.79); this risk remained significantly different for days 6 to 10 for both death (HR = 1.95, 95% CI, 1.32-2.88) and arrhythmia (HR = 1.75; 95% CI, 1.09-2.82). CONCLUSIONS: Compared with amoxicillin, azithromycin resulted in a statistically significant increase in mortality and arrhythmia risks on days 1 to 5, but not 6 to 10. Levofloxacin, which was predominantly dispensed for a minimum of 10 days, resulted in an increased risk throughout the 10-day period.

Linking traumatic brain injury to chronic traumatic encephalopathy: identification of potential mechanisms leading to neurofibrillary tangle development.

Significant attention has recently been drawn to the potential link between head trauma and the development of neurodegenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sports-related concussions in athletes and blast-induced traumatic brain injury in soldiers elevates the risk for future development of chronic neurodegenerative diseases such as CTE. CTE is a progressive disease distinguished by characteristic tau neurofibrillary tangles (NFTs) and, occasionally, transactive response DNA binding protein 43 (TDP43) oligomers, both of which have a predilection for perivascular and subcortical areas near reactive astrocytes and microglia. The disease is currently only diagnosed postmortem by neuropathological identification of NFTs. A recent workshop sponsored by National Institute of Neurological Disorders and Stroke emphasized the need for premortem diagnosis, to better understand disease pathophysiology and to develop targeted treatments. In order to accomplish this objective, it is necessary to discover the mechanistic link between acute neurotrauma and the development of chronic neurodegenerative and neuropsychiatric disorders such as CTE. In this review, we briefly summarize what is currently known about CTE development and pathophysiology, and subsequently discuss injury-induced pathways that warrant further investigation. Understanding the mechanistic link between acute brain injury and chronic neurodegeneration will facilitate the development of appropriate diagnostic and therapeutic options for CTE and other related disorders.

Disparity among neural injury models and the unfolded protein response.

Endoplasmic reticulum stress is activated following both stroke and traumatic brain injury producing reactive oxgygen species, increasing intracellular calcium levels, and inducing inflammation; however, the timing and duration of activation varies between injuries. Preventing the immediate effects of ischemic/reperfusion injury or traumatic brain injury is challenging due to short onset of injury, but mitigating the secondary effects is a therapeutically targetable option. Preventative therapies using pharmacological agents have been utilized in pre-clinical models of neural injury to ameliorate secondary effects such as apoptosis and neurodegeneration. The connection between ER stress activation, apoptosis, and subsequent neurodegeneration has been proposed, but not yet causally linked. Researchers are now pursuing effective treatment strategies to suppress the secondary effects of neural injury in order to mitigate the development of chronic deficits. Secondary effects such as endoplasimic reticulum stress and neuroinflammation can be prevented in pre-clinical models, but the results have yet to translate to meaningful treatment options for patients. Evidence suggests that targeting the right transcription factors, at the right time, will aid in the prevention of apoptosis and neurodegenerative disease development following neural injury. In this review, we examine therapeutic approaches that target secondary injury and how these may correlate to better treatment options for patients.

Angiotensin receptor blockers: are they related to lung cancer?

INTRODUCTION: Angiotensin receptor blockers (ARBs) are commonly used antihypertensive medication with several other additional proven benefits. Recent controversy on association of lung cancer and other solid malignancy with the use of ARBs is concerning, although the follow-up studies have shown no such association. METHODS: We used data from the Department of Veterans Affairs electronic medical record system and registries to conduct a retrospective cohort study that compared first-time ARB users with nonusers in 1:15 ratio, after balancing for many baseline differences using inverse probability of treatment weights. We conducted time-to-event survival analyses on the weighted cohort. RESULTS: Of the 1 229 902 patients in the analytic cohort, 346 (0.44%) of the 78 075 treated individuals had a newly incident lung cancer and 6577 (0.57%) of 1 151 826 nontreated individuals were diagnosed with lung cancer. On double robust regression, the weighted hazard ratio was 0.74 (0.67-0.83, P < 0.0001), suggesting a lung cancer reduction effect with ARB use. There was no difference in rates by ARB subtype. CONCLUSION: In this large nationwide cohort of United States Veterans, we found no evidence to support any concern of increased risk of lung cancer among new users of ARBs compared with nonusers. Our findings were consistent with a protective effect of ARBs.

Angiotensin receptor blockers and risk of prostate cancer among United States veterans.

To address concerns regarding increased risk of prostate cancer (PrCA) among angiotensin receptor blocker (ARB) users, we used national retrospective data from the Department of Veterans Affairs (VA) through the Veterans Affairs Informatics and Computing Infrastructure. We identified a total of 543,824 unique Veterans who were classified into either ARB treated or not-treated in 1:15 ratio. The two groups were balanced using inverse probability of treatment weights. A double-robust cox-proportional hazards model was used to estimate the hazard ratio for PrCA incidence. To evaluate for a potential Gleason score stage migration, we conducted weighted Cochrane-Armitage test. Post weighting, the rates of PrCA in treated and not-treated groups were 506 (1.5%) and 8,269 (1.6%), respectively; representing a hazard ratio of (0.91, p-value .049). There was no significant difference in Gleason scores between the two groups. We found a small, but statistically significant, reduction in the incidence of clinically detected PrCA among patients assigned to receive ARB with no countervailing effect on degree of differentiation (as indicated by Gleason score). Findings from this study support Food and Drug Administration's recent conclusion that ARB use does not increase risk of incident PrCA.

Caveat oncologist: clinical findings and consequences of distributing counterfeit erythropoietin in the United States.

PURPOSE: Counterfeit pharmaceuticals pose risks domestically. Because of their cost, cancer pharmaceuticals are vulnerable. We review findings from a domestic counterfeiting episode involving erythropoietin and outline anticounterfeiting recommendations for policy makers, patients, and health care professionals. MATERIALS AND METHODS: Information was obtained on patients who received counterfeit erythropoietin, its distribution, and criminal investigations into counterfeiting networks. Interview sources included a physician, an attorney, employees of the Florida Department of Health and Human Services and the US Food and Drug Administration's (FDA) Office of Criminal Investigation, manufacturers, and wholesalers. Other sources included the book "Dangerous Doses," LexisNexis (search terms "counterfeit" and "erythropoietin") and the FDA database. RESULTS: Counterfeit product consisted of 2,000 U vials with counterfeit labels denoting 40,000 U. The counterfeiters, in collaboration with a Miami pharmacy, purchased 110,000 erythropoietin 2,000 U vials and affixed counterfeit labels to each vial. Products were then sold via the pharmaceutical "gray market" to wholesalers, then pharmacy chains. Investigations by Florida government officials implicated 17 persons, all of whom were found guilty of trafficking in counterfeit pharmaceuticals. Despite the large size of the operation, the FDA received reports of only 12 patients who had received counterfeit erythropoietin and detailed information for only two individuals. A 17-year-old liver transplant recipient and a 61-year-old patient with breast cancer experienced loss of efficacy after receiving counterfeit erythropoietin. CONCLUSION: Wider use of FDA anticounterfeit initiatives, limiting pharmaceutical suppliers to reputable distributors, and educating providers and patients about signs of counterfeit drugs can improve the safety of cancer pharmaceuticals.