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Background Chronic inflammation is a known cause of prostate cancer (PCa) initiation and progression. Interleukin-1 (IL-1) is an inflammatory cytokine secreted by tumor cells and bone-derived immune cells that contributes to chronic inflammation in the tumor microenvironment. IL-1 is elevated in PCa patients and contributes to PCa progression and treatment resistance. IL-1 has been shown to promote PCa metastasis and bone colonization, shown to recruit mesenchymal stems cells to the tumor to support castration-resistant PCa (CRPCa) development and chronic IL-1 exposure was shown to promote PCa anti-androgen resistance. We previously reported that acute IL-1 exposure represses androgen receptor (AR) accumulation and activity, providing a possible mechanism for IL-1-mediated development of androgen- and AR-independent PCa. Given that acute inflammation is quickly resolved, and chronic inflammation is, instead, co-opted by cancer cells to promote tumorigenicity, we set out to determine if chronic IL-1 exposure leads to similar repression of AR and AR activity observed for acute IL-1 exposure and to determine if chronic IL-1 exposure selects for androgen- and AR-independent PCa cells. Methods We isolated isogenic LNCaP sublines from LNCaP cells chronically exposed for 3-4 months to IL-1α or IL-1β. LNCaP and the IL-1 sublines were treated with IL-1α, IL-1β, TNFα or conditioned medium from the HS-5 bone marrow stromal cell line to assess cell viability in the presence of cytotoxic inflammatory cytokines. Cell viability was also assessed following serum starvation, AR siRNA silencing and treatment with the anti-androgen, enzalutamide. RNA sequencing and bioinformatics analysis were also performed for the IL-1 sublines. Results MTT, RT-qPCR and western blot analysis show that the sublines evolved resistance to inflammation-induced cytotoxicity and intracellular signaling and evolved reduced sensitivity to siRNA-mediated loss of AR , serum deprivation and enzalutamide. Furthermore, differential gene expression reveals that canonical AR signaling is aberrant in the IL-1 sublines, where the cells show constitutive PSA repression and basally high KLK2 and NKX3.1 mRNA levels and bioinformatics analysis predicts that pro-survival and pro-tumorigenic pathways are activated in the sublines. Conclusions Our data provide evidence that chronic IL-1 exposure promotes PCa cell androgen and AR independence and, thus, supports CRPCa development.

The current study considers the use of a selection of engineered ground calcium carbonates in two different polyethylene film systems. The calcium carbonate grades selected cover a range of particle sizes and include uncoated and organically treated examples. Alterations in the processing requirements on mineral addition are reported and their implications for film and masterbatch production considered with respect to energy usage and throughput. Inclusion of the engineered additives allowed production of the same weight of material at lower energy uses or improved productivity at the same energy usage. The effects on the mechanical properties of the composite films with increasing mineral loading have also been measured, demonstrating enhancements particularly in the areas of tear strength and impact resistance. These enhancements allow the possibility of film downgauging relative to the unfilled film without loss of performance and yield a raw material cost saving by reduction of polymer usage.

Eighteen adults with extensive atopic dermatitis, resistant to conventional treatment, were treated by hypnotherapy, with statistically significant benefit (P < 0.01) measured both subjectively and objectively, which was maintained at up to 2 years where results were available. Twenty children with severe, resistant atopic dermatitis were treated by hypnosis. All but one showed immediate improvement, which was maintained at the following two clinic appointments. In 12 children, replies to a questionnaire at up to 18 months after treatment, showed that 10 had maintained improvement in itching and scratching, nine in sleep disturbance, and seven maintained improvement in itching and scratching, nine in sleep disturbance, and seven maintained improvement in mood.

The dissociations of energy-selected HNCO+ ions have been examined at ionisation energies up to 40 eV using photoelectron–photoion coincidence spectroscopy. The slow metastable dissociation to HCO+ is shown to occur from initial population of low vibrational levels within the doublet states corresponding to the third photoelectron band. Rate constants for the dissociation from several levels have been measured and the existence of an optical emission is predicted. High level calculations identify the third band in the photoelectron spectrum as an overlay of almost degenerate states arising from ionisation of the in-plane and out-of-plane bonding π-orbitals. The calculations suggest that at energies between 15.5 and 16 eV, the dominant pathway for dissociation involves slow internal conversion to the ground doublet state without surface crossing, followed by intersystem crossing to the quartet surface. At energies over 16 eV, two mechanisms are possible; intersystem crossing from the second excited doublet state to the lowest quartet surface in a cis-bent configuration, or internal conversion to the first excited doublet state via a surface crossing in the same region, followed by a second nonradiative transition to the doublet ground state and intersystem crossing to the quartet surface. In each case, the initial step is expected to be slow, consistent with the existence of an optical emission, and H-atom transfer occurs on the quartet surface via a ‘loose’ transition state leading to the direct formation of HCO+ and N(4Su).

Psoralen photochemotherapy [psoralen ultraviolet A (PUVA)] plays an important part in dermatological therapeutics, being an effective and generally safe treatment for psoriasis and other dermatoses. In order to maintain optimal efficacy and safety, guidelines concerning best practice should be available to operators and supervisors. The British Photodermatology Group (BPG) have previously published recommendations on PUVA, including UVA dosimetry and calibration, patient pretreatment assessment, indications and contraindications, and the management of adverse reactions.1 While most current knowledge relates to oral PUVA, the use of topical PUVA regimens is also popular and presents a number of questions peculiar to this modality, including the choice of psoralen, formulation, method of application, optimal timing of treatment, UVA regimens and relative benefits or risks as compared with oral PUVA. Bath PUVA, i.e. generalized immersion, is the most frequently used modality of topical treatment, practised by about 100 centres in the U.K., while other topical preparations tend to be used for localized diseases such as those affecting the hands and feet. This paper is the product of a recent workshop of the BPG and includes guidelines for bath, local immersion and other topical PUVA. These recommendations are based, where possible, on the results of controlled studies, or otherwise on the consensus view on current practice.

Squamous cell carcinoma complicating lichen planus is described in 3 patients. In 2, the cancers developed on the lower leg in chronic and hypertrophic lichen planus. In the other case, the cancer complicated lichen planus of the lip mucosa in a smoker. In the two cutaneous cases, the tumour and the adjacent skin showed features of lichen planus, including hypergranulosis, cytoid bodies and a lichenoid infiltrate. The association, though rare with cutaneous lichen planus when it tends to affect chronic hypertrophic lesions on the lower legs, is now well recognized with oral lichen planus. Patients with oral involvement warrant long-term follow-up, especially if they have other risk factors such as smoking or excessive ultraviolet exposure. Chronicity of lichen planus at other skin sites may also be a risk factor.

A 61–year-old woman, who was known to have Hailey–Hailey disease, presented with increasing vulval soreness. Biopsy showed vulval intraepithelial neoplasia (VIN) 3 and subsequent histology from a vulvectomy specimen showed extensive VIN with early invasive squamous cell carcinoma. This may be another example of chronic inflammation of the vulval area leading to the development of squamous cell carcinoma. However, in this case, chronic human papillomavirus may also have played a part, leading to VIN and reactivation of the Hailey–Hailey disease. We can find no previous reports of squamous cell carcinoma developing in the setting of Hailey–Hailey disease.

Galanin-like peptide (GALP) is a recently described neuropeptide, which shares a partial sequence identity with galanin but is derived from a separate gene. Central injections of GALP stimulate the secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) and induce the expression of Fos in several brain areas known to regulate male sexual behavior in the rat. We postulated that GALP may also stimulate sexual behavior in concert with its stimulatory effect on the hypothalamic-pituitary-gonadal (HPG) axis. To test this hypothesis, we administered GALP, galanin, or the vehicle (artificial cerebrospinal fluid, aCSF) alone to sexually experienced male rats and assessed the effects of these agents on sexual behavior. We observed that compared to aCSF alone, GALP significantly increased all aspects of male-typical sexual behavior, whereas galanin inhibited all of these same behaviors. To examine whether the stimulatory effects of GALP on sexual behavior were mediated by GALP's stimulatory effects on the HPG axis, we castrated the same male rats and repeated the behavioral experiment. We found that GALP maintained its inductive action on male-typical sexual behaviors in the castrated animals, suggesting that the effects of GALP on sexual behavior are not the result of GALP's ability to stimulate testosterone secretion. These observations suggest that GALP neurons are part of the hypothalamic circuitry controlling sexual behavior in the male rat.

Proteins binding oestradiol with high affinity and low capacity have been characterised and quantitated in 4 newly established canine mammary tumour lines, MS306, V5500, F5010 and PD6014, maintained in nude mice. These receptor proteins, specific for oestrogens, were found in all the tumour lines, both in initial implants and all subsequent passages. Receptors had equilibrium dissociation constants for oestradiol in the range of 33–210 pM , and sedimentation coefficients of 4 S and 8 S.

DNA-dependent RNA polymerase activity has been studied in isolated nuclei from canine mammary tumours. Initial experiments showed high levels of RNase activity in this tissue; accordingly, routine assays were terminated before loss of acid-precipitable radioactivity was evident. RNA polymerase A and B activity in isolated nuclei were shown to be increased by addition of receptor-containing cytosol previously incubated with oestradiol-17β, dihydrotestosterone or R5020. Where no receptor was present, as measured by saturation binding assays and sucrose density gradient analysis, there was no corresponding increase in polymerase activity. The steroid antagonists tamoxifen and cyproterone did not elicit any response even when their corresponding steroids produced a 1- to 2-fold stimulation of polymerase activity. Steroid-induced effects proved to be dose-dependent, with half maximal responses for oestradiol-17β 8 × 10 −8 M , R5020 2 × 10 −6 M and dihydrotestosterone 9 × 10 −6 M .

A colony of nude (BALB/c/Nu/Nu) mice has been established and used to produce and study transplantable tumour lines derived from spontaneously occurring canine mammary neoplasms. Four primary tumours of differing morphological types were studied. Two were adenocarcinomas (MS306 and PD6014) with varying degrees of differentiation, the third (F5010) was a complex adenocarcinoma composed of both stromal and epithelial elements and the fourth (V5500) was a fibrosarcoma. Tumour fragments were implanted into the subcutaneous tissue of 4- to 6-week-old mice and resulted in tumour growth in each case. There was a latent period of 1 month for tumours PD6014, F5010 and V5500 and of 3 months for tumour MS306 before tumour growth ensued. After serial transplantation this period decreased to 1–2 weeks for the first 3 tumours and to 6 weeks for the last. After the initial lag period, tumour volume increased logarithmically in all cases with doubling times of 6–20 days . Each tumour line has been passaged through 3 serial transplantations with 3 of the tumours retaining their original histological appearance whilst the fourth became slightly more dedifferentiated.

Summary Patients suffering from intractable pruritus are frequently referred for investigation by the dermatologist. We describe an unusual case in which severe generalized pruritus was the presenting symptom of oat cell carcinoma of the bronchus.

The isolation and characterisation of two fish attractants, a new dipeptide (Arcamine, hypotauryl-2-carboxyglycine), 1 and Strombine (C-methyl-imino diacetic acid), 2 are described.

SUMMARY Of 108 renal transplant recipients (53 men and 55 women) treated with azathioprine (0.8-2.9 mg/kg/day) and prednisolone (10 mg daily), 10 men had actinic keratoses, and five of these had squamous cell carcinoma, on light-exposed areas of skin. The time from transplantation to diagnosis of these skin lesions varied from 1.2 to 9.0 (mean 5.1) years. The concentration of the active azathioprine metabolite 6-thioguanine nucleotide was 120–425 (mean 276) pmol per 8×108 red blood cells in the transplant patients who developed skin lesions and 54–203 (mean 130) pmol per 8×108 red blood cells in a matched control group of renal transplant recipients. This difference was statistically significant (P=0.005). There was no statistically significant difference between patients and controls in azathioprine dosage, clinical features of immunosuppression, sunlight exposure or infection with human papilloma virus. The association of raised 6-thioguanine nucleotide concentrations in red blood cells with actinic keratoses and malignant skin tumours in these patinets supports chemical carcinogenesis as a possible cause.

Lesions of solar keratoses and squamous cell carcinoma maintained their histological appearance and an increased tritiated thymidine autoradiographic labelling index after being grafted on to nude mice. However, the values for their mean epidermal thickness and individual cell size appeared to decrease slightly during the 24-week period of study. As judged by the immunolocalization of involucrin antibodies, the grafts maintained a human epidermal antigenic profile. However, immunolocalization studies with HLA antibodies showed only a patchy positivity in the original premalignant lesions and were negative after grafting. These results indicate the potential value of the nude mouse as a model for studying the progress of premalignant and malignant skin lesions in an immunologically privileged non-human site and further indicate that solar keratoses can be maintained independently of systemic donor influences.

Solar keratoses are premalignant lesions of the epidermis and occur on the chronically sun exposed areas of individuals with a fair complexion. Solar keratoses can develop into squamous cell carcinomas. Montgomery and Dorffel [11] estimated that 20% of patients with solar keratoses develop squamous cell carcinomas. However, according to Lund [9] and Muller et al. [12] these squamous cell carcinomas do not metastasize. Solar keratoses can also completely resolve, and the so-called lichenoid keratoses [16] may represent lesions in which immunological rejection has begun. An important question for carcinogenesis in general and for solar keratoses in particular concerns the determinants that influence the fate of these premalignant lesions. Are such lesions more or less likely to transform to squamous cell carcinoma when isolated from their usual immunological milieu? Transplantation to an immunologically privileged site would be one way of answering these questions.

One hundred and twenty patients with chronic idiopathic urticaria, who entered a study at five centres (Sheffield, London, Bristol, Cardiff and Leeds) were treated with therapeutic doses of the H1 antagonist chlorpheniramine for 6 weeks. Histamine H1 non-responders (40 patients) were entered into a double-blind study and received chlorpheniramine plus cimetidine 400 mg q.d.s. (21 patients) or chlorpheniramine plus placebo (19 patients) for a further 8 weeks. The most important response measure was the change from baseline of the total symptom score: an assessment of the number and duration of new weals and degree of itching. There was a statistically significant difference between the average response in the two treatment groups in favour of chlorpheniramine plus cimetidine after 4 and 8 weeks' treatment (P less than 0.05 and P less than 0.01, respectively). No significant side-effects related to treatment were noted.

SUMMARY The sebum excretion rate (SER) was measured above and below the neurological lesion in seventeen male and four female paraplegic patients and at comparable sites in a similar number of age-matched controls. There was no significant difference between paraplegics and controls for forehead SER. For the thigh SER there was a highly significant difference between paraplegics and controls (t= 6.27; P < 0.001), the level for paraplegics being twice that for controls. Simultaneous thigh skin temperature measurements showed no significant difference between paraplegics and controls.