The study investigated attentional biases for pictorial and linguistic health-threat stimuli in high and low health anxious individuals, who were selected from the upper and lower quartile ranges of a normal sample using a screening measure of health anxiety. Attentional bias was assessed using a visual probe task which presented health-threat and neutral pictures and words at two exposure durations, 500 ms and 1250 ms. The prediction that the high health anxious group would show a greater attentional bias for health-threat cues than the low health anxious group was not supported despite the groups being well-differentiated on a general measure of health anxiety, the Illness Attitudes Scale (IAS). Instead, the results indicated that individuals with high levels of anxiety sensitivity showed a significantly greater initial attentional bias for threat pictures compared with those with low anxiety sensitivity, as assessed by the Anxiety Sensitivity Index (ASI).

p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting expression of FLIP(L) using siRNA or entinostat (a clinically relevant class-I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly induced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.

IntroductionCutaneous metastasis of bladder carcinoma is extremely rare with a limited number of published cases. An awareness of this rare clinical entity and high index of suspicion is needed for diagnosis, as it can occur months or rarely as in this case, even years, after the primary cancer.Case presentationAn 81-year-old Caucasian man presented with a one-year history of increasing left leg swelling and a two-month history of a macular-nodular rash on the anterior thigh, on a background of a high-grade (WHO Grade 2 of 3) papillary and invasive transitional cell carcinoma of the bladder in 2006. Following investigations, he was diagnosed as having probable locoregional recurrence of previously resected urothelial cancer of the bladder with extensive retrograde lymphatic permeation into the left thigh with cutaneous eruptions of malignancy. He completed a planned course of palliative radiation therapy to the left thigh lesions (30Gy divided over 10 fractions) as well as the left pelvic node (a total dose of 18Gy divided over six fractions). The disease ran an aggressive course and our patient died six months after the diagnosis of cutaneous metastases.ConclusionsMetastatic disease should always be considered in the differential diagnosis in patients with a previous history of bladder cancer who present with cutaneous nodules, even many years after the initial diagnosis at the primary site.

The p53 tumour suppressor is best known for its canonical role as “guardian of the genome”, activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.

Regulation of colonic motility depends on the integrity of enteric inhibitory neurotransmission mediated by nitric oxide (NO), purine neurotransmitters, and neuropeptides. Intramuscular interstitial cells of Cajal (ICC-IM) and platelet-derived growth factor receptor-α-positive (PDGFRα) cells are involved in generating responses to NO and purine neurotransmitters, respectively. Previous studies have suggested a decreased nitrergic and increased purinergic neurotransmission in ( ) mice that display lesions in ICC-IM along the gastrointestinal tract. However, contributions of NO to these phenotypes have not been evaluated. We used small-chamber superfusion assays and HPLC to measure the spontaneous and electrical field stimulation (EFS)-evoked release of nicotinamide adenine dinucleotide (NAD)/ADP-ribose, uridine adenosine tetraphosphate (Up4A), adenosine 5'-triphosphate (ATP), and metabolites from the tunica muscularis of human, monkey, and murine colons and circular muscle of monkey colon, and we tested drugs that modulate NO levels or blocked NO receptors. NO inhibited EFS-evoked release of purines in the colon via presynaptic neuromodulation. Colons from , and mice displayed augmented neural release of purines that was likely due to altered nitrergic neuromodulation. Colons from mice demonstrated decreased nitrergic and increased purinergic relaxations in response to nerve stimulation. mouse colons demonstrated reduced expression and reduced NO release. Our results suggest that enhanced purinergic neurotransmission may compensate for the loss of nitrergic neurotransmission in muscles with partial loss of ICC. The interactions between nitrergic and purinergic neurotransmission in the colon provide novel insight into the role of neurotransmitters and effector cells in the neural regulation of gastrointestinal motility. This is the first study investigating the role of nitric oxide (NO) and intramuscular interstitial cells of Cajal (ICC-IM) in modulating neural release of purines in colon. We found that NO inhibited release of purines in human, monkey, and murine colons and that colons from ( ) mice, which present with partial loss of ICC-IM, demonstrated augmented neural release of purines. Interactions between nitrergic and purinergic neurotransmission may affect motility in disease conditions with ICC-IM deficiencies.