Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers ...remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.
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•Spliceosome-targeted therapies (STTs) induce widespread mis-spliced mRNA in cancer•Mis-spliced, intron-retained mRNAs are an unexplored source of endogenous dsRNA•STTs trigger antiviral signaling and extrinsic apoptosis in TNBCs via dsRNA sensors•RNA mis-splicing in human breast cancers correlates with immune signatures
Spliceosome-targeted therapies generate intron-retained, double-stranded RNAs that activate downstream antiviral signaling and extrinsic apoptosis in breast cancer.
Summary
Objective
Abnormal serum liver function tests are common in patients with untreated thyrotoxicosis, even prior to the initiation of antithyroidal medications that may worsen the severity of ...the abnormal serum liver biochemistries. There is a wide range of the incidence of these abnormalities in the published literature. The aim of this study was to assess the risks factors and threshold of thyrotoxicosis severity for developing an abnormal liver biochemical test upon the diagnosis of new thyrotoxicosis.
Design
Single‐institution retrospective cohort study.
Patients
Patients of ≥18 years old receiving medical care at a large, academic, urban US medical centre between 2002–2016.
Measurements
Inclusion criteria were a serum thyroid stimulating hormone (TSH) concentration of <0·3 mIU/l or ICD‐9 code for thyrotoxicosis, with thyrotoxicosis confirmed by either a concurrent elevated serum triiodothyronine (T3) or thyroxine (T4) concentration (total or free within 3 months), and an available liver biochemical test(s) within 6 months of thyrotoxicosis. The biochemical liver tests assessed were serum aspartate transaminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), gamma‐glutamyltransferase (GGT), total bilirubin, and conjugated bilirubin concentrations.
Results
In this cohort of 1514 subjects, the overall incidence of any biochemical liver test abnormality within 6 months of thyrotoxicosis was 39%. An initial serum TSH concentration <0·02 mIU/l, male gender, and African‐American race were significant predictors of an abnormal serum liver biochemical test within 6 months of the diagnosis of new‐onset untreated thyrotoxicosis.
Conclusions
This study identifies risk factors for patients who develop an abnormal serum liver biochemical test result within 6 months of a diagnosis of untreated thyrotoxicosis.
Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, leads to durable weight loss and improves obesity-related comorbidities. However, it induces abnormalities in bone ...metabolism. One unexplored potential contributor is the gut microbiome, which influences bone metabolism and is altered after surgery. We characterized the relationship between the gut microbiome and skeletal health in severe obesity and after LSG. In a prospective cohort study, 23 adults with severe obesity underwent skeletal health assessment and stool collection preoperatively and 6 mo after LSG. Gut microbial diversity and composition were characterized using 16S rRNA gene sequencing, and fecal concentrations of short-chain fatty acids (SCFA) were measured with LC-MS/MS. Spearman's correlations and PERMANOVA analyses were applied to assess relationships between the gut microbiome and bone health measures including serum bone turnover markers (C-terminal telopeptide of type 1 collagen CTx and procollagen type 1 N-terminal propeptide P1NP), areal BMD, intestinal calcium absorption, and calciotropic hormones. Six months after LSG, CTx and P1NP increased (by median 188% and 61%, P < .01) and femoral neck BMD decreased (mean -3.3%, P < .01). Concurrently, there was a decrease in relative abundance of the phylum Firmicutes. Although there were no change in overall microbial diversity or fecal SCFA concentrations after LSG, those with greater within-subject change in gut community microbial composition (β-diversity) postoperatively had greater increases in P1NP level (ρ = 0.48, P = .02) and greater bone loss at the femoral neck (ρ = -0.43, P = .04). In addition, within-participant shifts in microbial richness/evenness (α-diversity) were associated with changes in IGF-1 levels (ρ = 0.56, P < .01). The lower the postoperative fecal butyrate concentration, the lower the IGF-1 level (ρ = 0.43, P = .04). Meanwhile, the larger the decrease in butyrate concentration, the higher the postoperative CTx (ρ = -0.43, P = .04). These findings suggest that LSG-induced gut microbiome alteration may influence skeletal outcomes postoperatively, and microbial influences on butyrate formation and IGF-1 are possible mechanisms.
The adverse skeletal effects of Roux-en-Y gastric bypass (RYGB) are partly caused by intestinal calcium absorption decline. Prebiotics, such as soluble corn fiber (SCF), augment colonic calcium ...absorption in healthy individuals.
We tested the effects of SCF on fractional calcium absorption (FCA), biochemical parameters, and the fecal microbiome in a post-RYGB population.
Randomized, double-blind, placebo-controlled trial of 20 postmenopausal women with history of RYGB a mean 5 years prior; a 2-month course of 20 g/day SCF or maltodextrin placebo was taken orally. The main outcome measure was between-group difference in absolute change in FCA (primary outcome) and was measured with a gold standard dual stable isotope method. Other measures included tolerability, adherence, serum calciotropic hormones and bone turnover markers, and fecal microbial composition via 16S rRNA gene sequencing.
Mean FCA ± SD at baseline was low at 5.5 ± 5.1%. Comparing SCF to placebo, there was no between-group difference in mean (95% CI) change in FCA (+3.4 -6.7, +13.6%), nor in calciotropic hormones or bone turnover markers. The SCF group had a wider variation in FCA change than placebo (SD 13.4% vs 7.0%). Those with greater change in microbial composition following SCF treatment had greater increase in FCA (r2 = 0.72, P = 0.05). SCF adherence was high, and gastrointestinal symptoms were similar between groups.
No between-group differences were observed in changes in FCA or calciotropic hormones, but wide CIs suggest a variable impact of SCF that may be due to the degree of gut microbiome alteration. Daily SCF consumption was well tolerated. Larger and longer-term studies are warranted.
Objective:
Psychiatric symptoms are frequently comorbid with Cushing’s syndrome (CS), a relatively rare condition that results from chronic hypercortisolism. Psychiatric manifestations might be ...present in the prodromal phase, during the course of the illness, and even after the resolution of CS. Our goals are to review the prevalence of psychiatric symptoms in CS; to determine the impact of psychiatric symptoms on morbidity, functioning, and quality of life; and to analyze the impact of treatment of CS on psychiatric symptoms.
Methods:
A systematic search of the literature database was conducted according to predefined criteria. Two authors independently conducted a focused analysis of the full-text articles and reached a consensus on 17 articles to be included in this review.
Results:
Overall, studies suggested that psychiatric symptoms—including, most prominently, depression—were present in a significant proportion of patients with CS. They reported lower health-related quality of life, which persisted even following the resolution of hypercortisolism. Though treatment and cure of CS significantly improved psychiatric symptoms, some patients did not achieve complete resolution of psychiatric symptoms and required continued psychiatric treatment.
Conclusion:
The majority of the literature indicates that psychiatric manifestations are an important part of CS and overall lower health-related quality of life and psychiatric symptoms can persist even after the cure of CS. This emphasizes the significance of early diagnosis for psychiatric management and stresses the importance of monitoring the long-term effects of neurocognitive and psychiatric symptoms and its impact on the quality of life, even after hypercortisolism resolution.
Monitoring the water quality of recreational beaches is only one step toward understanding microbial contamination—the primary cause of beach closings. The surf zone sediment reservoir is typically ...overlooked and may also be important. This study involved monitoring the fecal indicator bacteria (FIB) levels in water and sediment at three ocean beaches (two exposed and one enclosed) during a storm event, conducting laboratory microcosm experiments with sediment from these beaches, and surveying sediment FIB levels at 13 beaches (some exposed and some enclosed). Peaks in
Escherichia coli and enterococci concentrations in water and sediment coincided with storm activity at the two exposed beaches, while levels of both FIB were consistently high and irregular at the enclosed beach. Results from microcosm experiments showing similar, dramatic growth of FIB in both overlying water and sediment from all beaches, as well as results from the beach survey, support the hypothesis that the quiescent environment rather than sediment characteristics can explain the elevated sediment FIB levels observed at enclosed beaches. This work has implications for the predictive value of FIB measurements, and points to the importance of the sediment reservoir.
Biofilms can methylate mercury (Hg) at higher rates than unattached bacteria and are increasingly recognized as important Hg methylation sites in the environment. Our previous study showed that ...methylation rates in biofilm cultures were up to 1 order of magnitude greater than those in planktonic cultures of a sulfate-reducing bacterium. To probe whether the differential Hg methylation rates resulted from metabolic differences between these two cultures, Hg methylation assays following molybdate or chloroform inhibition (a specific inhibitor of the acetyl-CoA pathway) were conducted on biofilm and planktonic cultures of Desulfovibrio desulfuricans strains M8 and ND132. Molybdate was as effective in inhibiting Hg methylation as well as growth in both planktonic and biofilm cultures. The addition of chloroform only impacted Hg methylation in biofilm cultures, suggesting that different pathways are used for methylation in biofilm compared to planktonic cultures. To investigate this further, expression of the cooS gene, which encodes for carbon monoxide dehydrogenase, a key enzyme in the acetyl-CoA pathway, was compared in biofilm and planktonic cultures of ND132. Biofilm cultures showed up to 4 times higher expression of cooS than planktonic cultures. On the basis of these results, the acetyl-CoA pathway appears to play an important role in methylation in biofilm cultures of this organism, possibly by supplying the methyl group to Hg methylating enzymes; methylation in planktonic cultures appears to be independent of this pathway. This observation has important implications, particularly in developing reliable models to predict Hg methylation rates in different environments and perhaps eventually in being able to control this undesirable chemical transformation.
Panic Attacks in HYPERALDOSTERONISM Lin, Tiffany Y; Hedrick, Rebecca M; Ishak, Waguih William
Innovations in clinical neuroscience,
2019, Letnik:
16, Številka:
3-4
Journal Article
Recenzirano
Panic attacks and panic disorders are common in the general population. However, the presence of panic attacks associated with primary hyperaldosteronism has been rarely documented. We describe a ...patient with new-onset hyperaldosteronism secondary to adrenal adenoma who presented with recurrent panic attacks. The patient underwent adenoma resection, which was the definitive cure for the patient's hyperaldosteronism and panic attacks. Clinicians should include hyperaldosteronism on the differential for medical etiologies of panic attacks. Further research is needed to elucidate the mechanistic relationship between primary hyperaldosteronism and panic attacks.
Thyroid eye disease (TED), an autoimmune inflammatory process involving the orbital tissues around the eye, is the most common extra-thyroidal manifestation of Graves’ disease (GD). Due to changes in ...the patient’s appearance, TED is a socially and visually disabling condition with significant impacts on quality of life. The aim of this study is to assess predictors of strabismus, a severe manifestation of TED.
Single-institution retrospective case-control study. Cases of Graves’ ophthalmopathy patients with strabismus were matched 1:1 to controls of Graves’ ophthalmopathy patients without strabismus by age and sex.
Patients ≥18years old with severe Graves’ ophthalmopathy who received their medical care at UCLA with strabismus between 2012 and 2015.
Eligibility criteria for cases was a diagnosis of Graves’ ophthalmopathy with a subsequent diagnosis of strabismus. Using conditional logistic regression, the odds ratios of developing strabismus following the diagnosis of Graves’ disease were assessed. The prognostic indicators assessed include race, ethnicity, cigarette smoking (active), serum thyroid peroxidase (TPO) antibody positivity, serum thyroglobulin (Tg) antibody positivity, antithyroidal medication use, and steroid use.
The study sample (45 cases 1:1 matched against 45 controls) was comprised primarily of non-Hispanic, non-Latino Caucasian women with TED (mean±SD age 63.0±13.1years). There were no significant predictors for the development of strabismus, including cigarette smoking (active), serum thyroid peroxidase (TPO) antibody positivity, serum thyroglobulin (Tg) antibody positivity, antithyroidal medication, and steroid use.
No significant predictors of strabismus, a severe manifestation of Graves’ ophthalmopathy, were identified following a diagnosis of TED in this study.
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