Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To ...overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.
Background
The clinical predictors and biological mechanisms for localized prostate cancer (PCa) outcomes remain mostly unknown. We aim to evaluate the role of serum immune-checkpoint-related (ICK) ...proteins and genetic variations in predicting outcomes of localized PCa.
Methods
We profiled the serum levels of 14 ICK-related proteins (BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, Tim-3, CD28, CD80, 4-1BB, CD27, and CTLA-4) in 190 patients with localized PCa. The genotypes of 97 single nucleotide polymorphisms (SNPs) from 19 ICK-related genes were analyzed in an extended population (
N
= 1762). Meta-data from ArrayExpress and TCGA was employed to validate and to probe functional data. Patients were enrolled and tumor aggressiveness, biochemical recurrence (BCR), and progression information were obtained. Statistical analyses were performed analyzing associations between serum biomarkers, genotypes, mRNA and outcomes.
Results
We showed that serum (s)BTLA and sTIM3 levels were associated with PCa aggressiveness (
P
< 0.05). sCD28, sCD80, sCTLA4, sGITR, sHVEM and sIDO correlated with both BCR and progression risks (all
P
< 0.05). We further identified ICK variants were significantly associated with aggressiveness, BCR and progression. Among them, 4 SNPs located in
CD80
(rs7628626, rs12695388, rs491407, rs6804441) were not only associated with BCR and progression risk, but also correlated with sCD80 level (
P
< 0.01). rs491407 was further validated in an independent cohort. The
CD80
mRNA expression was associated with BCR (HR, 1.85, 95% CI 1.06–3.22,
P
= 0.03) in meta-analysis of validation cohorts.
Conclusion
We highlight the prognostic value of serum ICK-related proteins for predicting aggressiveness, BCR and progression of PCa. The genetic variations and mRNA expression in CD80 could be predictors and potential targets of localized PCa.
Human infections with avian influenza viruses (AIVs) have frequently raised global concerns of emerging, interspecies-transmissible viruses with pandemic potential. Waterfowl, the predominant ...reservoir of influenza viruses in nature, harbor precursors of different genetic lineages that have contributed to novel pandemic influenza viruses in the past.
Two duck influenza H5N2 viruses, DV518 and DV413, isolated through virological surveillance at a live-poultry market in Taiwan, showed phylogenetic relatedness but exhibited different replication capabilities in mammalian Madin-Darby Canine Kidney (MDCK) cells. This study characterizes the replication properties of the two duck H5N2 viruses and the determinants involved.
The DV518 virus replicated more efficiently than DV413 in both MDCK and chicken DF1 cells. Interestingly, the infection of MDCK cells by DV518 formed heterogeneous plaques with great differences in size large (L) and small (S), and the two viral strains (p518-L and p518-S) obtained from plaque purification exhibited distinguishable replication kinetics in MDCK cells. Nonetheless, both plaque-purified DV518 strains still maintained their growth advantages over the plaque-purified p413 strain. Moreover, three amino acid substitutions in PA (P224S), PB2 (E72D), and M1 (A128T) were identified in intra-duck variations (p518-L vs p518-S), whereas other changes in HA (N170D), NA (I56T), and NP (Y289H) were present in inter-duck variations (DV518 vs DV413). Both p518-L and p518-S strains had the N170D substitution in HA, which might be related to their greater binding to MDCK cells. Additionally, polymerase activity assays on 293T cells demonstrated the role of vRNP in modulating the replication capability of the duck p518-L viruses in mammalian cells.
These results demonstrate that intra-host phenotypic variation occurs even within an individual duck. In view of recent human infections by low pathogenic AIVs, this study suggests possible determinants involved in the stepwise selection of virus variants from the duck influenza virus population which may facilitate inter-species transmission.
Background
Muscle wasting may explain the paradoxical mortality of patients with high estimated glomerular filtration rates (eGFRs) derived from equation methods. However, empirical evidence and ...solutions remain insufficient.
Methods
In this retrospective cohort study, we compared the performance of equation methods for predicting all‐cause mortality; we used 24‐h creatinine clearance (24‐h CrCl), equation‐based eGFRs, and a new eGFR estimating equation weighting for population 24‐h urine creatinine excretion rate (U‐CER). From 2003 to 2018, we identified 4986 patients whose data constituted the first 24‐h CrCl measurement data in the Clinical Research Data Repository of China Medical University Hospital and were followed up for at least 5 years after careful exclusion. Three GFR estimation equations the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI), Modification of Diet in Renal Disease (MDRD) Study, and Taiwanese MDRD, 24‐h CrCl, and 24‐h U‐CER–adjusted eGFR were used.
Results
A high correlation was observed among the eGFR levels derived from the equation methods (0.995–1.000); however, the correlation decreased to 0.895–0.914 when equation methods were compared with the 24‐h CrCl or 24‐h U‐CER–adjusted equation‐based eGFR. In the Bland–Altman plots, the average discrepancy between the equation methods and the 24‐h CrCl method was close to zero (maximal bias range: 5.12 for the Taiwanese MDRD equation vs. 24‐h CrCl), but the range in limit of agreement was wide, from ±43.7 mL/min/1.73 m2 for the CKD‐EPI equation to ±54.3 mL/min/1.73 m2 for the Taiwanese MDRD equation. A J‐shaped dose–response relationship was observed between all equation‐based eGFRs and all‐cause mortality. Only 24‐h CrCl exhibited a non‐linear negative dose–response relationship with all‐cause mortality. After adjustment for 24‐h U‐CER in the statistical model, the paradoxical increase in mortality risk for an eGFR of >90 mL/min/1.73 m2 returned to null. When 24‐h U‐CER was used directly to correct eGFR, the monotonic non‐linear negative relationship with all‐cause mortality was almost identical to that of 24‐h CrCl.
Conclusions
The 24‐h U‐CER–adjusted eGFR and 24‐h CrCl are viable options for informing mortality risk. The 24‐h U‐CER adjustment method can be practically implemented to eGFR‐based care and effectively mitigate the inherent confounding biases from individual's muscle mass amount due to both sex and racial differences.
To explore the utility of multidisciplinary approaches in the treatment of patients with pancreatic cancer with liver metastases (PCLM).
From 2002 to 2007, a total of 164 consecutive patients with ...PCLM treated with chemotherapy, radiation therapy, and/or Chinese herbal medicine were included in this study. Clinical parameters, treatments received, and survival time from initial diagnosis were analyzed.
Of the 164 patients, 113 (69%) were men and 51 (31%) were women, with median age of 58 years. One hundred thirty-two patients (80%) had synchronous liver metastases, and 57 patients (35%) had extrahepatic metastases. Overall median survival time of the 164 patients was 4.7 months; 23 (14%) were alive at least 12 months after initial diagnosis of liver metastases. Karnofsky performance status of less than 80, weight loss (>10% within 6 months), ascites, and carbohydrate antigen 19-9 of 1000 U/mL or greater were the most relevant predictors of poor survival. Multivariate analysis showed that chemotherapy and Chinese herbal medicine were protective factors.
Multimodality treatment is well tolerated by patients with PCLM and may be effective in prolonging their survival. Awareness of the implications of these prognostic factors may assist in evaluating the survival potential of patients and selecting the most appropriate treatments.
Abstract Background Nonrandomized studies of unilateral nerve-sparing (UNS) radical prostatectomy (RP) have reported improved recovery of erectile function if the sacrificed cavernous nerve is ...reconstructed with a sural nerve graft (SNG). Objective To determine whether UNS RP plus SNG results in a 50% relative increase in potency at 2 yr compared to UNS RP alone. Design, setting, and participants The study enrolled patients from October 2001–May 2006 from a single academic center and was randomized, open label. Participants were men with localized prostate cancer recommended for UNS RP, less than 66 yr old, normal baseline erectile function, and willing to participate in early erectile dysfunction (ED) therapy. Patients were followed up to 2 yr. Intervention Patients underwent UNS RP and ED therapy starting at 6 wk: oral prostaglandin type-5 (PDE5) inhibitor, vacuum erection device (VED), and intracavernosal injection therapy. In the SNG group, a plastic surgeon performed the procedure at the time of RP. Measurements The ability to have an erection suitable for intercourse with or without a PDE5 inhibitor at 2 yr. The hypothesis was that SNG would result in a 60% potency rate compared to 40% for controls (80% power, 5% two-way significance). Results and Limitations The trial planned to enroll 200 patients, but an interim analysis at 107 patients met criteria for futility and the trial was closed. For patients completing the protocol to 2 yr, potency was recovered in 32 of 45 (71%) of SNG and 14 of 21 (67%) of controls ( p = 0.777). By intent-to-treat analysis, potency recovered in 32 of 66 (48.5%) of SNG and 14 of 41 (34%) of controls ( p = 0.271). No differences were seen in time to potency or quality of life scores for ED and urinary function. Limitations included slower-than-expected accrual and poor compliance with ED therapy: <65% for VED and <40% for injections. Conclusions The addition of SNG to a UNS RP did not improve potency at 2 yr following surgery. Trial Registration ClinicalTrials.gov, Identifier: NCT00080808 , http://www.clinicaltrials.gov/ct2/show/NCT00080808?term=NCT00080808&rank=1.
Background: To analyse the magnitude of cylindrical corrections over which cyclotorsion compensation with iris recognition (IR) technology is beneficial during wavefront laser‐assisted in situ ...keratomileusis.
Design: A retrospectively comparative case series.
Participants or Samples: Fifty‐four eyes that underwent wavefront laser‐assisted in situ keratomileusis without IR (non‐IR group) and 53 eyes that underwent wavefront laser‐assisted in situ keratomileusis with IR (IR group) were recruited.
Methods: Subgroup analysis based on baseline astigmatism were: a low degree of astigmatism (≥1.00 D to <2.00 D), a moderate degree of astigmatism (≥2.00 D to <3.00 D) and a high degree of astigmatism (≥3.00 D).
Main Outcome Measures: Vector and non‐vector analyses were used for comparison.
Results: The mean cylinder was −1.89 ± 0.76 D in the non‐IR group and −2.00 ± 0.77 D in the IR group. Postoperatively, 38 eyes (74.50%) in the IR group and 31 eyes (57.50%) in the non‐IR group were within ± 0.50 D of the target induced astigmatism vector (P = 0.063). The difference vector was 0.49 ± 0.28 in the IR group and 0.63 ± 0.40 in the non‐IR group (P = 0.031). In the analysis of subgroups, the magnitude of error was significantly lower in the moderate IR subgroup than that of the moderate non‐IR subgroup (P = 0.034). Furthermore, the moderate IR subgroup had a lower mean difference vector (P = 0.0078) and a greater surgically induced astigmatism (P = 0.036) than those of the moderate non‐IR group.
Conclusions: Wavefront laser‐assisted in situ keratomileusis for the treatment of astigmatism using IR technology was effective and accurate for the treatment of myopic astigmatism.
AIM： To examine light-emitting-diode（LED）-induced retinal neuronal cell damage and its wavelength-driven pathogenic mechanisms.METHODS： Sprague-Dawley rats were exposed to blue LEDs（460 nm）,green ...LEDs（530 nm）,and red LEDs（620 nm）.Electroretinography（ERG）,Hematoxylin and eosin（H＆E） staining,transmission electron microscopy（TEM）,terminal deoxynucleotidyl transferase d UTP nick end labeling（TUNEL）,and immunohistochemical（IHC） staining,Western blotting（WB） and the detection of superoxide anion（O2^-·）,hydrogen peroxide（H2O2）,total iron,and ferric（Fe^3＋） levels were applied.RESULTS： ERG results showed the blue LED group induced more functional damage than that of green or red LED groups.H＆E staining,TUNEL,IHC,and TEM revealed apoptosis and necrosis of photoreceptors and RPE,which indicated blue LED also induced more photochemical injury.Free radical production and iron-related molecular marker expressions demonstrated that oxidative stress and ironoverload were associated with retinal injury.WB assays correspondingly showed that defense gene expression was up-regulated after the LED light exposure with a wavelength dependency.CONCLUSION： The study results indicate that LED bluelight exposure poses a great risk of retinal injury in awake,task-oriented rod-dominant animals.The wavelengthdependent effect should be considered carefully when switching to LED lighting applications.
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