Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS

In persons with HIV/AIDS (PWHAs), Hodgkin lymphoma (HL) risk is increased. However, HL incidence in PWHAs has unexpectedly increased since highly active antiretroviral therapy (HAART) was introduced. We linked nationwide HIV/AIDS and cancer registry data from 1980 through 2002. Immunity was assessed by CD4 T-lymphocyte counts at AIDS onset. Annual HL incidence rates were calculated for 4 through 27 months after AIDS onset. During 477 368 person years (py's) of follow-up in 317 428 persons with AIDS (PWAs), 173 HL cases occurred (36.2 per 105 py's). Incidence was significantly higher in 1996 to 2002 than earlier. Incidence in PWAs with 150 to 199 CD4 cells/μL was 53.7 per 105 py's, whereas in PWAs with fewer than 50 CD4 cells/μL, it was 20.7 per 105 py's (Ptrend = .002). For each HL subtype, incidence decreased with declining CD4 counts, but nodular sclerosing decreased more precipitously than mixed cellularity, thereby increasing the proportion of mixed cellularity HL seen in PWAs. We conclude that HL incidence is lower with severe immunosuppression than with moderate immunosuppression, and HAART-related improvements in CD4 counts likely explain the increasing HL incidence in PWHAS observed since 1996. With more severe immunosuppression, nodular sclerosing HL becomes infrequent, explaining the higher proportion of mixed cellularity HL found in PWAs. Pathogenesis implications are discussed.

Human Kallikrein 4 signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients.

Immunotherapy is a promising new treatment for patients with advanced prostate and ovarian cancer, but its application is limited by the lack of suitable target antigens that are recognized by CD8+ cytotoxic T lymphocytes (CTL). Human kallikrein 4 (KLK4) is a member of the kallikrein family of serine proteases that is significantly overexpressed in malignant versus healthy prostate and ovarian tissue, making it an attractive target for immunotherapy. We identified a naturally processed, HLA-A*0201-restricted peptide epitope within the signal sequence region of KLK4 that induced CTL responses in vitro in most healthy donors and prostate cancer patients tested. These CTL lysed HLA-A*0201+ KLK4 + cell lines and KLK4 mRNA-transfected monocyte-derived dendritic cells. CTL specific for the HLA-A*0201-restricted KLK4 peptide were more readily expanded to a higher frequency in vitro compared to the known HLA-A*0201-restricted epitopes from prostate cancer antigens; prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP). These data demonstrate that KLK4 is an immunogenic molecule capable of inducing CTL responses and identify it as an attractive target for prostate and ovarian cancer immunotherapy.

Kallikrein 14 is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness

Kallikrein 14 (KLK14) has been proposed as a useful prognostic marker in prostate cancer, with expression reported to be associated with tumour characteristics such as higher stage and Gleason score. KLK14 tumour expression has also shown the potential to predict prostate cancer patients at risk of disease recurrence after radical prostatectomy. The KLKs are a remarkably hormone-responsive family of genes, although detailed studies of androgen regulation of KLK14 in prostate cancer have not been undertaken to date. Using in vitro studies, we have demonstrated that unlike many other prostatic KLK genes that are strictly androgen responsive, KLK14 is more broadly expressed and inversely androgen regulated in prostate cancer cells. Given these results and evidence that KLK14 may play a role in prostate cancer prognosis, we also investigated whether common genetic variants in the KLK14 locus are associated with risk and/or aggressiveness of prostate cancer in approximately 1200 prostate cancer cases and 1300 male controls. Of 41 single nucleotide polymorphisms assessed, three were associated with higher Gleason score (≥7): rs17728459 and rs4802765, both located upstream of KLK14, and rs35287116, which encodes a p.Gln33Arg substitution in the KLK14 signal peptide region. Our findings provide further support for KLK14 as a marker of prognosis in prostate cancer.

Endocrine and immune responses to resistance training in prostate cancer patients

This study examined the effect of 20 weeks resistance training on a range of serum hormones and inflammatory markers at rest, and following acute bouts of exercise in prostate cancer patients undergoing androgen deprivation. Ten patients exercised twice weekly at high intensity for several upper and lower-body muscle groups. Neither testosterone nor prostate-specific antigen changed at rest or following an acute bout of exercise. However, serum growth hormone (GH), dehydroepiandrosterone (DHEA), interleukin-6, tumor necrosis factor-alpha and differential blood leukocyte counts increased (P < 0.05) following acute exercise. Resistance exercise does not appear to compromise testosterone suppression, and acute elevations in serum GH and DHEA may partly underlie improvements observed in physical function.

Constitutive production of IL-13 promotes early-life Chlamydia respiratory infection and allergic airway disease

Deleterious responses to pathogens during infancy may contribute to infection and associated asthma. Chlamydia respiratory infections in early life are common causes of pneumonia and lead to reduced lung function and asthma. We investigated the role of interleukin-13 (IL-13) in promoting early-life Chlamydia respiratory infection, infection-induced airway hyperresponsiveness (AHR), and severe allergic airway disease (AAD). Infected infant Il13−/− mice had reduced infection, inflammation, and mucus-secreting cell hyperplasia. Surprisingly, infection of wild-type (WT) mice did not increase IL-13 production but reduced IL-13Rα2 decoy receptor levels compared with sham-inoculated controls. Infection of WT but not Il13−/− mice induced persistent AHR. Infection and associated pathology were restored in infected Il13−/− mice by reconstitution with IL-13. Stat6−/− mice were also largely protected. Neutralization of IL-13 during infection prevented subsequent infection-induced severe AAD. Thus, early-life Chlamydia respiratory infection reduces IL-13Rα2 production, which may enhance the effects of constitutive IL-13 and promote more severe infection, persistent AHR, and AAD.

Changes in the site distribution of common melanoma subtypes in Queensland, Australia over time: implications for public health campaigns

Abstract BACKGROUND: An examination of melanoma incidence according to anatomical region may be one method of monitoring the impact of public health initiatives. OBJECTIVES:   To examine melanoma incidence trends by body site, sex and age at diagnosis or body site and morphology in a population at high risk. MATERIALS AND METHODS:   Population-based data on invasive melanoma cases (n = 51473) diagnosed between 1982 and 2008 were extracted from the Queensland Cancer Registry. Age-standardized incidence rates were calculated using the direct method (2000 world standard population) and joinpoint regression models were used to fit trend lines. RESULTS:   Significantly decreasing trends for melanomas on the trunk and upper limbs/shoulders were observed during recent years for both sexes under the age of 40 years and among males aged 40-59years. However, in the 60 and over age group, the incidence of melanoma is continuing to increase at all sites (apart from the trunk) for males and on the scalp/neck and upper limbs/shoulders for females. Rates of nodular melanoma are currently decreasing on the trunk and lower limbs. In contrast, superficial spreading melanoma is significantly increasing on the scalp/neck and lower limbs, along with substantial increases in lentigo maligna melanoma since the late 1990s at all sites apart from the lower limbs. CONCLUSIONS:   In this large study we have observed significant decreases in rates of invasive melanoma in the younger age groups on less frequently exposed body sites. These results may provide some indirect evidence of the impact of long-running primary prevention campaigns.

Intranasal immunization with C. muridarum major outer membrane protein (MOMP) and cholera toxin elicits local production of neutralising IgA in the prostate

Successful control of sexually transmitted diseases (STDs) through vaccination will require the development of vaccine strategies that target protective immunity to both the female and male reproductive tracts (MRT). In the male, the immune privileged nature of the male reproductive tract provides a barrier to entry of serum immunoglobulins into the male reproductive ducts, thereby preventing the induction of protective immunity using conventional injectable vaccination techniques. In this study we investigated the potential of intranasal (IN) immunization to elicit anti-chlamydial immunity in BALB/c male mice. Intranasal immunization with Chlamydia muridarum major outer membrane protein (MOMP) admixed with cholera toxin (CT) resulted in high levels of MOMP-specific IgA in prostatic fluids (PF) and MOMP-specific IgA-secreting cells in the prostate. Prostatic fluid IgA inhibited in vitro infection of McCoy cells with C. muridarum. Using RT-PCR we also show that mRNA for the polymeric immunoglobulin receptor (PIgR), which transports IgA across mucosal epithelia, is expressed only in the prostate but not in other regions of the male reproductive ducts upstream of the prostate. These data suggest that using intranasal immunization to target IgA to the prostate may protect males against STDs while at the same time maintaining the state of immune privilege within the MRT.

The epidemiology of basal cell carcinoma

Basal cell carcinoma (BCC) is a skin cancer of particular importance to the Australian community. Its rate of occurrence is highest in Queensland, where 1% to 2% of people are newly affected annually. This is an order of magnitude higher than corresponding incidence estimates in European and North American populations. Individuals with a sun-sensitive complexion are particularly susceptible because sun exposure is the single most important causative agent, as shown by the anatomic distribution of BCC which is in general consistent with the levels of sun exposure across body sites. A distinguishing feature of BCC is the occurrence of multiple primary tumours within individuals, synchronously or over time, and their diagnosis and treatment costs contribute substantially to the major public health burden caused by BCC. A primary knowledge gap about BCC pathogenesis however was an understanding of the true frequency of multiple BCC occurrences and their body distribution, and why a proportion of people do develop more than one BCC in their life. This research project sought to address this gap under an overarching research aim to better understand the detailed epidemiology of BCC with the ultimate goal of reducing the burden of this skin cancer through prevention. The particular aim was to document prospectively the rate of BCC occurrence and its associations with constitutional and environmental (solar) factors, all the while paying special attention to persons affected by more than one BCC. The study built on previous findings and recent developments in the field but set out to confirm and extend these and propose more adequate theories about the complex epidemiology of this cancer. Addressing these goals required a new approach to researching basal cell carcinoma, due to the need to account for the phenomenon of multiple incident BCCs per person. This was enabled by a 20 year community-based study of skin cancer in Australians that provided the methodological foundation for this thesis. Study participants were originally randomly selected in 1986 from the electoral register of all adult residents of the subtropical township of Nambour in Queensland, Australia. On various occasions during the study, participants were fully examined by dermatologists who documented cumulative photodamage as well as skin cancers. Participants completed standard questionnaires about skin cancer-related factors, and consented to have any diagnosed skin cancers notified to the investigators by regional pathology laboratories in Queensland. These methods allowed 100% ascertainment of histologically confirmed BCCs in this study population. 1339 participants had complete follow-up to the end of 2007. Statistical analyses in this thesis were carried out using SAS and SUDAAN statistical software packages. Modelling methods, including multivariate logistic regressions, allowed for repeated measures in terms of multiple BCCs per person. This innovative approach gave new findings on two levels, presented in five chapters as scientific papers: 1. Incidence of basal cell carcinoma multiplicity and detailed anatomic distribution: longitudinal study of an Australian population The incidence of people affected multiple times by BCC was 705 per 100,000 person years compared to an incidence rate of people singly affected of 935 per 100,000 person years. Among multiply and singly affected persons alike, site-specific BCC incidence rates were far highest on facial subsites, followed by upper limbs, trunk, and then lower limbs 2. Melanocytic nevi and basal cell carcinoma: is there an association? BCC risk was significantly increased in those with forearm nevi (Odds Ratios (OR) 1.43, 95% Confidence Intervals (CI) 1.09-1.89) compared to people without forearm nevi, especially among those who spent their time mainly outdoors (OR 1.6, 95%CI 1.1-2.3) compared to those who spent their time mainly indoors. Nevi on the back were not associated with BCC. 3. Clinical signs of photodamage are associated with basal cell carcinoma multiplicity and site: a 16-year longitudinal study Over a 16-year follow-up period, 58% of people affected by BCC developed more than one BCC. Among these people 60% developed BCCs across different anatomic sites. Participants with high numbers of solar keratoses, compared to people without solar keratoses, were most likely to experience the highest BCC counts overall (OR 3.3, 95%CI 1.4-13.5). Occurrences of BCC on the trunk (OR 3.3, 95%CI 1.4-7.6) and on the limbs (OR 3.7, 95%CI 2.0-7.0) were strongly associated with high numbers of solar keratoses on these sites. 4. Occurrence and determinants of basal cell carcinoma by histological subtype in an Australian community Among 1202 BCCs, 77% had a single growth pattern and 23% were of mixed histological composition. Among all BCCs the nodular followed by the superficial growth patterns were commonest. Risk of nodular and superficial BCCs on the head was raised if 5 or more solar keratoses were present on the face (OR 1.8, 95%CI 1.2-2.7 and OR 4.5, 95%CI 2.1-9.7 respectively) and similarly on the trunk in the presence of multiple solar keratoses on the trunk (OR 4.2, 95%CI 1.5-11.9 and OR 2.2, 95%CI 1.1-4.4 respectively). 5. Basal cell carcinoma and measures of cumulative sun exposure: an Australian longitudinal community-based study Dermal elastosis was more likely to be seen adjacent to head and neck BCCs than trunk BCCs (p=0.01). Severity of dermal elastosis increased on each site with increasing clinical signs of cutaneous sun damage on that site. BCCs that occurred without perilesional elastosis per se, were always found in an anatomic region with signs of photodamage. This thesis thus has identified the magnitude of the burden of multiple BCCs. It does not support the view that people affected by more than one BCC represent a distinct group of people who are prone to BCCs on certain body sites. The results also demonstrate that BCCs regardless of site, histology or order of occurrence are strongly associated with cumulative sun exposure causing photodamage to the skin, and hence challenge the view that BCCs occurring on body sites with typically low opportunities for sun exposure or of the superficial growth pattern are different in their association with the sun from those on typically sun-exposed sites, or nodular BCCs, respectively. Through dissemination in the scientific and medical literature, and to the community at large, these findings can ultimately assist in the primary and secondary prevention of BCC, perhaps especially in high-risk populations.

Molecular characterization of "Candidatus Parilichlamydia carangidicola," a novel Chlamydia-like epitheliocystis agent in yellowtail kingfish, Seriola lalandi (Valenciennes), and the proposal of a new family, "Candidatus Parilichlamydiaceae" fam. nov. (order Chlamydiales).

Three cohorts of farmed yellowtail kingfish (Seriola lalandi) from South Australia were examined for Chlamydia-like organisms associated with epitheliocystis. To characterize the bacteria, 38 gill samples were processed for histopathology, electron microscopy, and 16S rRNA amplification, sequencing, and phylogenetic analysis. Microscopically, the presence of membrane-enclosed cysts was observed within the gill lamellae. Also observed was hyperplasia of the epithelial cells with cytoplasmic vacuolization and fusion of the gill lamellae. Transmission electron microscopy revealed morphological features of the reticulate and intermediate bodies typical of members of the order Chlamydiales. A novel 1,393-bp 16S chlamydial rRNA sequence was amplified from gill DNA extracted from fish in all cohorts over a 3-year period that corresponded to the 16S rRNA sequence amplified directly from laser-dissected cysts. This sequence was only 87% similar to the reported "Candidatus Piscichlamydia salmonis" (AY462244) from Atlantic salmon and Arctic charr. Phylogenetic analysis of this sequence against 35 Chlamydia and Chlamydia-like bacteria revealed that this novel bacterium belongs to an undescribed family lineage in the order Chlamydiales. Based on these observations, we propose this bacterium of yellowtail kingfish be known as "Candidatus Parilichlamydia carangidicola" and that the new family be known as "Candidatus Parilichlamydiaceae."

A review of the profile of endothelin axis in cancer and its management

The endothelins and their associated receptors are important controllers of vascular growth, inflammation and vascular tone. In cancer, they have roles in the control of numerous factors in cancer development and progression, including angiogenesis, stromal reaction, epithelial mesenchymal transitions, apoptosis, invasion, metastases and drug resistance. Also, we consider current information on the role of this signalling system in cancer and examine the state of the current cell, animal and clinical trials utilizing endothelin targeted drugs for cancer management. Although targeting the endothelin axis in cell lines and xenografts show some promise in retarding cellular growth, results from limited clinical trials in prostatic cancer are less encouraging and did not offer significant survival benefit. The ability to target both cancer cells and vasculature via endothelin is an important consideration that necessitates the further refining of therapeutic strategies as we continue to explore the possibilities of the endothelin axis in cancer treatment.

Furan substituted diketopyrrolopyrrole and thienylenevinylene based low band gap copolymer for high mobility organic thin film transistors

A novel solution processable donor-acceptor (D-A) based low band gap polymer semiconductor poly{3,6-difuran-2-yl-2,5-di(2-octyldodecyl)-pyrrolo[3,4- c]pyrrole-1,4-dione-alt-thienylenevinylene} (PDPPF-TVT), was designed and synthesized by a Pd-catalyzed Stille coupling route. An electron deficient furan based diketopyrrolopyrrole (DPP) block and electron rich thienylenevinylene (TVT) donor moiety were attached alternately in the polymer backbone. The polymer exhibited good solubility, film forming ability and thermal stability. The polymer exhibits wide absorption bands from 400 nm to 950 nm (UV-vis-NIR region) with absorption maximum centered at 782 nm in thin film. The optical band gap (Eoptg) calculated from the polymer film absorption onset is around 1.37 eV. The π-energy band level (ionization potential) calculated by photoelectron spectroscopy in air (PESA) for PDPPF-TVT is around 5.22 eV. AFM and TEM analyses of the polymer reveal nodular terrace morphology with optimized crystallinity after 200 °C thermal annealing. This polymer exhibits p-channel charge transport characteristics when used as the active semiconductor in organic thin-film transistor (OTFT) devices. The highest hole mobility of 0.13 cm 2 V -1 s -1 is achieved in bottom gate and top-contact OTFT devices with on/off ratios in the range of 10 6-10 7. This work reveals that the replacement of thiophene by furan in DPP copolymers exhibits such a high mobility, which makes DPP furan a promising block for making a wide range of promising polymer semiconductors for broad applications in organic electronics.

Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models

Approximately half of prostate cancers (PCa) carry TMPRSS2-ERG translocations; however, the clinical impact of this genomic alteration remains enigmatic. Expression of v-ets erythroblastosis virus E26 oncogene like (avian) gene (ERG) promotes prostatic epithelial dysplasia in transgenic mice and acquisition of epithelial-to-mesenchymal transition (EMT) characteristics in human prostatic epithelial cells (PrECs). To explore whether ERG-induced EMT in PrECs was associated with therapeutically targetable transformation characteristics, we established stable populations of BPH-1, PNT1B and RWPE-1 immortalized human PrEC lines that constitutively express flag-tagged ERG3 (fERG). All fERG-expressing populations exhibited characteristics of in vitro and in vivo transformation. Microarray analysis revealed >2000 commonly dysregulated genes in the fERG-PrEC lines. Functional analysis revealed evidence that fERG cells underwent EMT and acquired invasive characteristics. The fERG-induced EMT transcript signature was exemplified by suppressed expression of E-cadherin and keratins 5, 8, 14 and 18; elevated expression of N-cadherin, N-cadherin 2 and vimentin, and of the EMT transcriptional regulators Snail, Zeb1 and Zeb2, and lymphoid enhancer-binding factor-1 (LEF-1). In BPH-1 and RWPE-1-fERG cells, fERG expression is correlated with increased expression of integrin-linked kinase (ILK) and its downstream effectors Snail and LEF-1. Interfering RNA suppression of ERG decreased expression of ILK, Snail and LEF-1, whereas small interfering RNA suppression of ILK did not alter fERG expression. Interfering RNA suppression of ERG or ILK impaired fERG-PrEC Matrigel invasion. Treating fERG-BPH-1 cells with the small molecule ILK inhibitor, QLT-0267, resulted in dose-dependent suppression of Snail and LEF-1 expression, Matrigel invasion and reversion of anchorage-independent growth. These results suggest that ILK is a therapeutically targetable mediator of ERG-induced EMT and transformation in PCa.

Glutathione transferase isozyme genotypes in patients with prostate and bladder carcinoma

Genotype distributions for GSTP1, GSTM1, and GSTT1 were determined in 91 patients with prostatic carcinoma and 135 patients with bladder carcinoma and compared with those in 127 abdominal surgery patients without malignancies. None of the genotypes differed significantly with respect to age or sex among controls or cancer patients. In the group of prostatic carcinoma patients, GSTT1 null allele homozygotes were more prevalent (25% in carcinoma patients vs 13% in controls, Fisher P=0.02, χ2 P = 0.02, OR = 2.31, CI = 1.17-4.59) and the combined M1-/T1-null genotype was also more frequent (9% vs 3%, χ2 P= 0.02, Fisher P = 0.03). Homozygosity for the GSTM1 null allele was more frequent among bladder carcinoma patients (59% in bladder carcinoma patients vs 45% in controls, Fisher P = 0.03, χ2 P = 0.02, OR = 1.76, CI = 1.08-2.88). In contrast to a previous report, no significant increase in the frequency of the GSTP1b allele was found in the tumor patients. Except for the combined GSTM1-/T1-null genotype in prostatic carcinoma, none of the combined genotypes showed a significant association with either of the cancers. These findings suggest that specific single polymorphic GST genes, that is GSTM1 in the case of bladder cancer and GSTT1 in the case of prostatic carcinoma, are most relevant for the development of these urological malignancies among the general population in Central Europe.

Establishing prostate cancer patient derived xenografts: Lessons learned from older studies

Background Understanding the progression of prostate cancer to androgen-independence/castrate resistance and development of preclinical testing models are important for developing new prostate cancer therapies. This report describes studies performed 30 years ago, which demonstrate utility and shortfalls of xenografting to preclinical modeling. Methods We subcutaneously implanted male nude mice with small prostate cancer fragments from transurethral resection of the prostate (TURP) from 29 patients. Successful xenografts were passaged into new host mice. They were characterized using histology, immunohistochemistry for marker expression, flow cytometry for ploidy status, and in some cases by electron microscopy and response to testosterone. Two xenografts were karyotyped by G-banding. Results Tissues from 3/29 donors (10%) gave rise to xenografts that were successfully serially passaged in vivo. Two, (UCRU-PR-1, which subsequently was replaced by a mouse fibrosarcoma, and UCRU-PR-2, which combined epithelial and neuroendocrine features) have been described. UCRU-PR-4 line was a poorly differentiated prostatic adenocarcinoma derived from a patient who had undergone estrogen therapy and bilateral castration after his cancer relapsed. Histologically, this comprised diffusely infiltrating small acinar cell carcinoma with more solid aggregates of poorly differentiated adenocarcinoma. The xenografted line showed histology consistent with a poorly differentiated adenocarcinoma and stained positively for prostatic acid phosphatase (PAcP), epithelial membrane antigen (EMA) and the cytokeratin cocktail, CAM5.2, with weak staining for prostate specific antigen (PSA). The line failed to grow in female nude mice. Castration of three male nude mice after xenograft establishment resulted in cessation of growth in one, growth regression in another and transient growth in another, suggesting that some cells had retained androgen sensitivity. The karyotype (from passage 1) was 43–46, XY, dic(1;12)(p11;p11), der(3)t(3:?5)(q13;q13), -5, inv(7)(p15q35) x2, +add(7)(p13), add(8)(p22), add(11)(p14), add(13)(p11), add(20)(p12), -22, +r4[cp8]. Conclusions Xenografts provide a clinically relevant model of prostate cancer, although establishing serially transplantable prostate cancer patient derived xenografts is challenging and requires rigorous characterization and high quality starting material. Xenografting from advanced prostate cancer is more likely to succeed, as xenografting from well differentiated, localized disease has not been achieved in our experience. Strong translational correlations can be demonstrated between the clinical disease state and the xenograft model