Altered microbiome composition and aberrant promoter hypermethylation of tumor suppressor genes (TSGs) are two important hallmarks of colorectal cancer (CRC). Here we performed concurrent 16S rRNA ...gene sequencing and methyl-CpG binding domain-based capture sequencing in 33 tissue biopsies (5 normal colonic mucosa tissues, 4 pairs of adenoma and adenoma-adjacent tissues, and 10 pairs of CRC and CRC-adjacent tissues) to identify significant associations between TSG promoter hypermethylation and CRC-associated bacteria, followed by functional validation of the methylation-associated bacteria.
Fusobacterium nucleatum and Hungatella hathewayi were identified as the top two methylation-regulating bacteria. Targeted analysis on bona fide TSGs revealed that H. hathewayi and Streptococcus spp. significantly correlated with CDX2 and MLH1 promoter hypermethylation, respectively. Mechanistic validation with cell-line and animal models revealed that F. nucleatum and H. hathewayi upregulated DNA methyltransferase. H. hathewayi inoculation also promoted colonic epithelial cell proliferation in germ-free and conventional mice.
Our integrative analysis revealed previously unknown epigenetic regulation of TSGs in host cells through inducing DNA methyltransferase by F. nucleatum and H. hathewayi, and established the latter as CRC-promoting bacteria. Video abstract.
Ovarian high‐grade serous carcinoma (HGSC) is the most lethal gynecological malignancy. Prevailing evidences suggest that drug resistance and recurrence of ovarian HGSC are caused by the presence of ...cancer stem cells. Therefore, targeting cancer stems is appealing, however, all attempts to date, have failed. To circumvent this limit, we analyzed differential transcriptomes at early differentiation of ovarian HGSC stem cells and identified the developmental transcription factor GATA3 as highly expressed in stem, compared to progenitor cells. GATA3 expression associates with poor prognosis of ovarian HGSC patients, and was found to recruit the histone H3, lysine 27 (H3K27) demethylase, UTX, activate stemness markers, and promote stem‐like phenotypes in ovarian HGSC cell lines. Targeting UTX by its inhibitor, GSKJ4, impeded GATA3‐driven stemness phenotypes, and enhanced apoptosis of GATA3‐expressing cancer cells. Combinations of gemcitabine or paclitaxel with GSKJ4, resulted in a synergistic cytotoxic effect. Our findings provide evidence for a new role for GATA3 in ovarian HGSC stemness, and demonstrate that GATA3 may serve as a biomarker for precision epigenetic therapy in the future.
What's new?
Cancer stem cells (CSCs) routinely evade conventional cancer therapies and fuel tumor regrowth. However, while CSC targeting is an appealing therapeutic strategy, studies are needed to better understand CSC differentiation. Here, in multipotent CSCs from ovarian high‐grade serous carcinomas (HGSCs), complexes consisting of the stemness regulator GATA3 and the histone demethylase UTX were found to maintain cancer stemness via epigenetic activation of c‐MYC, CD44, and NANOG. GATA3 was further identified as an independent risk factor in early‐stage ovarian HGSC. The results suggest that GATA3 is a prognostic marker in ovarian tumorigenesis and that targeting GATA3/UTX is a promising therapeutic approach.
Aim
The aim of the present study was to evaluate the treatment outcome of craniopharyngioma at a neurosurgery centre in Hong Kong over an 18‐year period.
Patients and Methods
The study design was a ...retrospective review of patients with craniopharyngioma. Clinical records of all patients with histologically‐confirmed craniopharyngioma during the period from January 1998 to December 2015 at a neurosurgery centre in Hong Kong were reviewed. Outcome measures included recurrence, morbidities and mortalities.
Results
From January 1998 to December 2015, 13 patients with histologically‐diagnosed craniopharyngioma were identified. Gross total resection (GTR) was achieved in 75 per cent (9/12) of primary craniopharyngiomas; a total of 25 per cent (3/12) had recurrence requiring reoperation, which was comparable to the 24.5 per cent reported in the literature. Morbidities included visual field defect (16.7 per cent), visual acuity deficit (8.3 per cent) and endocrinopathy (83.3 per cent). All patients with adjuvant radiotherapy in the present study had no tumour recurrence or progression. There was no perioperative mortality.
Conclusion
The treatment outcome of craniopharyngioma at a regional neurosurgical centre in Hong Kong had a recurrence rate comparable to the international standard. Consistent with other reported studies, postoperative morbidities are high with GTR. Further large‐scale, randomized, controlled trials are needed to demonstrate a superior long‐term outcome from a more conservative approach.
Head and neck cancers are characterized by both genetic and epigenetic aberrations. In treating head and neck cancers, ionizing radiation (IR) is an essential modality in either definitive or ...adjuvant setting. However, radiation-resistant head and neck cancers are not uncommon. The major biological determinator for IR resistance was previously considered at genetic level because DNA is the major target of irradiation damage. However, in head and neck cancers, recent evidence demonstrated epigenetic disturbance after IR, implicating its role in IR resistance. Hence, this chapter intends to establish an in vitro model for investigating DNA methylation changes in IR-resistant head and neck cancer cells. Bisulfite pyrosequencing is the main methodology it introduced.
Experimental evidence has indicated the benefit of simvastatin in the treatment of subarachnoid hemorrhage. However, no clinical data are available to answer whether a high-dose regimen is more ...effective than a normal-dose regimen, even though the biochemical actions and related neuroprotective mechanisms are thought to be dose related.
To determine whether 80 mg simvastatin daily (high dose) over 3 weeks initiated within 96 hours of the ictus will reduce the incidence of delayed ischemic deficits after subarachnoid hemorrhage compared with 40 mg simvastatin daily (normal dose), leading to improvements in clinical outcomes and thus cost-effectiveness.
The study design is a randomized, controlled, double-blind clinical trial (www.ClinicalTrials.gov; identifier: NCT01077206). Two hundred forty patients with aneurysmal subarachnoid hemorrhage (presenting within 96 hours of the ictus) from 6 neurosurgical centers are being recruited over 3 years. The primary outcome measure is the presence of delayed ischemic deficits. Secondary outcome measures include modified Rankin Disability Score at 3 months and cost-effectiveness analysis.
This will be the first study to clarify whether high-dose simvastatin is better than normal-dose simvastatin for patients with acute aneurysmal subarachnoid hemorrhage in terms of neurological outcomes and cost-effectiveness.
In the present trial, we compare high-dose and normal-dose simvastatin; we know that another ongoing phase III multicenter trial (Simvastatin in Aneurysmal Subarachnoid Haemorrhage; http://www.stashtrial.com/home.html) is comparing normal-dose and no simvastatin. When the results are interpreted together, the research question of a possible beneficial effect of high-dose simvastatin in acute aneurysmal subarachnoid hemorrhage could be answered.
This study aimed to evaluate the safety and efficacy of subdural urokinase in reducing the recurrence of chronic subdural hematoma (cSDH).
Consecutive adults with cSDH and burr-hole drainage from 1 ...January 2013 to 31 December 2017 were retrospectively analyzed. Clinical records, radiologic images, laboratory data, and medication records were reviewed. The primary outcome was the recurrence rate of cSDH in patients with or without urokinase instillation. Secondary outcomes included complication rates such as infection and acute intracranial hemorrhage. Univariate and multivariate analyses were conducted to identify independent factors associated with cSDH recurrence.
A total of 297 consecutive patients were identified for analysis. The average dosage of urokinase instillation via the subdural drain into the subdural space was 15,800 units (5000−60,000 units) over a mean duration of 2 days (1−6 days). The symptomatic recurrence rate of cSDH was significantly lower with urokinase at 3.0% versus 11.7% with no urokinase (odds ratio: 0.234; P = 0.022). Univariate analysis and multivariate analysis showed that bilateral cSDH and the presence of underlying liver disease were significantly associated with higher recurrence, while the instillation of urokinase was significantly and independently associated with lower recurrence (odds ratio = 0.311; P = 0.005). Complication rates including infection and hemorrhage were comparable with patients with or without urokinase and had no significant difference.
Instillation of urokinase was safe for patients with cSDH. The recurrence rate of cSDH was significantly lower with urokinase.
Abstract
BACKGROUND:
Experimental evidence has indicated the benefit of simvastatin in the treatment of subarachnoid hemorrhage. However, no clinical data are available to answer whether a high-dose ...regimen is more effective than a normal-dose regimen, even though the biochemical actions and related neuroprotective mechanisms are thought to be dose related.
OBJECTIVE:
To determine whether 80 mg simvastatin daily (high dose) over 3 weeks initiated within 96 hours of the ictus will reduce the incidence of delayed ischemic deficits after subarachnoid hemorrhage compared with 40 mg simvastatin daily (normal dose), leading to improvements in clinical outcomes and thus cost-effectiveness.
METHODS:
The study design is a randomized, controlled, double-blind clinical trial (www.ClinicalTrials.gov; identifier: NCT01077206). Two hundred forty patients with aneurysmal subarachnoid hemorrhage (presenting within 96 hours of the ictus) from 6 neurosurgical centers are being recruited over 3 years. The primary outcome measure is the presence of delayed ischemic deficits. Secondary outcome measures include modified Rankin Disability Score at 3 months and cost-effectiveness analysis.
EXPECTED OUTCOMES:
This will be the first study to clarify whether high-dose simvastatin is better than normal-dose simvastatin for patients with acute aneurysmal subarachnoid hemorrhage in terms of neurological outcomes and cost-effectiveness.
DISCUSSION:
In the present trial, we compare high-dose and normal-dose simvastatin; we know that another ongoing phase III multicenter trial (Simvastatin in Aneurysmal Subarachnoid Haemorrhage; http://www.stashtrial.com/home.html) is comparing normal-dose and no simvastatin. When the results are interpreted together, the research question of a possible beneficial effect of high-dose simvastatin in acute aneurysmal subarachnoid hemorrhage could be answered.
Bladder cancer is the ninth most common cancer in the world and eighth most common in Hong Kong. Urothelial carcinoma (UC) comprised the majority of bladder cancer. Genetic and epigenetic alterations ...played a very important role of bladder cancer development, however detailed high resolution mapping of genetic and epigenetic abnormalities are lacking. We aimed to investigate the genetic and epigenetic alterations in bladder urothelial carcinoma (UC) by allelotyping analysis and gene promoter hypermethylation respectively. Moreover, the diagnostic potential of epigenetic alterations in urine were also assessed. In allelotyping analysis, high frequency of allelic imbalance was observed in chromosome arm 1q (61.9%), 3p (61.9%), 4q (66.67%), 8p (57.14%), 9p (76.2%), and 9q (66.67%). Allelic imbalance with frequency above average was also observed in chromosome arm 2q, 10p, 10q, 11p, 11q, 12q, 13q, 15q, 17p, and 19q. The allelic imbalance of each case and fractional allelic loss (FAL) for each chromosome was associated with higher tumor grade and stage. We have also delineated several minimal deletion regions (MDR) on chromosome 3p, 4q, 5q, 8p, 9p, 9q, 11p, 13q, 16q, 17p, and 19p. MDR on 4q, 11p, 16q, and 19p were first described in bladder cancer. In methylation study, frequent methylation was detected in RAR β (87.8%), 14-3-3σ (76.9%), E-cadherin (63.3%), DAPK (58.2%), hMLH1 (48.7%), RASSF1A (46.2%), p14 (35.9%), APC (30.8%), and p16 (26.5%). Methylation was also detected in HLTF (20.5%), p15 (13.3%), SOCS-1 (12.8%) and HIC-1 (12.8%) of the tumor cases. However, methylation of GSTP1 (5.1%), MGMT (5.1%) and TSLC1 (0%) was rare in bladder UC. Normal bladder epithelium did not show any aberrant hypermethylation except for RARβ (42.9%), and 14-3-3σ (16.6%). Methylation index of each case was significantly correlated with tumor grade, stage and muscle invasiveness. Meanwhile, methylation of 14-3-3σ, HLTF, SOCS-1, and HIC-1 was first reported in bladder cancer. In voided urine samples, methylation can be detected in DAPK, RARβ, E-cadherin, RASSF1A and p16. The sensitivity of methylation analysis (95.5%) was higher than that of urine cytology (45.5%) in cancer detection. Moreover, we are the first group to demonstrate the potential diagnostic value of methylation detection in urine of bladder cancer patients. In conclusion, we have demonstrated a distinct genetic and epigenetic pattern in bladder cancer that a progressive increase in genetic and epigenetic alterations was observed. Detection of gene methylation in routine voided urine using selected markers appeared to be more sensitive than conventional urine cytology. The potential application of such observations may be explored in both diagnosis and detection, as well as in monitoring relapse in patient treated for urothelial carcinoma.
Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene ...expression in TP53-mutated AML, we identified pololike kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms, and therapeutic potential in TP53-mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wild-type AML and was increased in TP53-mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wild-type AML. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wild-type and mutated AML, resulting in histone modification through PLK4-induced PRMT5 phosphorylation. In TP53-mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon coculture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients, and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53-mutated AML.
Insomnia and eveningness are common and often comorbid conditions in youths. While cognitive behavioural therapy for insomnia (CBT-I) has been suggested as a promising intervention, it remains ...unclear whether it is sufficient to also address circadian issues in youths. In addition, despite that light has been shown to be effective in phase-shifting one's circadian rhythm, there has been limited data on the effects of bright light therapy and its combination with CBT-I on sleep and circadian outcomes in youths. The current protocol outlines a randomised controlled trial that examines the efficacy of CBT-I and CBT-I plus bright light therapy (BLT) in reducing insomnia severity, improving mood symptoms and daytime functioning (e.g. sleepiness, fatigue, cognitive function), and improving subjective and objective sleep and circadian measures compared to a waitlist control group.
We will carry out a randomised controlled trial (RCT) with 150 youths aged 12-24 who meet the criteria of insomnia and eveningness. Participants will be randomised into one of three groups: CBT-I with bright light therapy, CBT-I with placebo light, and waitlist control. Six sessions of CBT-I will be delivered in a group format, while participants will be currently asked to use a portable light device for 30 min daily immediately after awakening throughout the intervention period for bright light therapy. The CBT-I with light therapy group will receive bright constant green light (506 lx) while the CBT-I with placebo light group will receive the modified light device with the LEDs emitting less than 10 lx. All participants will be assessed at baseline and post-treatment, while the two active treatment groups will be additionally followed up at 1 month and 6 months post-intervention. The primary outcome will be insomnia severity, as measured by the Insomnia Severity Index. Secondary outcomes include self-reported mood, circadian, daytime functioning, and quality of life measures, as well as sleep parameters derived from actigraphy and sleep diary and neurocognitive assessments. Objective measures of the circadian phase using dim-light melatonin onset assessment and sleep parameters using polysomnography will also be included as the secondary outcomes.
This study will be the first RCT to directly compare the effects of CBT-I and BLT in youths with insomnia and eveningness. Findings from the study will provide evidence to inform the clinical management of insomnia problems and eveningness in youths.
ClinicalTrials.gov NCT04256915. Registered on 5 February 2020.
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