Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42.

Inflammation is a major driver of tumor progression and metastasis, although the mechanisms by which proinflammatory cytokines drive metastatic invasion are unknown. Interleukin-6 (IL-6) is a potent proinflammatory cytokine that is elevated in individuals with pancreatic cancer (PDAC), is required for PDAC progression in mice, and increases tumor cell invasion in vitro Here, we provide insights into the mechanisms by which IL-6 activates tumor cell invasion. We found that IL-6 stimulation rapidly and robustly activates the small GTPase cell division cycle 42 (CDC42) in human PDAC cells and promotes the formation of premigratory filopodia. The CDC42 activation was required for IL-6-induced invasion as blocking CDC42 activity rendered the cells insensitive to IL-6's proinvasive effects. Loss of Janus kinase 2 (JAK2) or signal transducer and activator of transcription 3 (STAT3) prevented IL-6-mediated CDC42 activation, indicating that IL-6 activates CDC42 through both JAK2 and STAT3. However, the rapid activation of CDC42 suggested that this activation may be distinct from canonical STAT3-mediated transcriptional activation. Importantly, we observed an interaction between STAT3 and IQ motif-containing GTPase-activating protein 1 (IQGAP1), a scaffolding platform that binds CDC42. STAT3 colocalized with CDC42 and IQGAP1 at the plasma membrane, suggesting cross-talk between IL-6-mediated STAT3 signaling and CDC42 activation. These results suggest that IL-6 promotes metastatic invasion, at least partially, through CDC42 and that, along with its pleiotropic effects on tumor growth and progression, IL-6 signaling also activates proinvasive GTPase signaling, priming tumor cells for metastatic invasion.

Persistence of deeply sourced iron in the Pacific Ocean.

Biological carbon fixation is limited by the supply of Fe in vast regions of the global ocean. Dissolved Fe in seawater is primarily sourced from continental mineral dust, submarine hydrothermalism, and sediment dissolution along continental margins. However, the relative contributions of these three sources to the Fe budget of the open ocean remains contentious. By exploiting the Fe stable isotopic fingerprints of these sources, it is possible to trace distinct Fe pools through marine environments, and through time using sedimentary records. We present a reconstruction of deep-sea Fe isotopic compositions from a Pacific Fe-Mn crust spanning the past 76 My. We find that there have been large and systematic changes in the Fe isotopic composition of seawater over the Cenozoic that reflect the influence of several, distinct Fe sources to the central Pacific Ocean. Given that deeply sourced Fe from hydrothermalism and marginal sediment dissolution exhibit the largest Fe isotopic variations in modern oceanic settings, the record requires that these deep Fe sources have exerted a major control over the Fe inventory of the Pacific for the past 76 My. The persistence of deeply sourced Fe in the Pacific Ocean illustrates that multiple sources contribute to the total Fe budget of the ocean and highlights the importance of oceanic circulation in determining if deeply sourced Fe is ever ventilated at the surface.

HPV status and favourable outcome in vulvar squamous cancer.

It is universally accepted that high-risk human papillomavirus (HR-HPV) is the cause of cervical dysplasia and cancer. More recently, it has been shown that HPV is also a marker of clinical outcome in oropharyngeal cancer. However, contemporary information is lacking on both the prevalence of HPV infection in vulvar cancer (VSCC), its precursor lesion, vulvar intraepithelial neoplasia (VIN) and the influence of HPV-status on the prognosis of this malignancy. We have conducted a detailed population-based study to examine rates of progression of VIN to VSCC, type-specific HPV prevalence in vulvar disease and the influence of HPV status on clinical outcome in VSCC. We observed that the age at which women are diagnosed with VSCC is falling and there is a significant time gap between first diagnosis of VIN and progression to invasive disease. HR-HPV infection was detected in 87% (97/112) cases of VIN and 52% cases (32/62) of VSCC. The presence of HR-HPV in squamous intraepithelial lesion was associated with lower rates of progression to invasive cancer (hazard ratio, 0.22, p = 0.001). In the adjusted analysis, HR-HPV was associated with improved progression-free survival of VSCC compared to those with HPV negative tumours (hazard ratio, 0.32, p = 0.02).

The Current Burden of Follow-up of Stage 1A1 Cervical Cancer.

OBJECTIVE: The aim of this study was to assess the current burden and consistency of stage 1A1 cervical cancer follow-up within Greater Glasgow and Clyde Health Board. METHODS: A retrospective review was undertaken of women diagnosed with and treated of, between 2007 and 2011, stage 1A1 cervical cancer in Greater Glasgow and Clyde Health Board. Data were collected on referral cytology, definitive method of treatment, posttreatment cytology, and rate of recurrence. Outcomes included rate of recurrence, abnormal cytology, and number of interventions during follow-up. RESULTS: Of the 78 women diagnosed with stage 1A1 cervical cancer, 43 had a LLETZ (large loop excision of the transformation zone) as definitive treatment. Ninety percent of stage 1A1 cervical cancers were diagnosed following abnormal screening cytology. Almost 86% of all cytology post-LLETZ were negative. Only 1 woman had a recurrence. No posthysterectomy vault smears were low-grade dyskaryosis or worse. CONCLUSIONS: There is a very low rate of abnormal cytology after LLETZ. Vault smears are of limited benefit in the management of women posthysterectomy for stage 1A1 cervical cancer.

Multifocal FIGO Stage IA1 Squamous Carcinoma of the Cervix: Criteria for Identification, Staging, and its Good Clinical Outcome.

Multifocal squamous cervical carcinomas account for up to 25% of IA1 tumors identified on excisional biopsy, yet there are no uniformly accepted histopathologic criteria for defining and staging these lesions. Here, we use a strict case definition and meticulous specimen processing from colposcopist to pathologist to identify and follow-up 25 cases of multifocal IA1 cervical squamous carcinomas identified in excisional biopsies. We stage these tumors using the dimensions of the largest focus and a minimum of 2 mm between each foci to define multifocality. The cases are followed up for a median of 7 yr with no episodes of tumor recurrence or metastasis. We also show that the prevalence of residual preinvasive (20%) and invasive disease (5%) on repeat excision/surgery are comparable to data available for unifocal IA1 cases. Our study supports the hypothesis that multifocal lesions should be staged according to largest individual focus of invasion and we emphasize the importance of meticulous specimen handling to appropriately identify multifocal tumors. In addition, our analysis suggests that outcomes are comparable to unifocal lesions and supports the hypothesis that they may be managed in a similar manner.

Intrathecal application of the nimodipine slow-release microparticle system eg-1962 for prevention of delayed cerebral ischemia and improvement of outcome after aneurysmal subarachnoid hemorrhage.

The effective reduction of delayed cerebral ischemia (DCI), a main contributor for poor outcome following aneurysmal subarachnoid hemorrhage (SAH), remains challenging. Previous clinical trials on systemic pharmaceutical treatment of SAH mostly failed to improve outcome, probably because of insensitive pharmaceutical targets and outcome measures, small sample size, insufficient subarachnoid drug concentrations and also detrimental, systemic effects of the experimental treatment per se. Interestingly, in studies that are more recent, intrathecal administration of nicardipine pellets following surgical aneurysm repair was suggested to have a beneficial effect on DCI and neurological outcome. However, this positive effect remained restricted to patients who were treated surgically for a ruptured aneurysm. Because of the favorable results of the preclinical data on DCI and neurological outcome in the absence of neurotoxicity or systemic side effects, we are initiating clinical trials. The PROMISE (Prolonged Release nimOdipine MIcro particles after Subarachnoid hemorrhage) trial is designed as an unblinded, nonrandomized, single-center, single-dose, dose-escalation safety and tolerability phase 1 study in patients surgically treated for aSAH and will investigate the effect of intracisternal EG-1962 administration. The NEWTON (Nimodipine microparticles to Enhance recovery While reducing TOxicity after subarachNoid hemorrhage) trial is a phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation, safety, tolerability, and pharmacokinetic study comparing EG-1962 and nimodipine in patients with aneurysmal SAH.

Fertility conserving management of early cervical cancer: our experience of LLETZ and pelvic lymph node dissection.

BACKGROUND: Presently, for those diagnosed with early cervical cancer who wish to conserve their fertility, there is the option of radical trachelectomy. Although successful, this procedure is associated with significant obstetric morbidity. The recurrence risk of early cervical cancer is low and in tumors measuring less than 2 cm; if the lymphatics are negative, the likelihood of parametrial involvement is less than 1%. Therefore, pelvic lymph nodes are a surrogate marker of parametrial involvement and radical excision of the parametrium can be omitted if they are negative. OBJECTIVE: The aim of this study was to report our experience of the fertility conserving management of early cervical cancer with repeat large loop excision of the transformation zone and laparoscopic pelvic lymph node dissection. METHODS: Between 2004 and 2011, a retrospective review of cases of early cervical cancer who had fertility conserving management within Glasgow Royal Infirmary was done. RESULTS: Forty-three patients underwent fertility conserving management of early cervical cancer. Forty were screen-detected cancers; 2 were stage IA1, 4 were stage IA2, and 37 were stage IB1. There were 2 central recurrences during the follow-up period. There have been 15 live children to 12 women and there are 4 ongoing pregnancies. CONCLUSIONS: To our knowledge, this is the largest case series described and confirms the low morbidity and mortality of this procedure. However, even within our highly select group, there have been 2 cases of central recurrent disease. We, therefore, are urging caution in the global adoption of this technique and would welcome a multicenter multinational randomized controlled trial.

Intrinsic cardiac origin of human cardiosphere-derived cells.

AIMS: Cardiosphere-derived cells (CDCs) are in clinical development as a regenerative cell product which can be expanded ex vivo from patient cardiac biopsies. Cardiosphere-derived cells are clonogenic, exhibit multilineage differentiation, and exert functional benefits in preclinical models of heart failure. The origin of CDCs remains unclear: are these cells endogenous to the heart, or do they arise from cells that populate the heart via blood-borne seeding? METHODS AND RESULTS: Right ventricular endomyocardial biopsies were obtained from cardiac transplant recipients (n = 10, age 57 ± 15 years), and CDCs expanded from each biopsy. Donor-recipient mismatches were used to probe the origin of CDCs in three complementary ways. First, DNA analysis of short-tandem nucleotide repeats (STRs) was performed on genomic DNA from donor and recipient, then compared with the STR pattern of CDCs. Second, in two cases where the donor was male and the recipient female, CDCs were examined for the presence of X and Y chromosomes by fluorescence in situ hybridization. Finally, in two cases, quantitative PCR (qPCR) was performed for individual-specific polymorphisms of a major histocompatability locus to quantify the contribution of recipient cells to CDCs. In no case was recipient DNA detectable in the CDCs by STR analysis. In the two cases in which a female patient had received a male heart, all CDCs examined had an X and Y chromosome, similarly indicating exclusively donor origin. Likewise, qPCR on CDCs did not detect any recipient DNA. CONCLUSION: Cardiosphere-derived cells are of endogenous cardiac origin, with no detectable contribution from extra-cardiac seeding.

Vulvar reconstruction using the "lotus petal" fascio-cutaneous flap.

INTRODUCTION: Vulvar reconstruction using the "lotus petal" fascio-cutaneous flap offers a relatively novel means to restore symmetry and functionality after extirpative gynecologic or oncologic procedures. We sought to assess the success rates and morbidity in a large series of consecutively treated patients. METHODS: We performed a retrospective review of 59 consecutive cases of lotus petal flaps performed at a single institution to more accurately assess success and complication rates. RESULTS: We identified 80 flaps performed among the 59 patients between September 1, 2008 and March 30, 2013. The median (range) age was 59 years (24-89) and the median (range) BMI was 27 kg/m(2) (19-34). The indications for vulvar/perineal excision were as follows: 39 (66.1%) vulvar carcinoma or melanoma, 12 (20.3%) vulvar dysplasia, 5 (8.5%) colorectal disease and 3 (5.1%) cases of hidradenitis suppurativa. The mean defect area, determined by post-fixation pathology specimen was 29 cm(2). Medical or surgical complications occurred in 36% of patients of which superficial wound separation was the most common (15%). There were no cases of complete flap loss, but partial loss occurred in 7 (8.8%) cases. 3 (5.1%) patients required re-operation prior to discharge with one case requiring skin grafting. Delayed surgical revision was required in 4 patients for partial flap loss (2) or stricture/stenosis (2). CONCLUSION: The lotus petal flap is safe for use in gynecologic reconstruction, with acceptable short- and long-term complication rates. Previous reports of smaller series likely underestimate the risk of complications through case selection.

"Unresectable" vulval cancers: is neoadjuvant chemotherapy the way forward?

Squamous cell carcinoma of the vulva is an uncommon gynaecological malignancy, but the incidence is increasing. A significant proportion of patients present with locally advanced disease, and management can prove challenging because of the size and/or location of the tumour. Surgery forms the mainstay of treatment, but the role of neoadjuvant therapy in minimizing morbidity is under investigation. Although chemotherapy alone has been largely neglected in favour of chemoradiotherapy, concerns about the toxicity of trimodality therapy and suboptimal results, particularly in node-positive patients, have led to renewed interest in neoadjuvant chemotherapy (NACT). A review of the available literature illustrates that NACT can produce dramatic responses, but operability rates and overall survival differ widely. The effect is dependent on as yet unidentified factors, although we speculate that age and tumour biology are important. Further work is required to delineate the optimal NACT regimen and the patient population(s) most likely to benefit from this practice.

British Gynaecological Cancer Society Recommendations for Evidence Based, Population Data Derived Quality Performance Indicators for Ovarian Cancer.

Ovarian cancer survival in the UK lags behind comparable countries. Results from the ongoing National Ovarian Cancer Audit feasibility pilot (OCAFP) show that approximately 1 in 4 women with advanced ovarian cancer (Stage 2, 3, 4 and unstaged cancer) do not receive any anticancer treatment and only 51% in England receive international standard of care treatment, i.e., the combination of surgery and chemotherapy. The audit has also demonstrated wide variation in the percentage of women receiving anticancer treatment for advanced ovarian cancer, be it surgery or chemotherapy across the 19 geographical regions for organisation of cancer delivery (Cancer Alliances). Receipt of treatment also correlates with survival: 5 year Cancer survival varies from 28.6% to 49.6% across England. Here, we take a systems wide approach encompassing both diagnostic pathways and cancer treatment, derived from the whole cohort of women with ovarian cancer to set out recommendations and quality performance indicators (QPI). A multidisciplinary panel established by the British Gynaecological Cancer Society carefully identified QPI against criteria: metrics selected were those easily evaluable nationally using routinely available data and where there was a clear evidence base to support interventions. These QPI will be valuable to other taxpayer funded systems with national data collection mechanisms and are to our knowledge the only population level data derived standards in ovarian cancer. We also identify interventions for Best practice and Research recommendations.

In situ Os isotopes in abyssal peridotites bridge the isotopic gap between MORBs and their source mantle.

Abyssal peridotites are assumed to represent the mantle residue of mid-ocean-ridge basalts (MORBs). However, the osmium isotopic compositions of abyssal peridotites and MORB do not appear to be in equilibrium, raising questions about the cogenetic relationship between those two reservoirs. However, the cause of this isotopic mismatch is mainly due to a drastic filtering of the data based on the possibility of osmium contamination by sea water. Here we present a detailed study of magmatic sulphides (the main carrier of osmium) in abyssal peridotites and show that the 187Os/188Os ratio of these sulphides is of primary mantle origin and can reach radiogenic values suggesting equilibrium with MORB. Thus, the effect of sea water on the osmium systematics of abyssal peridotites has been overestimated and consequently there is no true osmium isotopic gap between MORBs and abyssal peridotites.

Distinct forms of the actin cross-linking protein α-actinin support macropinosome internalization and trafficking.

The α-actinin family of actin cross-linking proteins have been implicated in driving tumor cell metastasis through regulation of the actin cytoskeleton; however, there has been little investigation into whether these proteins can influence tumor cell growth. We demonstrate that α-actinin 1 and 4 are essential for nutrient uptake through the process of macropinocytosis in pancreatic ductal adenocarcinoma (PDAC) cells, and inhibition of these proteins decreases tumor cell survival in the presence of extracellular protein. The α-actinin proteins play essential roles throughout the macropinocytic process, where α-actinin 4 stabilizes the actin cytoskeleton on the plasma membrane to drive membrane ruffling and macropinosome internalization and α-actinin 1 localizes to actin tails on macropinosomes to facilitate trafficking to the lysosome for degradation. In addition to tumor cell growth, we also observe that the α-actinin proteins can influence uptake of chemotherapeutics and extracellular matrix proteins through macropinocytosis, suggesting that the α-actinin proteins can regulate multiple tumor cell properties through this endocytic process. In summary, these data demonstrate a critical role for the α-actinin isoforms in tumor cell macropinocytosis, thereby affecting the growth and invasive potential of PDAC tumors.

Multidisciplinary management of anal intraepithelial neoplasia and rate of progression to cancer: A retrospective cohort study.

PURPOSE: To describe the regional burden of AIN and rate of progression to cancer in patients managed in specialist and non-specialist clinic settings. METHODS: Patients with a histopathological diagnosis of AIN between 1994 and 2018 were retrospectively identified. Clinicopathological characteristics including high-risk status (chronic immunosuppressant use or HIV positive), number and type of biopsy (punch/excision) and histopathological findings were recorded. The relationship between clinicopathological characteristics and progression to cancer was assessed using logistic regression. RESULTS: Of 250 patients identified, 207 were eligible for inclusion: 144 from the specialist and 63 from the non-specialist clinic. Patients in the specialist clinic were younger (<40 years 31% vs 19%, p = 0.007), more likely to be male (34% vs 16%, p = 0.008) and HIV positive (15% vs 2%, p = 0.012). Patients in the non-specialist clinic were less likely to have AIN3 on initial pathology (68% vs 79%, p = 0.074) and were more often followed up for less than 36 months (46% vs 28%, p = 0.134). The rate of progression to cancer was 17% in the whole cohort (20% vs 10%, p = 0.061). On multivariate analysis, increasing age (OR 3.02, 95%CI 1.58-5.78, p < 0.001), high risk status (OR 3.53, 95% CI 1.43-8.74, p = 0.006) and increasing number of excisions (OR 4.88, 95%CI 2.15-11.07, p < 0.001) were related to progression to cancer. CONCLUSION: The specialist clinic provides a structured approach to the follow up of high-risk status patients with AIN. Frequent monitoring with specialist assessments including high resolution anoscopy in a higher volume clinic are required due to the increased risk of progression to anal cancer.

Fossil records of early solar irradiation and cosmolocation of the CAI factory: A reappraisal.

Calcium-aluminum­rich inclusions (CAIs) in meteorites carry crucial information about the environmental conditions of the nascent Solar System prior to planet formation. Based on models of 50V­10Be co-production by in-situ irradiation, CAIs are considered to have formed within ~0.1 AU from the proto-Sun. Here, we present vanadium (V) and strontium (Sr) isotopic co-variations in fine- and coarse-grained CAIs and demonstrate that kinetic isotope effects during partial condensation and evaporation best explain V isotope anomalies previously attributed to solar particle irradiation. We also report initial excesses of 10Be and argue that CV CAIs possess essentially a homogeneous level of 10Be, inherited during their formation. Based on numerical modeling of 50V­10Be co-production by irradiation, we show that CAI formation during protoplanetary disk build-up likely occurred at greater heliocentric distances than previously considered, up to planet-forming regions (~1AU), where solar particle fluxes were sufficiently low to avoid substantial in-situ irradiation of CAIs.

British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: Recommendations for practice.

Cervix cancer in many countries is declining and screening programmes and immunisation will reduce the incidence in the next few decades. This guideline attempts to cover management of invasive disease reflecting diagnosis and imaging including new imaging and sentinel lymph node biopsies. Smaller volume disease is usually managed surgically whereas advanced disease is treated with (chemo)- radiation. It also includes discussion of fertility sparing procedures. Practices are changing frequently for all aspects of care usually in attempts to reduce complications and improve quality of life. The management of advanced disease is treated by chemotherapy and the use of newer agents is also discussed. Other sections discuss specialist situations such as cancer in pregnancy, rare cervical tumours, late effects and supportive measures and fertility preserving approaches.

An agonist of liver X receptor slows valvular disease in a hypercholesterolemia mouse model.

BACKGROUND AND AIM OF THE STUDY: Cholesterol is a known risk factor in aortic stenosis and valve degeneration, and the liver X receptor (LXR) is a regulator of cholesterol and phospholipid metabolism. It was hypothesized that an LXR agonist would reduce calcium and lipid deposition in aortic valves. METHODS: Apolipoprotein E-/- (ApoE-/-) mice fed a high-fat diet were implanted with glutaraldehyde-fixed porcine valve fragments. The animals were treated with either the LXR agonist T1317 or vehicle for eight weeks. RESULTS: The LXR agonist reduced lipid deposition in native aortic roots and sinuses about two-fold (p < 0.05), and echocardiography revealed lower transvalvular velocities in vivo (p < 0.05). Similarly, treatment with the LXR agonist significantly reduced the calcium content (by ca. 50%, p < 0.05) and lipid content (by ca. 20%, p < 0.01) of explanted porcine valve tissue. Serum low-density lipoprotein (LDL) and total cholesterol levels were also lower in treated mice (p < 0.01). Serum levels of the inflammatory chemokine platelet factor 4 were reduced by 30% compared to controls. Cultured valvular cells treated with oxidized LDL (ox-LDL) developed greater numbers of calcific nodules. The ox-LDL treatment of valvular endothelial cells increased adhesion to mononuclear cells, while the LXR agonist reversed both the increase in adhesion and vascular cell adhesion protein-1 expression mediated by ox-LDL. CONCLUSION: The data acquired suggested that calcium and lipid deposition in heart valves can be altered by inhibiting lipid metabolism via LXR, and that the mechanism may involve inflammatory cell signaling. These results indicate that enhancement of cholesterol efflux activity may have the potential to reduce bioprosthetic and native valve degeneration.

Dynamin 2 interacts with α-actinin 4 to drive tumor cell invasion.

The large GTPase Dynamin 2 (Dyn2) is known to increase the invasiveness of pancreatic cancer tumor cells, but the mechanisms by which Dyn2 regulates changes in the actin cytoskeleton to drive cell migration are still unclear. Here we report that a direct interaction between Dyn2 and the actin-bundling protein alpha-actinin (α-actinin) 4 is critical for tumor cell migration and remodeling of the extracellular matrix in pancreatic ductal adenocarcinoma (PDAC) cells. The direct interaction is mediated through the C-terminal tails of both Dyn2 and α-actinin 4, and these proteins interact at invasive structures at the plasma membrane. While Dyn2 binds directly to both α-actinin 1 and α-actinin 4, only the interaction with α-actinin 4 is required to promote tumor cell invasion. Specific disruption of the Dyn2-α-actinin 4 interaction blocks the ability of PDAC cells to migrate in either two dimensions or invade through extracellular matrix as a result of impaired invadopodia stability. Analysis of human PDAC tumor tissue additionally reveals that elevated α-actinin 4 or Dyn2 expression are predictive of poor survival. Overall, these data demonstrate that Dyn2 regulates cytoskeletal dynamics, in part, by interacting with the actin-binding protein α-actinin 4 during tumor cell invasion.

Rapid CO2 mineralisation into calcite at the CarbFix storage site quantified using calcium isotopes.

The engineered removal of atmospheric CO2 is now considered a key component of mitigating climate warming below 1.5 °C. Mineral carbonation is a potential negative emissions technique that, in the case of Iceland's CarbFix experiment, precipitates dissolved CO2 as carbonate minerals in basaltic groundwater settings. Here we use calcium (Ca) isotopes in both pre- and post-CO2 injection waters to quantify the amount of carbonate precipitated, and hence CO2 stored. Ca isotope ratios rapidly increase with the pH and calcite saturation state, indicating calcite precipitation. Calculations suggest that up to 93% of dissolved Ca is removed into calcite during certain phases of injection. In total, our results suggest that 165 ± 8.3 t CO2 were precipitated into calcite, an overall carbon storage efficiency of 72 ± 5%. The success of this approach opens the potential for quantification of similar mineral carbonation efforts where drawdown rates cannot be estimated by other means.