Responsible agriculture must adapt to the wetland character of mid-latitude peatlands.

Drained, lowland agricultural peatlands are greenhouse gas (GHG) emission hotspots and a large but vulnerable store of irrecoverable carbon. They exhibit soil loss rates of ~2.0 cm yr-1 and are estimated to account for 32% of global cropland emissions while producing only 1.1% of crop kilocalories. Carbon dioxide emissions account for >80% of their terrestrial GHG emissions and are largely controlled by water table depth. Reducing drainage depths is, therefore, essential for responsible peatland management. Peatland restoration can substantially reduce emissions. However, this may conflict with societal needs to maintain productive use, to protect food security and livelihoods. Wetland agriculture strategies will, therefore, be required to adapt agriculture to the wetland character of peatlands, and balance GHG mitigation against productivity, where halting emissions is not immediately possible. Paludiculture may substantially reduce GHG emissions but will not always be viable in the current economic landscape. Reduced drainage intensity systems may deliver partial reductions in the rate of emissions, with smaller modifications to existing systems. These compromise systems may face fewer hurdles to adoption and minimize environmental harm until societal conditions favour strategies that can halt emissions. Wetland agriculture will face agronomic, socio-economic and water management challenges, and careful implementation will be required. Diversity of values and priorities among stakeholders creates the potential for conflict. Successful implementation will require participatory research approaches and co-creation of workable solutions. Policymakers, private sector funders and researchers have key roles to play but adoption risks would fall predominantly on land managers. Development of a robust wetland agriculture paradigm is essential to deliver resilient production systems and wider environmental benefits. The challenge of responsible use presents an opportunity to rethink peatland management and create thriving, innovative and green wetland landscapes for everyone's future benefit, while making a vital contribution to global climate change mitigation.

Patient and Caregiver Considerations and Priorities When Selecting Hospitals for Complex Cancer Care.

BACKGROUND: Healthcare policies have focused on centralizing care to high-volume centers in an effort to optimize patient outcomes; however, little is known about patients' and caregivers' considerations and selection process when selecting hospitals for care. We aim to explore how patients and caregivers select hospitals for complex cancer care and to develop a taxonomy for their selection considerations. METHODS: This was a qualitative study in which data were gathered from in-depth interviews conducted from March to November 2019 among patients with hepatopancreatobiliary cancers who were scheduled to undergo a pancreatectomy (n = 20) at a metropolitan, urban regional, or suburban medical center and their caregivers (n = 10). RESULTS: The interviews revealed six broad domains that characterized hospital selection considerations: hospital factors, team characteristics, travel distance to hospital, referral or recommendation, continuity of care, and insurance considerations. The identified domains were similar between participants seen at the metropolitan center and urban/suburban medical centers, with the following exceptions: participants receiving care specifically at the metropolitan center noted operative volume and access to specific services such as clinical trials in their hospital selection; participants receiving care at urban/suburban centers noted health insurance considerations and having access to existing medical records in their hospital selection. CONCLUSIONS: This study delineates the many considerations of patients and caregivers when selecting hospitals for complex cancer care. These identified domains should be incorporated into the development and implementation of centralization policies to help increase patient access to high-quality cancer care that is consistent with their priorities and needs.

Short-term Preoperative Diet Decreases Bleeding After Partial Hepatectomy: Results From a Multi-institutional Randomized Controlled Trial.

BACKGROUND: Our previous case series suggested that a 1-week, low-calorie and low-fat diet was associated with decreased intraoperative blood loss in patients undergoing liver surgery. OBJECTIVE: The current study evaluates the effect of this diet in a randomized controlled trial. METHODS: We randomly assigned 60 patients with a body mass index ≥25 kg/m(2) to no special diet or an 800-kcal, 20 g fat, and 70 g protein diet for 1 week before liver resection. Surgeons were blinded to diet assignment. Hepatic glycogen stores were evaluated using periodic acid Schiff (PAS) stains. RESULTS: Ninety four percent of the patients complied with the diet. The diet group consumed fewer daily total calories (807 vs 1968 kcal, P < 0.001) and fat (21 vs 86 g, P < 0.001) than the no diet group. Intraoperative blood loss was less in the diet group: mean blood loss 452 vs 863 mL (P = 0.021). There was a trend towards decreased transfusion in the diet group (138 vs 322 mL, P = 0.06). The surgeon judged the liver to be easier to manipulate in the diet group: 1.86 versus 2.90, P = 0.004. Complication rate (20% vs 17%), length of stay (median 5 vs 4 days) and mortality did not differ between groups. There was no difference in hepatic steatosis between groups. There was less glycogen in hepatocytes in the diet group (PAS stain score 1.61 vs 2.46, P < 0.0001). CONCLUSIONS: A short-course, low-fat, and low-calorie diet significantly decreases bleeding and makes the liver easier to manipulate in hepatic surgery.

AGI-134: a fully synthetic α-Gal glycolipid that converts tumors into in situ autologous vaccines, induces anti-tumor immunity and is synergistic with an anti-PD-1 antibody in mouse melanoma models.

BACKGROUND: Treatments that generate T cell-mediated immunity to a patient's unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galα1-3Galß1-4GlcNAc (α-Gal) in situ leading to opsonization with pre-existing natural anti-α-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity. METHODS: Various immunological effects of coating tumor cells with α-Gal via AGI-134 in vitro were measured by flow cytometry: (1) opsonization with anti-Gal and complement, (2) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, and (3) phagocytosis and antigen cross-presentation by antigen presenting cells (APCs). A viability kit was used to test AGI-134 mediated complement dependent cytotoxicity (CDC) in cancer cells. The anti-tumoral activity of AGI-134 alone or in combination with an anti-programmed death-1 (anti-PD-1) antibody was tested in melanoma models in anti-Gal expressing galactosyltransferase knockout (α1,3GT-/-) mice. CDC and phagocytosis data were analyzed by one-way ANOVA, ADCC results by paired t-test, distal tumor growth by Mantel-Cox test, C5a data by Mann-Whitney test, and single tumor regression by repeated measures analysis. RESULTS: In vitro, α-Gal labelling of tumor cells via AGI-134 incorporation into the cell membrane leads to anti-Gal binding and complement activation. Through the effects of complement and ADCC, tumor cells are lysed and tumor antigen uptake by APCs increased. Antigen associated with lysed cells is cross-presented by CD8α+ dendritic cells leading to activation of antigen-specific CD8+ T cells. In B16-F10 or JB/RH melanoma models in α1,3GT-/- mice, intratumoral AGI-134 administration leads to primary tumor regression and has a robust abscopal effect, i.e., it protects from the development of distal, uninjected lesions. Combinations of AGI-134 and anti-PD-1 antibody shows a synergistic benefit in protection from secondary tumor growth. CONCLUSIONS: We have identified AGI-134 as an immunotherapeutic drug candidate, which could be an excellent combination partner for anti-PD-1 therapy, by facilitating tumor antigen processing and increasing the repertoire of tumor-specific T cells prior to anti-PD-1 treatment.

Developmental therapeutics for patients with breast cancer and central nervous system metastasis: current landscape and future perspectives.

Breast cancer is the second-leading cause of metastatic disease in the central nervous system (CNS). Recent advances in the biological understanding of breast cancer have facilitated an unprecedented increase of survival in a subset of patients presenting with metastatic breast cancer. Patients with HER2 positive (HER2+) or triple negative breast cancer are at highest risk of developing CNS metastasis, and typically experience a poor prognosis despite treatment with local and systemic therapies. Among the obstacles ahead in the realm of developmental therapeutics for breast cancer CNS metastasis is the improvement of our knowledge on its biological nuances and on the interaction of the blood­brain barrier with new compounds. This article reviews recent discoveries related to the underlying biology of breast cancer brain metastases, clinical progress to date and suggests rational approaches for investigational therapies.

A genomic portrait of the emergence, evolution, and global spread of a methicillin-resistant Staphylococcus aureus pandemic.

The widespread use of antibiotics in association with high-density clinical care has driven the emergence of drug-resistant bacteria that are adapted to thrive in hospitalized patients. Of particular concern are globally disseminated methicillin-resistant Staphylococcus aureus (MRSA) clones that cause outbreaks and epidemics associated with health care. The most rapidly spreading and tenacious health-care-associated clone in Europe currently is EMRSA-15, which was first detected in the UK in the early 1990s and subsequently spread throughout Europe and beyond. Using phylogenomic methods to analyze the genome sequences for 193 S. aureus isolates, we were able to show that the current pandemic population of EMRSA-15 descends from a health-care-associated MRSA epidemic that spread throughout England in the 1980s, which had itself previously emerged from a primarily community-associated methicillin-sensitive population. The emergence of fluoroquinolone resistance in this EMRSA-15 subclone in the English Midlands during the mid-1980s appears to have played a key role in triggering pandemic spread, and occurred shortly after the first clinical trials of this drug. Genome-based coalescence analysis estimated that the population of this subclone over the last 20 yr has grown four times faster than its progenitor. Using comparative genomic analysis we identified the molecular genetic basis of 99.8% of the antimicrobial resistance phenotypes of the isolates, highlighting the potential of pathogen genome sequencing as a diagnostic tool. We document the genetic changes associated with adaptation to the hospital environment and with increasing drug resistance over time, and how MRSA evolution likely has been influenced by country-specific drug use regimens.

Advantages of day-before lymphoscintigraphy and undiluted methylene blue dye injections for sentinel lymph node biopsies for melanoma.

BACKGROUND AND OBJECTIVES: Lymphatic mapping (LM) and blue dye injections are essential to identification of sentinel lymph nodes (SLN) for melanoma. LM is performed the day before (DB) or the same day (SD) of surgery, but the optimal timing is unknown. Similarly, methylene blue (MB), used during SLN biopsy (SLNB), is administered diluted (dMB) or undiluted (uMB), but the relative efficacies are unknown. METHODS: Patients who underwent SLNB for melanoma from 2009 to 2013 at our institution were evaluated. Outcomes included operative correlation with LM, SLN identification, and postoperative complications. RESULTS: One hundred seventy-one patients underwent SLNB. Sixty-seven (39%) had DB LM. Sixty-seven (39%) received uMB. Operative findings correlated with both LM groups, though the DB patients had lower background count (P = 0.018) and lower highest SLN radioactive signal count (P = 0.046). More uMB patients had blue SLNs (90% vs. 68%, P = 0.001). There was no difference in the total number of SLNs or complication rates in the LM and MB groups. CONCLUSIONS: This is the first study to compare the use of DB LM with SD LM and the efficacy of uMB versus dMB. DB LM and uMB offer advantageous alternatives for patients and their surgeons without loss of accuracy or increased morbidity. J. Surg. Oncol. 2016;114:947-950. © 2016 Wiley Periodicals, Inc.

Thirty-day outcomes underestimate endocrine and exocrine insufficiency after pancreatic resection.

BACKGROUND: Long-term incidence of endocrine and exocrine insufficiency after pancreatectomy is poorly described. We analyze the long-term risks of pancreatic insufficiency after pancreatectomy. METHODS: Subjects who underwent pancreatectomy from 2002 to 2012 were identified from a prospective database (n = 227). Subjects who underwent total pancreatectomy or pancreatitis surgery were excluded. New post-operative endocrine and exocrine insufficiency was defined as the need for new pharmacologic intervention within 1000 days from resection. RESULTS: 28 (16%) of 178 subjects without pre-existing endocrine insufficiency developed post-operative endocrine insufficiency: 7 (25%) did so within 30 days, 8 (29%) between 30 and 90 days, and 13 (46%) after 90 days. 94 (43%) of 214 subjects without pre-operative exocrine insufficiency developed exocrine insufficiency: 20 (21%) did so within 30 days, 29 (31%) between 30 and 90 days, and 45 (48%) after 90 days. Adjuvant radiation was associated with new endocrine insufficiency. On multivariate regression, pancreaticoduodenectomy and chemotherapy were associated with a greater risk of exocrine insufficiency. CONCLUSION: Reporting 30-day functional outcomes for pancreatic resection is insufficient, as nearly 45% of subjects who develop disease do so after 90 days. Reporting of at least 90-day outcomes may more reliably assess risk for post-operative endocrine and exocrine insufficiency.

Treatment of peritoneal carcinomatosis with intraperitoneal administration of Ad-hARF.

BACKGROUND: Peritoneal dissemination of cancer is a terminal condition with limited therapeutic options. Because the peritoneal cavity is a single enclosed space, regional treatment approaches for isolated peritoneal cancrinomatosis are appealing. There is a potential role for gene therapy in the management of peritoneal cancrinomatosis. MATERIALS AND METHODS: An adenoviral construct of the human p14ARF gene (a tumor suppressor) and a 22 amino acid sequence of the ARF gene product, which has cell membrane penetrating properties, were assayed for proapoptotic properties in a human colorectal cancer cell line (Clone A) cells in vitro. Peritoneal carcinomatosis derived from Clone A cells was also established in nude mice and then treated with intraperitoneal administration of an adenoviral construct of the human p14ARF gene. RESULTS: Treatment of ARF-negative Clone A cells with Ad-hARF in vitro reestablished ARF function. However, the cell penetrating ARF-related peptide did not restore ARF function in Clone A cells. Treatment of Clone A peritoneal xenografts with a single intraperitoneal dose of Ad-hARF (9 × 10(6) viral particles) suppressed the progression of peritoneal disease. Weekly (six times) administration of the Ad-hARF at a lower dose (3 × 10(6) viral particles) also suppressed tumor progression. CONCLUSIONS: Treatment of peritoneal carcinomatosis by intraperitoneal administration of adenoviral constructs of inactivated tumor suppressor genes may be a feasible clinical approach, and ARF may represent a suitable molecular target for tumors where the ARF gene is inactivated.

Molecular tracing of the emergence, adaptation, and transmission of hospital-associated methicillin-resistant Staphylococcus aureus.

Hospital-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a global health burden dominated by a small number of bacterial clones. The pandemic EMRSA-16 clone (ST36-II) has been widespread in UK hospitals for 20 y, but its evolutionary origin and the molecular basis for its hospital association are unclear. We carried out a Bayesian phylogenetic reconstruction on the basis of the genome sequences of 87 S. aureus isolates including 60 EMRSA-16 and 27 additional clonal complex 30 (CC30) isolates, collected from patients in three continents over a 53-y period. The three major pandemic clones to originate from the CC30 lineage, including phage type 80/81, Southwest Pacific, and EMRSA-16, shared a most recent common ancestor that existed over 100 y ago, whereas the hospital-associated EMRSA-16 clone is estimated to have emerged about 35 y ago. Our CC30 genome-wide analysis revealed striking molecular correlates of hospital- or community-associated pandemics represented by mobile genetic elements and nonsynonymous mutations affecting antibiotic resistance and virulence. Importantly, phylogeographic analysis indicates that EMRSA-16 spread within the United Kingdom by transmission from hospitals in large population centers in London and Glasgow to regional health-care settings, implicating patient referrals as an important cause of nationwide transmission. Taken together, the high-resolution phylogenomic approach used resulted in a unique understanding of the emergence and transmission of a major MRSA clone and provided molecular correlates of its hospital adaptation. Similar approaches for hospital-associated clones of other bacterial pathogens may inform appropriate measures for controlling their intra- and interhospital spread.

Genome-wide analysis of estrogen receptor binding sites.

The estrogen receptor is the master transcriptional regulator of breast cancer phenotype and the archetype of a molecular therapeutic target. We mapped all estrogen receptor and RNA polymerase II binding sites on a genome-wide scale, identifying the authentic cis binding sites and target genes, in breast cancer cells. Combining this unique resource with gene expression data demonstrates distinct temporal mechanisms of estrogen-mediated gene regulation, particularly in the case of estrogen-suppressed genes. Furthermore, this resource has allowed the identification of cis-regulatory sites in previously unexplored regions of the genome and the cooperating transcription factors underlying estrogen signaling in breast cancer.

Novel mutations in penicillin-binding protein genes in clinical Staphylococcus aureus isolates that are methicillin resistant on susceptibility testing, but lack the mec gene.

OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) is an important global health problem. MRSA resistance to ß-lactam antibiotics is mediated by the mecA or mecC genes, which encode an alternative penicillin-binding protein (PBP) 2a that has a low affinity to ß-lactam antibiotics. Detection of mec genes or PBP2a is regarded as the gold standard for the diagnosis of MRSA. We identified four MRSA isolates that lacked mecA or mecC genes, but were still phenotypically resistant to pencillinase-resistant ß-lactam antibiotics. METHODS: The four human S. aureus isolates were investigated by whole genome sequencing and a range of phenotypic assays. RESULTS: We identified a number of amino acid substitutions present in the endogenous PBPs 1, 2 and 3 that were found in the resistant isolates but were absent in closely related susceptible isolates and which may be the basis of resistance. Of particular interest are three identical amino acid substitutions in PBPs 1, 2 and 3, occurring independently in isolates from at least two separate multilocus sequence types. Two different non-conservative substitutions were also present in the same amino acid of PBP1 in two isolates from two different sequence types. CONCLUSIONS: This work suggests that phenotypically resistant MRSA could be misdiagnosed using molecular methods alone and provides evidence of alternative mechanisms for ß-lactam resistance in MRSA that may need to be considered by diagnostic laboratories.

Electronic medical record: research tool for pancreatic cancer?

BACKGROUND: A novel data warehouse based on automated retrieval from an institutional health care information system (HIS) was made available to be compared with a traditional prospectively maintained surgical database. METHODS: A newly established institutional data warehouse at a single-institution academic medical center autopopulated by HIS was queried for International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes for pancreatic neoplasm. Patients with ICD-9-CM diagnosis codes for pancreatic neoplasm were captured. A parallel query was performed using a prospective database populated by manual entry. Duplicated patients and those unique to either data set were identified. All patients were manually reviewed to determine the accuracy of diagnosis. RESULTS: A total of 1107 patients were identified from the HIS-linked data set with pancreatic neoplasm from 1999-2009. Of these, 254 (22.9%) patients were also captured by the surgical database, whereas 853 (77.1%) patients were only in the HIS-linked data set. Manual review of the HIS-only group demonstrated that 45.0% of patients were without identifiable pancreatic pathology, suggesting erroneous capture, whereas 36.3% of patients were consistent with pancreatic neoplasm and 18.7% with other pancreatic pathology. Of the 394 patients identified by the surgical database, 254 (64.5%) patients were captured by HIS, whereas 140 (35.5%) patients were not. Manual review of patients only captured by the surgical database demonstrated 85.9% with pancreatic neoplasm and 14.1% with other pancreatic pathology. Finally, review of the 254 patient overlap demonstrated that 80.3% of patients had pancreatic neoplasm and 19.7% had other pancreatic pathology. CONCLUSIONS: These results suggest that cautious interpretation of administrative data rely only on ICD-9-CM diagnosis codes and clinical correlation through previously validated mechanisms.

Higher flow rates improve heating during hyperthermic intraperitoneal chemoperfusion.

BACKGROUND/OBJECTIVES: Heated intraperitoneal chemotherapy (HIPEC) kills cancer cells via thermal injury and improved chemotherapeutic cytotoxicity. We hypothesize that higher HIPEC flow rates improve peritoneal heating and HIPEC efficacy. METHODS: (1) A HIPEC-model (30.8 L cooler with attached extracorporeal pump) was filled with 37°C water containing a suspended 1 L saline bag (SB) wrapped in a cooling sleeve, creating a constant heat sink. (2) HIPECs were performed in a swine model. Inflow, outflow, and peritoneal temperatures were monitored as flow rates varied. (3) Flow rates and temperatures during 20 HIPECs were reviewed. RESULTS: Higher flow rates decreased time required to increase water bath (WB) and SB temperature to 43°C. With a constant heat sink, the minimum flow rate required to reach 43°C in the WB was 1.75 L/min. Higher flow rates lead to greater temperature gradients between the WB and SB. In the swine model, the minimum flow rate required to reach 43°C outflow was 2.5-3.0 L/min. Higher flows led to more rapid heating of the peritoneum and greater peritoneal/outflow temperature gradients. Increased flow during clinical HIPEC suggested improved peritoneal heating with lower average visceral temperatures. CONCLUSIONS: There is a minimum flow rate required to reach goal temperature during HIPEC. Flow rate is an important variable in achieving and maintaining goal temperatures during HIPEC.

Effect of uncertainty during the lunge in fencing.

The aim of this study is to determine the effect that uncertainty, in relation to the probability of error, exerts on the reaction response and speed during the lunge in fencing. The participants were 18 regional-level fencers with over five years' experience. Force platforms under the feet recorded the horizontal components of the reaction forces, from which the kinematic parameters of the center of mass were calculated. An electronic system to present stimuli, controlled by a programmable clock, projected a target onto a screen that represented a plastron. In situations without uncertainty, the fencers had to lunge as swiftly as possible when a circle (the target) appeared in the center of the plastron, trying to touch the center of the circle with the tip of the sword. In situations with uncertainty, the fencers had the same target as in the previous situation but they received the information that they had to change the lunge into a defensive move if the target disappeared from the plastron during the action. The results indicate that the reaction time and the movement time increased with uncertainty. Although there were no differences for the horizontal velocity of the center of mass at the end of the acceleration phase, the mean horizontal velocity of the lunge was reduced by the effect of the uncertainty. Prior knowledge of the opponent´s possible action implies a reduction in uncertainty, reducing movement time as well as meaning faster execution, thereby increasing the success of the lunge in fencing. Key PointsReaction time (RT) and the movement time (MT) increase when doubts arise about being able to reach the target as planned during the lunge.The horizontal velocity of the lunge decreases by the effect of uncertainty due to the possibility that the events might not occur as planned.These results highlight the importance that tactical intent has in fencing for successfully predicting the defensive movements of the opponent during the attack.

The novel toluidine sulphonamide EL102 shows pre-clinical in vitro and in vivo activity against prostate cancer and circumvents MDR1 resistance.

BACKGROUND: Taxanes are routinely used for the treatment of prostate cancer, however the majority of patients eventually develop resistance. We investigated the potential efficacy of EL102, a novel toluidine sulphonamide, in pre-clinical models of prostate cancer. METHODS: The effect of EL102 and/or docetaxel on PC-3, DU145, 22Rv1 and CWR22 prostate cancer cells was assessed using cell viability, cell cycle analysis and PARP cleavage assays. Tubulin polymerisation and immunofluorescence assays were used to assess tubulin dynamics. CWR22 xenograft murine model was used to assess effects on tumour proliferation. Multidrug-resistant lung cancer DLKPA was used to assess EL102 in a MDR1-mediated drug resistance background. RESULTS: EL102 has in vitro activity against prostate cancer, characterised by accumulation in G2/M, induction of apoptosis, inhibition of Hif1α, and inhibition of tubulin polymerisation and decreased microtubule stability. In vivo, a combination of EL102 and docetaxel exhibits superior tumour inhibition. The DLKP cell line and multidrug-resistant DLKPA variant (which exhibits 205 to 691-fold greater resistance to docetaxel, paclitaxel, vincristine and doxorubicin) are equally sensitive to EL102. CONCLUSION: EL102 shows potential as both a single agent and within combination regimens for the treatment of prostate cancer, particularly in the chemoresistance setting.

Development of a real-time quadruplex PCR assay for simultaneous detection of nuc, Panton-Valentine leucocidin (PVL), mecA and homologue mecALGA251.

BACKGROUND: The recent discovery of a mecA homologue (mecA(LGA251)) with a high level of variability between the two gene variants suggested that Staphylococcus aureus harbouring mecA(LGA251) could be wrongly identified as methicillin-susceptible S. aureus (MSSA), in the absence of antimicrobial susceptibility testing. METHODS: In this context we designed a real-time quadruplex PCR assay to distinguish unequivocally between mecA and mecA(LGA251), alongside the nuc gene (a species-specific marker) and detection of the lukS-PV gene [encoding the Panton-Valentine leucocidin (PVL) toxin]. RESULTS AND DISCUSSION: The assay was validated using a collection of (i) PVL-positive and PVL-negative MSSA and methicillin-resistant S. aureus (MRSA) and (ii) known MRSA harbouring mecA(LGA251) from the UK, Denmark and France. When applied to a retrospective collection of oxacillin-non-susceptible, mecA-negative human isolates, three were found to encode mecA(LGA251), including one from blood, representing the first hitherto recognized case of bacteraemia due to S. aureus possessing the mecA(LGA251) in England. Finally, the assay was introduced into the routine Staphylococcus Reference Unit (HPA Microbiology Services, London, UK) workflow in August 2011, and, during the first 5 months of use, 10 isolates harbouring the mecA homologue were identified out of 2263 S. aureus tested, suggesting a low but continuous circulation within the human population in England.

Targeting PIM kinase enhances the activity of sunitinib in renal cell carcinoma.

BACKGROUND: Upregulation of PIM kinase expression has been reported in many malignancies, suggesting that inhibition of PIM kinase activity may be an attractive therapeutic strategy. We hypothesised that inhibition of PIM kinase activity with SGI-1776, a novel small molecule inhibitor of PIM kinase activity, would reduce the viability of renal cell carcinoma (RCC) cells and enhance the activity of sunitinib. METHODS: Immunoblotting, qRT-PCR, and gene expression arrays were carried out to identify genes modulated by SGI-1776 treatment. The anticancer activity of SGI-1776 and sunitinib was determined by viability and apoptosis assays and in tumour xenografts in vivo. RESULTS: Treatment with SGI-1776 led to a decrease in phosphorylated and total c-Myc levels, which resulted in the modulation of c-Myc target genes. SGI-1776 in combination with sunitinib induced a further reduction in c-Myc levels, which was associated with enhanced anticancer activity. siRNA-mediated knockdown of c-Myc demonstrated that its expression has a key role in regulating the sensitivity to the combination of SGI-1776 and sunitinib. Importantly, the combination significantly reduced tumour burden in two RCC xenograft models compared with single-agent therapy and was very well tolerated. CONCLUSION: These data indicate that targeting PIM kinase signalling is a promising treatment strategy for RCC.

ELR510444, a novel microtubule disruptor with multiple mechanisms of action.

Although several microtubule-targeting drugs are in clinical use, there remains a need to identify novel agents that can overcome the limitations of current therapies, including acquired and innate drug resistance and undesired side effects. In this study, we show that ELR510444 has potent microtubule-disrupting activity, causing a loss of cellular microtubules and the formation of aberrant mitotic spindles and leading to mitotic arrest and apoptosis of cancer cells. ELR510444 potently inhibited cell proliferation with an IC(50) value of 30.9 nM in MDA-MB-231 cells, inhibited the rate and extent of purified tubulin assembly, and displaced colchicine from tubulin, indicating that the drug directly interacts with tubulin at the colchicine-binding site. ELR510444 is not a substrate for the P-glycoprotein drug transporter and retains activity in ßIII-tubulin-overexpressing cell lines, suggesting that it circumvents both clinically relevant mechanisms of drug resistance to this class of agents. Our data show a close correlation between the concentration of ELR510444 required for inhibition of cellular proliferation and that required to cause significant loss of cellular microtubule density, consistent with its activity as a microtubule depolymerizer. ELR510444 also shows potent antitumor activity in the MDA-MB-231 xenograft model with at least a 2-fold therapeutic window. Studies in tumor endothelial cells show that a low concentration of ELR510444 (30 nM) rapidly alters endothelial cell shape, similar to the effect of the vascular disrupting agent combretastatin A4. These results suggest that ELR510444 is a novel microtubule-disrupting agent with potential antivascular effects and in vivo antitumor efficacy.