Pushing the Frontiers of Cancer Research: Highlights from the Frontiers in Cancer Science Conference 2023.

The 15th annual Frontiers in Cancer Science (FCS) conference gathered scientific experts who shared the latest research converging upon several themes of cancer biology. These themes included the dysregulation of metabolism, cell death, and other signaling processes in cancer cells; using patient "omics" datasets and single-cell and spatial approaches to investigate heterogeneity, understand therapy resistance, and identify targets; innovative strategies for inhibiting tumors, including rational drug combinations and improved drug delivery mechanisms; and advances in models that can facilitate screening for cancer vulnerabilities and drug testing. We hope the insights from this meeting will stimulate further progress in the field.

Short-hairpin RNA library: identification of therapeutic partners for gefitinib-resistant non-small cell lung cancer.

Somatic mutations of the epidermal growth factor receptor often cause resistance to therapy with tyrosine kinase inhibitor in non-small cell lung cancer (NSCLC). In this study, we aimed to identify partner drugs and pathways that can induce cell death in combination with gefitinib in NSCLC cells. We undertook a genome-wide RNAi screen to identify synthetic lethality with gefitinib in tyrosine kinase inhibitor resistant cells. The screening data were utilized in different approaches. Firstly, we identified PRKCSH as a candidate gene, silencing of which induces apoptosis of NSCLC cells treated with gefitinib. Next, in an in silico gene signature pathway analysis of shRNA library data, a strong correlation of genes involved in the CD27 signaling cascade was observed. We showed that the combination of dasatinib (NF-κB pathway inhibitor) with gefitinib synergistically inhibited the growth of NSCLC cells. Lastly, utilizing the Connectivity Map, thioridazine was identified as a top pharmaceutical perturbagen. In our experiments, it synergized with gefitinib to reduce p-Akt levels and to induce apoptosis in NSCLC cells. Taken together, a pooled short-hairpin library screen identified several potential pathways and drugs that can be therapeutic targets for gefitinib resistant NSCLC.

Do genitourinary physicians report notifiable diseases? A survey in South East England.

Genitourinary medicine work requires public health actions. Notifiable infections may be seen in genitourinary medicine, but concerns over confidentiality could delay public health actions and outbreak management. To assess genitourinary medicine clinicians' awareness of notification of infectious disease, reporting practices and liaison with Health Protection Units, we sent postal surveys to 140 genitourinary medicine clinicians (SE HPA region) that explored prior public health training, Health Protection Unit liaison and management of possible clinical scenarios. Fifty-seven respondents reported median genitourinary medicine experience of 12 years; 29% had prior public health training, nine on the British Association for Sexual Health and HIV course. A total of 90% had heard of Health Protection Units and understood their role. Approximately one-third would not report key diseases at all, most reporting only on laboratory confirmation. In all, 83% would only notify acute hepatitis on lab confirmation; 50% would report suspected measles immediately (44% awaiting lab confirmation) and 40% would not pass on any patient details without consent. Clinicians have good knowledge of notification of infectious disease conditions but responses suggest it is not always used in clinical context. Reporting delays occur waiting for lab confirmation and liaison with local Health Protection Units may be hindered by confidentiality concerns, potentially delaying public health action. Doctors with prior public health training are more likely to report appropriately.

Belinostat and panobinostat (HDACI): in vitro and in vivo studies in thyroid cancer.

PURPOSE: Advanced thyroid cancer responds poorly to most therapies. New therapies and combinations are needed. The aim of this study was to examine both in vitro and in vivo activity of two relatively new histone deacetylase inhibitors (HDACIs), belinostat and panobinostat, and a variety of tyrosine kinase inhibitors (TKIs) against a panel of nine human thyroid cancer cell lines. METHODS: The anti-proliferative activity and the effects of HDACIs, TKIs and their combinations on thyroid cancer cells were determined by cytotoxicity assays, microarray and immunoblot analyses. Synergism between HDACIs and TKIs was assessed by the median effects model of Chou-Talalay (Calcusyn(®)). RESULTS: Belinostat and panobinostat were active against the thyroid cancer cell lines irrespective of their mutational composition, and belinostat was effective in preventing growth of human thyroid cancer xenografts in immunodeficient mice. Further studies showed that both HDACIs induced apoptosis. HDACI also elevated acetylated histone 3, p21(Waf), and PARP, and decreased levels of phosphorylated ERK and AKT (Ser473). RNA assay analysis suggested both HDACIs modulated genes associated with the cell cycle, DNA damage and apoptosis. Most of the TKI (pazopanib, motesanib, sorafenib and dasatinib) were either inactive in vitro or were active only at high doses. However, the novel combinations of either pazopanib or dasatinib TKIs with either belinostat or panobinostat synergistically inhibited cell growth of thyroid cancer cells in vitro. CONCLUSIONS: In summary, these HDACIs either alone or combined with selected TKIs may have a role in treatment of aggressive thyroid cancer.

SOX7 is down-regulated in lung cancer.

BACKGROUND: SOX7 is a transcription factor belonging to the SOX family. Its role in lung cancer is unknown. METHODS: In this study, whole genomic copy number analysis was performed on a series of non-small cell lung cancer (NSCLC) cell lines and samples from individuals with epidermal growth factor receptor (EGFR) mutations using a SNP-Chip platform. SOX7 was measured in NSCLC samples and cell lines, and forced expressed in one of these lines. RESULTS: A notable surprise was that the numerous copy number (CN) changes observed in samples of Asian, non-smoking EGFR mutant NSCLC were nearly the same as those CN alterations seen in a large collection of NSCLC from The Cancer Genome Atlas which is presumably composed of predominantly Caucasians who often smoked. However, four regions had CN changes fairly unique to the Asian EGFR mutant group. We also examined CN changes in NSCLC lines. The SOX7 gene was homozygously deleted in one (HCC2935) of 10 NSCLC cell lines and heterozygously deleted in two other NSCLC lines. Expression of SOX7 was significantly downregulated in NSCLC cell lines (8/10, 80%) and a large collection of NSCLC samples compared to matched normal lung (57/62, 92%, p= 0.0006). Forced-expression of SOX7 in NSCLC cell lines markedly reduced their cell growth and enhanced their apoptosis. CONCLUSION: These data suggest that SOX7 is a novel tumor suppressor gene silenced in the majority of NSCLC samples.

Repeat infection with gonorrhoea in Sheffield, UK: predictable and preventable?

BACKGROUND: Repeat infection with gonorrhoea may contribute significantly to infection persistence and health service workload. The authors investigated whether repeat infection is associated with particular subgroups who may benefit from tailored interventions. METHODS: Data on gonorrhoea diagnoses between 2004 and 2008 were obtained from Sheffield sexually transmitted infection clinic. Kaplan-Meier survival curves were used to estimate the percentage of patients with repeat diagnoses within a year, and a Cox proportional hazard model was used to investigate associated risk factors. RESULTS: Of 1650 patients diagnosed with gonorrhoea, 7.7% (95% CI 6.5% to 9.1%) had a repeat diagnosis within 1 year. Men who have sex with men under 30, teenage heterosexuals, black Caribbeans, people living in deprived areas and those diagnosed in 2004 were most likely to re-present. Of those patients (53%) providing additional behavioural data, repeat diagnosis was more common in those reporting prior history of gonorrhoea, any previous sexually transmitted infection diagnoses, two or more partners in the past 3 months and a high-risk partner in the past year. In an adjusted analysis, repeat diagnosis was independently associated with being a young man who has sex with men, living in a deprived area, a history of gonorrhoea and being diagnosed in 2004 but was most strongly associated with non-completion of behavioural data forms. CONCLUSIONS: Groups most at risk of repeat infection with gonorrhoea are highly predictable but are disinclined to provide detailed information on their sexual behaviour. Care pathways including targeted and intensive one-to-one risk reduction counselling, effective partner notification and offers of re-testing could deliver considerable public health benefit.

A more cost effective and rapid high percentage germ-line transmitting chimeric mouse generation procedure via microinjection of 2-cell, 4-cell, and 8-cell embryos with ES and iPS cells.

The long-standing traditional method of delivering embryonic stem (ES) cells adjacent to the inner cell mass (ICM) of blastocysts to generate chimeras improved with the advent of laser- or Piezo assisted 8-cell embryo microinjection. Building on this technology but omitting either the laser or the Piezo to penetrate the zona pellucida and making use of earlier embryonic stages (2-cell and 4-cell), we were able to significantly speed up and economize our ES cell microinjection and chimera production throughput. We demonstrate here that embryonic (ES) and induced pluripotent stem (iPS) cells can stay fully pluripotent when delivered into 2-cell- and 4-cell-stage embryos, long before they would naturally be incorporated into the ICM of a blastocyst (E3.5) and give rise to high percentage and germline transmitting chimeras.

The macromolecular assembly of pathogen-recognition receptors is impelled by serine proteases, via their complement control protein modules.

Although the innate immune response is triggered by the formation of a stable assembly of pathogen-recognition receptors (PRRs) onto the pathogens, the driving force that enables this PRR-PRR interaction is unknown. Here, we show that serine proteases, which are activated during infection, participate in associating with the PRRs. Inhibition of serine proteases gravely impairs the PRR assembly. Using yeast two-hybrid and pull-down methods, we found that two serine proteases in the horseshoe crab Carcinoscorpius rotundicauda are able to bind to the following three core members of PRRs: galactose-binding protein, Carcinolectin-5 and C-reactive protein. These two serine proteases are (1) Factor C, which activates the coagulation pathway, and (2) C2/Bf, a protein from the complement pathway. By systematic molecular dissection, we show that these serine proteases interact with the core "pathogen-recognition complex" via their complement control protein modules.

Data from UK genitourinary medicine clinics, 2006: a mixed picture.

OBJECTIVE: To give an overview of the latest latest trends in diagnoses made and services provided by genitourinary medicine (GUM) clinics in the UK. METHODS: Aggregate data collected from the KC60 statistical returns for GUM clinics in England, Wales and Northern Ireland and disaggregate data collected using the STI Surveillance System for GUM Clinics in Scotland. These data were collated and numbers of diagnoses were adjusted for missing clinic data. RESULTS & CONCLUSION: Overall, numbers of new diagnoses of sexually transmitted infections (STIs) continued to rise in 2006. However, there was some evidence of improvement, with new diagnoses of gonorrhoea falling for the fourth successive year. Chlamydia continued to be the most common STI diagnosed in GUM clinics, and the sharp rise in new diagnoses over the last 10 years was most likely associated with an increase in testing volume and accuracy. The highest rates of STI diagnoses continued, in the main, to be among 16-24-year-olds, and there were some notable rises among this age group also: new diagnoses of genital herpes in teenage women rose by 16% in 2006. Improving the sexual health of men who have sex with men (MSM) must remain a priority, as the increase in numbers of new STI diagnoses among MSM over the past 10 years continued unabated into 2006. However, despite facing the challenge of reducing patient waiting times, there has been a considerable rise in sexual health screens and HIV tests being provided by GUM services, and this could, if sustained, result in significant improvements in sexual health in the coming years.