The transcription factor NF-κB is a critical regulator of inflammatory and cell survival signals. Proteasomal degradation of NF-κB subunits plays an important role in the termination of NF-κB ...activity, and at least one of the identified ubiquitin ligases is a multimeric complex containing Copper Metabolism Murr1 Domain 1 (COMMD1) and Cul2. We report here that GCN5, a histone acetyltransferase, associates with COMMD1 and other components of the ligase, promotes RelA ubiquitination, and represses κB-dependent transcription. In this role, the acetyltransferase activity of GCN5 is not required. Interestingly, GCN5 binds more avidly to RelA after phosphorylation on Ser 468, an event that is dependent on IKK activity. Consistent with this, we find that both GCN5 and the IκB Kinase (IKK) complex promote RelA degradation. Collectively, the data indicate that GCN5 participates in the ubiquitination process as an accessory factor for a ubiquitin ligase, where it provides a novel link between phosphorylation and ubiquitination.
Hamartomatous polyposis syndromes (HPS) are rare autosomal-dominant inherited disorders associated with gastrointestinal (GI) tract and other cancers. HPS include Peutz-Jeghers syndrome (PJS), ...juvenile polyposis syndrome (JPS), and phosphatase and tensin homolog hamartomatous tumor syndromes (PHTS). Diagnosis, management, and outcome prediction of HPS pose a clinical challenge. To characterize genotype, phenotype, histology and outcomes of individuals with HPS.
A retrospective cohort study (2004-2017) of consecutive patients that were clinically diagnosed with HPS that visited a specialized GI oncology clinic. Demographic, clinicopathological, and genetic data were obtained from medical records.
Fifty-two individuals from 34 families were included. Common clinical manifestations were GI bleeding (40% JPS, 23% PJS, and 25% PHTS) and bowel obstruction (46.15% PJS and 11.4% JPS). Twenty patients (38.4%) underwent surgery, 5 of whom required multiple procedures. Higher polyp burden was associated with the need for surgery (P = 0.007). Polyp histology varied widely with 69.2% of patients exhibiting histology different from the syndrome hallmark. GI cancer history was positive in 65%, 40%, and 50% of JPS, PJS, and PHTS families, respectively. Five (9.6%) patients developed cancers (one patient each had small bowel-1, colon-1, and thyroid-1, one patient had both small bowel adenocarcinoma and breast cancer, and one had both breast cancer and liposarcoma). Twenty (38.4%) patients tested positive for STK11, PTEN, SMAD4, BMPR1A, or AKT1 mutations: Sanger sequencing and multi-gene next generation sequencing panels detected mutations in 40.9% and 100% of tested cases, respectively.
HPS patients present versatile phenotypes with overlapping clinical and histological characteristics. Polyp burden is associated with the need for surgery. Next-generation sequencing increases mutation detection.
NF-κB is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled ...degradation of inhibitory IκB proteins. In addition, the inactivation of DNA-bound NF-κB is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-κB blockade. Indeed, patient-derived cells demonstrated impaired NF-κB activation due to decreased IκB ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of IκB proteins. Taken together, our results indicate that CCDC22 participates in NF-κB activation and that its deficiency leads to decreased IκB turnover in humans, highlighting an important regulatory component of this pathway.
This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery RRS) in carriers of pathogenic MMR ...(path_MMR) variants.
The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30–69 years.
Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.
Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.
•Premenopausal oophorectomies in patients not at increased risk of ovarian cancer.•Uptake of risk-reducing surgery (RRS) in Lynch syndrome aligns poorly with cancer risk and mortality.•Uptake of RRS does not correspond well with current clinical guidelines.•There is an unmet need for multidisciplinary planning to avoid repeated surgery.
Hepatotoxicity due to intravenous amiodarone (HIVAD) is a rare side effect with a distinct pattern of enzyme disturbances compared to liver damage from oral amiodarone. Intravenous amiodarone is ...administered for acute arrhythmias often causing heart failure. The enzyme abnormalities and clinical setting are very similar to that of ischemic hepatitis, a far more common condition.
To ascertain if acute HIVAD exists as a separate entity or whether reported cases may be explained by ischemic hepatitis
In this case-control retrospective study the files of hospitalized patients with markedly elevated aminotransferases were reviewed for the diagnoses of HIVAD or ischemic hepatitis. Medline was searched for published cases of HIVAD. Pooled data of all patients with HIVAD were compared to a control group with ischemic hepatitis.
There were no significant differences in the clinical characteristics, laboratory results or histological findings between HIVAD and ischemic hepatitis patients.
In our opinion, there is currently insufficient data to support the existence of distinct HIVAD, and ischemic hepatitis is a more probable diagnosis in most reported cases. Withdrawing amiodarone because of assumed hepatic damage could deprive patients of a life-saving therapy.
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Background: More than 1.8 million new cancer cases are expected to be diagnosed in 2020. Only in the U.S, about 606,520 Americans are expected to die this year, which translates ...to about 1,660 deaths per day. However, when found early, in the asymptomatic phase, cancer is often effectively treated or even cured. The few cancer screens available today, including mammograms and colonoscopies, each look for a single type of cancer. CD24 is hardly expressed in normal cells (but to B-lymphocytes, differentiating neuroblasts and neutrophils) but is overexpressed in numerous human cancers. Aim: To establish a universal cancer screening blood test. Methods: Blood samples were obtained from consecutive patients and healthy volunteers. 1x10
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leukocytes were stained using anti-CD11b-PerCp-Cy5.5 and anti-CD24-FITC and analyzed by flow cytometry (CyFlow Cube 6, Sysmex, Germany). Percentage of positive cells was determined by subtracting the percentage of CD24 and CD11b-positive cells (dual stain) from CD24-positive cells (single stain). The cut off for cancer detection was 25. Healthy subjects underwent a thorough evaluation at the health promotion center and integrated cancer prevention center. All cancers were verified histologically. Results: CD24/CD11b expression in the healthy population was evaluated in 337 women and 408 men, ages 20-85. There were 222 cancer patients. After excluding thyroid and bladder cancers, the assay detected 146 out of 196 (75%) cancers at all stages and even in 31 out of colonic adenomas (table). The levels of CD24 drop back to near normal level following successful surgery/chemotherapy. The test score was not affected by age, gender, fasting and the time of the day that the blood sample is taken. In 55 cases the test was performed twice, with similar results, as well as when the test was performed in another flow cytometry, after 1d, 1w, 1m after freezing . Conclusions: 1. CD24 is a universal cancer screening. 2. It can detect pre malignant lesions like adenomas in the colon. 3. Preliminary results suggest that it can serve as a predictive marker. Table: see text
Colorectal cancer (CRC) is largely preventable with routine screening and surveillance colonoscopy; however, interval cancers arising from precancerous lesions missed by standard colonoscopy still ...occur. An increased adenoma detection rate (ADR) has been found to be inversely associated with interval cancers. The G-EYE device includes a reusable balloon integrated at the distal tip of a standard colonoscope, which flattens haustral folds, centralizes the colonoscope’s optics, and reduces bowel slippage. The insufflated balloon also aims to enhance visualization of the colon during withdrawal, thereby increasing the ADR.
In this randomized, controlled, international, multicenter study (11 centers), patients (aged ≥50 years) referred to colonoscopy for screening, surveillance, or changes in bowel habits were randomized to undergo either balloon-assisted colonoscopy by using an insufflated balloon during withdrawal or standard high-definition colonoscopy. The primary endpoint was the ADR.
One thousand patients were enrolled between May 2014 and September 2016 to undergo colonoscopy by experienced endoscopists; 803 were finally analyzed (standard colonoscopy n = 396; balloon-assisted colonoscopy n = 407). Baseline parameters were similar in both groups. Balloon-assisted colonoscopy provided a 48.0% ADR compared with 37.5% in the standard colonoscopy group (28% increase; P = .0027). Additionally, balloon-assisted colonoscopy provided for a significant increase in detection of advanced (P = .0033) flat adenomas (P < .0001) and sessile serrated adenomas/polyps (P = .0026).
Balloon-assisted colonoscopy yielded a higher ADR and increased the detection of advanced, flat, and sessile serrated adenomas/polyps when compared with standard colonoscopy. Improved detection by the G-EYE device could impact the quality of CRC screening by reducing miss rates and consequently reducing interval cancer incidence. (Clinical trial registration number: NCT01917513.)
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