Loweallison7684

Treatment of KrasG12D/+;Trp53fl/fl mice with 5E1 and N-acetylcysteine, as a ROS scavenger, decreased tumor DNA damage, inhibited tumor growth and prolonged mouse survival. selleck inhibitor Thus, IHH induces stromal activation of the canonical Hh signaling pathway to suppress tumor growth and metastases, in part, by limiting ROS activity.Perturbations in ribosome biogenesis have been associated with cancer. Such aberrations activate p53 through the RPL5/RPL11/5S rRNA complex-mediated inhibition of HDM2. Studies using animal models have suggested that this signaling pathway might constitute an important anticancer barrier. To gain a deeper insight into this issue in humans, here we analyze somatic mutations in RPL5 and RPL11 coding regions, reported in The Cancer Genome Atlas and International Cancer Genome Consortium databases. Using a combined computational and statistical approach, complemented by a range of biochemical and functional analyses in human cancer cell models, we demonstrate the existence of several mechanisms by which RPL5 mutations may impair wild-type p53 upregulation and ribosome biogenesis. Unexpectedly, the same approach provides only modest evidence for a similar role of RPL11, suggesting that RPL5 represents a preferred target during human tumorigenesis in cancers with wild-type p53. Furthermore, we find that several functional cancer-associated RPL5 somatic mutations occur as rare germline variants in general population. Our results shed light on the so-far enigmatic role of cancer-associated mutations in genes encoding ribosomal proteins, with implications for our understanding of the tumor suppressive role of the RPL5/RPL11/5S rRNA complex in human malignancies.Cancer stem cells (CSCs) play a central role in cancer initiation, progression, therapeutic resistance, and recurrence in patients. Here we present Capicua (CIC), a developmental transcriptional repressor, as a suppressor of CSC properties in breast cancer cells. CIC deficiency critically enhances CSC self-renewal and multiple CSC subpopulations of breast cancer cells without altering their growth rate or invasiveness. Loss of CIC relieves repression of ETV4 and ETV5 expression, consequently promoting self-renewal capability, EpCAM+/CD44+/CD24low/- expression, and ALDH activity. In xenograft models, CIC deficiency significantly increases CSC frequency and drives tumor initiation through derepression of ETV4. Consistent with the experimental data, the CD44high/CD24low CSC-like feature is inversely correlated with CIC levels in breast cancer patients. We also identify SOX2 as a downstream target gene of CIC that partly promotes CSC properties. Taken together, our study demonstrates that CIC suppresses breast cancer formation via restricting cancer stemness and proposes CIC as a potential regulator of stem cell maintenance.Seasonal differences in mood and depressive symptoms affect a large percentage of the general population, with seasonal affective disorder (SAD) representing the most common presentation. SAD affects up to 3% of the world's population, and it tends to be more predominant in females than males. The brainstem has been shown to be affected by photoperiodic changes, and that longer photoperiods are associated with higher neuronal density and decreased depressive-like behaviours. We predict that longer photoperiod days are associated with larger brainstem volumes and lower depressive scores, and that brainstem volume mediates the seasonality of depressive symptoms. Participants (N = 9289, 51.8% females and 48.1% males) ranging in age from 44 to 79 years were scanned by MRI at a single location. Photoperiod was found to be negatively correlated with low mood and anhedonia in females while photoperiod was found to be positively correlated with brainstem volumes. In females, whole brainstem, pons and medulla volumes individually mediated the relationship between photoperiod and both anhedonia and low mood, while midbrain volume mediated the relationship between photoperiod and anhedonia. No mediation effects were seen in males. Our study extends the understanding of the neurobiological factors that contribute to the pathophysiology of seasonal mood variations.Office cystoscopy may be associated with urinary tract infection (UTI) in up to 10-20% of patients. Current practice of surgical part preparation in males with povidone-iodine excludes distal urethra in males, leaving a possibility for resident intra-urethral flora to cause post-procedural UTI. We designed this randomized study to assess whether additional cleaning of distal urethra with povidone-iodine solution can help reduce post-procedural incidence of UTIs in this setting. Additionally, urethral swab culture was done in the entire cohort to identify the prevalent microflora in the distal male urethra and to evaluate its role in causation of post-procedural UTI. Using a specialized urethral swab culture methodology, 85% males demonstrated some bacteria and 16% showed common uro-pathogens. 28 (14.5%) cases had post-procedure culture positive UTI. The incidence of UTI in control group (22%) was significantly more than the intervention group (7%) (p value less then 0.007). This result strongly supports inclusion of distal urethral irrigation with povidone-iodine in males before office cystoscopy, even when pre-procedure mid-stream urine culture is sterile.Lung infections play a critical role in cystic fibrosis (CF) pathogenesis. CF respiratory tract is now considered to be a polymicrobial niche and advances in high-throughput sequencing allowed to analyze its microbiota and mycobiota. However, no NGS studies until now have characterized both communities during CF pulmonary exacerbation (CFPE). Thirty-three sputa isolated from patients with and without CFPE were used for metagenomic high-throughput sequencing targeting 16S and ITS2 regions of bacterial and fungal rRNA. We built inter-kingdom network and adapted Phy-Lasso method to highlight correlations in compositional data. The decline in respiratory function was associated with a decrease in bacterial diversity. The inter-kingdom network revealed three main clusters organized around Aspergillus, Candida, and Scedosporium genera. Using Phy-Lasso method, we identified Aspergillus and Malassezia as relevantly associated with CFPE, and Scedosporium plus Pseudomonas with a decline in lung function. We corroborated in vitro the cross-domain interactions between Aspergillus and Streptococcus predicted by the correlation network.