Abstract
In oncology, “immunotherapy” is a broad term encompassing multiple means of utilizing the patient’s immune system to combat malignancy. Prominent among these are immune checkpoint ...inhibitors, cellular therapies including chimeric antigen receptor T-cell therapy, vaccines, and oncolytic viruses. Immunotherapy for glioblastoma (GBM) has had mixed results in early trials. In this context, the past, present, and future of immune oncology for the treatment of GBM was discussed by clinical, research, and thought leaders as well as patient advocates at the first annual Remission Summit in 2019. The goal was to use current knowledge (published and unpublished) to identify possible causes of treatment failures and the best strategies to advance immunotherapy as a treatment modality for patients with GBM. The discussion focuses on past failures, current limitations, failure analyses, and proposed best practices moving forward.
To provide a comprehensive and more representative national data on the disease, especially on treatment options and outcomes, and to determine access of retinoblastoma patients from Luzon, Visayas ...and Mindanao to eye care, and determine if access is associated with delay in consultation, staging and outcomes.
Cohort study of retinoblastoma patients seen in eleven institutions located in the three major areas of the Philippines namely Luzon, Vizayas and Mindanao from 2010-2020.
Totally 636 patients, involving 821 eyes, were included. Majority (57%) were from Luzon and were seen in institutions in Luzon (72%). Annually, 58±10 new cases were seen with 71% having unilateral disease. Median delay of consultation remained long at 9 (3, 17)mo, longest in patients with unilateral disease (
<0.02) and those from the Visayas (
<0.003). Based on the International Retinoblastoma Staging System, only 35% of patients had Stage 1 while 47% already had extraocular disease. Enucleation was the most common treatment received by 484 patients while intravenous chemotherapy was received by 469. There were 250 (39%) patients alive, 195 (31%) dead, 85 (13%) abandoned, 17 (3%) refused and 89 (14%) with no data.
This study presents the largest cohort of retinoblastoma patients in the Philippines in terms of patients' and participating institutions' number and geographical location and type of institution (private and public). It also presents more comprehensive data on the treatments used and outcomes (survival, globe salvage, and vision retention rates). Delay in consultation was still long among patients leading to advanced disease stage and lower survival rate. Despite increasing capacity to diagnose and manage retinoblastoma in the country, the delay of consultation remains long primarily due to accessibility issues to eye care institutions especially in the Visayas and financial concerns. The delay was still significant that overall survival rate remain low.
Estrogen has an important role in regulating female metabolism. Whereas the role of estrogen receptor (ER) α on female reproductive system is well defined, the role of ERβ (encoded by Esr2) remains ...unclear. Here we examined the metabolic effects of high-fat diet (HFD) in male Esr2-/- mice on BALB/c background (n=8∼9). After 6 weeks of HFD, Esr2-/- mice became more obese than wild type (WT) mice (Figure 1; *P<0.05). Surprisingly, metabolic cage study showed significantly increased energy expenditure in Esr2-/- mice, likely resulting from skeletal muscle as lean mass tended to be higher in these mice (Figure 2). We performed a hyperinsulinemic-euglycemic clamp to measure insulin sensitivity in awake mice. Despite being more obese, HFD-fed Esr2-/- mice tended to show increased insulin sensitivity with 20% increases in whole body glucose turnover and glycolysis (Figure 3). This was mostly due to a significant increase (52%) in skeletal muscle glucose uptake in HFD-fed Esr2-/- mice (Figure 4). Interestingly, glucose uptake into brown fat tended to be reduced by 50% in HFD-fed Esr2-/- mice.
In conclusion, these results indicate that deletion of Esr2 in male mice increases diet-induced obesity, but selectively prevents muscle insulin resistance. Our findings implicate a potential therapeutic role of estrogen signaling to treat insulin resistance.
Disclosure
R.H. Friedline: None. H. Noh: None. S. Suk: None. C. Goral: None. K.A. Dunphy: None. A.L. Roberts: None. D.A. Tran: None. L.A. Tauer: None. X. Hu: None. L.H. Kim: None. A.M. Kim: None. D. Jerry: None. J.K. Kim: None.
Funding
National Institutes of Health (5U2CDK093000)
Purpose or objective
The COVID-19 pandemic has resulted in significant healthcare implications, with care for cancer patients compromised due to resource diversion towards battling the pandemic. We ...aim to investigate the impact of the peak wave of the pandemic in 2020 on the delivery of cancer care in Singapore, specifically via our nasopharyngeal carcinoma (NPC) treatment data. This study applies real world numbers to the impact of COVID-19 on cancer care delivery in Singapore. The choice of nasopharyngeal cancer allows a good direct estimate of common treatment measures such as time to biopsy, time to staging scans, time to treatment commencement, due to its clear protocol and algorithms for staging and treatment; thus serving as an excellent surrogate for the effectiveness and timeliness of the different aspects of cancer care delivery.
Materials and methods
In this retrospective study, we included all patients with newly diagnosed NPC from 1st January to 31st May from 2017 to 2020 at our centre. This time period was chosen as it coincided with the period in 2020 during the COVID-19 pandemic where there was the most strain on healthcare resources and the most restrictions on population movement within Singapore, which may impact on healthcare seeking behaviour. Narrowing down the time period to the first 5 months of the 4 respective years also allowed us to reduce the effect of annual seasonal variation in patient numbers seen as a result of holidays and festive periods such as the Lunar New Year and scheduled school holidays. Electronic medical records (EMR) were accessed. Only newly diagnosed NPC cases were included in our analysis. Patients with second synchronous primary malignancies or NPC disease recurrence were excluded. Data analysis was carried out using a combination of SPSS and Microsoft Excel.
Results
Significantly, there was a reduction of 37–46.3% in newly diagnosed NPC cases during the peak of the COVID-19 pandemic from January to end May 2020 compared to the preceding three years. Despite the reduction in numbers of newly diagnosed NPC, there was no statistically significant differences in delay from biopsy to the first radiation oncology visit and from biopsy to the first day of treatment in 2020 compared to the preceding years. All the patients treated in our centre also received the standard NPC treatment for their disease stage as per international guidelines.
Conclusion
We recommend a heightened awareness of the dangers of delaying cancer presentation and care in healthcare policies and resource allocation and at the same time, encourage patient’s confidence in their ability to seek care. With the resurgence of new COVID-19 variants and case numbers worldwide and in Singapore, this study focuses upon the need to be aware of the exigencies of other clinical groups in resource utilization. It would be instructive to compare this study with future long term follow up to investigate the trajectory of our cancer care delivery, as well as survival outcomes.
Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer that is driven by aberrant signaling of growth factor receptors, particularly the epidermal growth factor receptor ...(EGFR). EGFR signaling is tightly regulated by receptor endocytosis and lysosome-mediated degradation, although the molecular mechanisms governing such regulation, particularly in the context of cancer, remain poorly delineated. Here, high-resolution genomic profiles of GBM identified a highly recurrent focal 1p36 deletion encompassing the putative tumor suppressor gene, Mig-6. We show that Mig-6 quells the malignant potential of GBM cells and dampens EGFR signaling by driving EGFR into late endosomes and lysosome-mediated degradation upon ligand stimulation. Mechanistically, this effect is mediated by the binding of Mig-6 to a SNARE protein STX8, a protein known to be required for late endosome trafficking. Thus, Mig-6 functions to ensure recruitment of internalized receptor to late endosomes and subsequently the lysosomal degradation compartment through its ability to specifically link EGFR and STX8 during ligand-stimulated EGFR trafficking. In GBM, the highly frequent loss of Mig-6 would therefore serve to sustain aberrant EGFR-mediated oncogenic signaling. Together, these data uncover a unique tumor suppression mechanism involving the regulation of receptor trafficking.
Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is associated with significant morbidity and mortality. Mechanical circulatory support (MCS) devices increase systemic blood ...pressure and end organ perfusion while reducing cardiac filling pressures.
The National Cardiogenic Shock Initiative (NCT03677180) is a single-arm, multicenter study. The purpose of this study was to assess the feasibility and effectiveness of utilizing early MCS with Impella in patients presenting with AMI-CS. The primary end point was in-hospital mortality. A total of 406 patients were enrolled at 80 sites between 2016 and 2020. Average age was 64±12 years, 24% were female, 17% had a witnessed out-of-hospital cardiac arrest, 27% had in-hospital cardiac arrest, and 9% were under active cardiopulmonary resuscitation during MCS implantation. Patients presented with a mean systolic blood pressure of 77.2±19.2 mm Hg, 85% of patients were on vasopressors or inotropes, mean lactate was 4.8±3.9 mmol/L and cardiac power output was 0.67±0.29 watts. At 24 hours, mean systolic blood pressure improved to 103.9±17.8 mm Hg, lactate to 2.7±2.8 mmol/L, and cardiac power output to 1.0±1.3 watts. Procedural survival, survival to discharge, survival to 30 days, and survival to 1 year were 99%, 71%, 68%, and 53%, respectively.
Early use of MCS in AMI-CS is feasible across varying health care settings and resulted in improvements to early hemodynamics and perfusion. Survival rates to hospital discharge were high. Given the encouraging results from our analysis, randomized clinical trials are warranted to assess the role of utilizing early MCS, using a standardized, multidisciplinary approach.
N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal ...Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.
Abstract
To determine the repeatability and reproducibility figures of the AOAC First Action Official MethodSM 2014.02 (Vitamin B12 in Infant Formula and Adult/Pediatric Formula by Liquid ...Chromatography with UV Detection), a collaborative study was organized. Twenty-one laboratories located in 13 different countries agreed to participate. The study was divided into two parts. During the first part, the laboratories analyzed two samples in duplicate by using the method described in the protocol. The laboratories that provided results within the expected range were qualified for part two, during which they analyzed 10 samples in blind duplicates. Eighteen laboratories managed to provide results on time for reporting. The results were compared with the Standard Method Performance Requirement (SMPR® 2011.005) established for vitamin B12. The precision results met the requirements stated in the SMPR except for one sample. Repeatability and reproducibility relative standard deviation ranged from 1.1 to 6.5% and from 6.0 to 23.8%, respectively, with only one matrix showing reproducibility values higher than the required 11%. Horwitz ratio values were all well below 2 (0.17–0.78). The AOAC Expert Review Panel (Stakeholder Panel for Infant Formula and Adult Nutritional Expert Review Panel) determined that the data presented met the SMPR and, hence, recommended the method to be granted Final Action status in September 2016.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
White specks in the esophageal mucosa have been observed in children with eosinophilic esophagitis. The aim of this study was to determine the relationship between white specks in the esophageal ...mucosa and allergic (non-reflux) eosinophilic esophagitis.
Endoscopic data, pH probe results, and histopathology reports for children with esophageal endoscopic abnormalities seen during a 17-month period were reviewed. Eosinophilic esophagitis was grouped according to the number of eosinophils per high power field (non-allergic, <15 eosinophils/high power field; allergic, ≥15 eosinophils/high power field).
Of 1041 endoscopies performed during the study period, 153 revealed evidence of eosinophilic esophagitis. Of these 153, 61 had fewer than 15 eosinophils/high power field and 92 had 15 or more eosinophils/high power field. At 31 of the 153 procedures, white specks were noted in the esophageal mucosa. The sensitivity of white specks in the esophageal mucosa for allergic eosinophilic esophagitis was only 30%, but the specificity was 95%. pH probe testing was performed in 21 patients with white specks and was normal in all.
This report describes a new endoscopic finding associated with allergic eosinophilic esophagitis in children. Eosinophilic esophagitis tends to be severe when white specks are present (≥15 eosinophils/high power field) and is not associated with pathologic gastroesophageal reflux, as demonstrated by pH probe testing.
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