The conduction of heat through minerals and melts at extreme pressures and temperatures is of central importance to the evolution and dynamics of planets. In the cooling Earth's core, the thermal ...conductivity of iron alloys defines the adiabatic heat flux and therefore the thermal and compositional energy available to support the production of Earth's magnetic field via dynamo action. Attempts to describe thermal transport in Earth's core have been problematic, with predictions of high thermal conductivity at odds with traditional geophysical models and direct evidence for a primordial magnetic field in the rock record. Measurements of core heat transport are needed to resolve this difference. Here we present direct measurements of the thermal conductivity of solid iron at pressure and temperature conditions relevant to the cores of Mercury-sized to Earth-sized planets, using a dynamically laser-heated diamond-anvil cell. Our measurements place the thermal conductivity of Earth's core near the low end of previous estimates, at 18-44 watts per metre per kelvin. The result is in agreement with palaeomagnetic measurements indicating that Earth's geodynamo has persisted since the beginning of Earth's history, and allows for a solid inner core as old as the dynamo.
Insulator-metal transition in dense fluid deuterium Celliers, Peter M; Millot, Marius; Brygoo, Stephanie ...
Science (American Association for the Advancement of Science),
08/2018, Letnik:
361, Številka:
6403
Journal Article
Recenzirano
Odprti dostop
Dense fluid metallic hydrogen occupies the interiors of Jupiter, Saturn, and many extrasolar planets, where pressures reach millions of atmospheres. Planetary structure models must describe ...accurately the transition from the outer molecular envelopes to the interior metallic regions. We report optical measurements of dynamically compressed fluid deuterium to 600 gigapascals (GPa) that reveal an increasing refractive index, the onset of absorption of visible light near 150 GPa, and a transition to metal-like reflectivity (exceeding 30%) near 200 GPa, all at temperatures below 2000 kelvin. Our measurements and analysis address existing discrepancies between static and dynamic experiments for the insulator-metal transition in dense fluid hydrogen isotopes. They also provide new benchmarks for the theoretical calculations used to construct planetary models.
Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. ...MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer.
MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov, number NCT02091141.
Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20–45). The most common treatment-emergent adverse events were diarrhoea (19 33% of 57 patients), fatigue (18 32% patients), and nausea (17 30% patients). Grade 3–4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three 5% patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths.
Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer.
F Hoffmann-La Roche/Genentech.
To identify predictive factors associated with operative morbidity, mortality, and survival outcomes in patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal ...adenocarcinoma (PDAC) undergoing total neoadjuvant therapy (TNT).
The optimal preoperative treatment sequencing for BR/LA PDA is unknown. TNT, or systemic chemotherapy followed by chemoradiation (CRT), addresses both occult metastases and positive margin risks and thus is a potentially optimal strategy; however, factors predictive of perioperative and survival outcomes are currently undefined.
We reviewed our experience in BR/LA patients undergoing resection from 2010 to 2017 following TNT assessing operative morbidity, mortality, and survival in order to define outcome predictors and response endpoints.
One hundred ninety-four patients underwent resection after TNT, including 123 (63%) BR and 71 (37%) LA PDAC. FOLFIRINOX or gemcitabine along with nab-paclitaxel were used in 165 (85%) and 65 (34%) patients, with 36 (19%) requiring chemotherapeutic switch before long-course CRT and subsequent resection. Radiologic anatomical downstaging was uncommon (28%). En bloc venous and/or arterial resection was required in 125 (65%) patients with 94% of patients achieving R0 margins. The 90-day major morbidity and mortality was 36% and 6.7%, respectively. Excluding operative mortalities, the median, 1-year, 2-year, and 3-year recurrence-free survival (RFS) overall survival (OS) rates were 23.5 (58.8) months, 65 (96)%, 48 (78)%, and 32 (62)%, respectively. Radiologic downstaging, vascular resection, and chemotherapy regimen/switch were not associated with survival. Only 3 factors independently associated with prolonged survival, including extended duration (≥6 cycles) chemotherapy, optimal post-chemotherapy CA19-9 response, and major pathologic response. Patients achieving all 3 factors had superior survival outcomes with a survival detriment for each failing factor. In a subset of patients with interval metabolic (PET) imaging after initial chemotherapy, complete metabolic response highly correlated with major pathologic response.
Our TNT experience in resected BR/LA PDAC revealed high negative margin rates despite low radiologic downstaging. Extended duration chemotherapy with associated biochemical and pathologic responses highly predicted postoperative survival. Potential modifications of initial chemotherapy treatment include extending cycle duration to normalize CA19-9 or achieve complete metabolic response, or consideration of chemotherapeutic switch in order to achieve these factors may improve survival before moving forward with CRT and subsequent resection.
Diatomic nitrogen is an archetypal molecular system known for its exceptional stability and complex behavior at high pressures and temperatures, including rich solid polymorphism, formation of ...energetic states, and an insulator-to-metal transformation coupled to a change in chemical bonding. However, the thermobaric conditions of the fluid molecular-polymer phase boundary and associated metallization have not been experimentally established. Here, by applying dynamic laser heating of compressed nitrogen and using fast optical spectroscopy to study electronic properties, we observe a transformation from insulating (molecular) to conducting dense fluid nitrogen at temperatures that decrease with pressure and establish that metallization, and presumably fluid polymerization, occurs above 125 GPa at 2500 K. Our observations create a better understanding of the interplay between molecular dissociation, melting, and metallization revealing features that are common in simple molecular systems.
Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in ...these genes are not well defined.
To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer.
Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in a Mayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database.
Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer.
Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction-based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls.
Comparing 3030 case patients with pancreatic cancer (43.2% female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 SD, 10.7 years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3% of cases and 0.02% of controls; odds ratio OR, 12.33; 95% CI, 5.43-25.61); TP53 (0.2% of cases and 0.02% of controls; OR, 6.70; 95% CI, 2.52-14.95); MLH1 (0.13% of cases and 0.02% of controls; OR, 6.66; 95% CI, 1.94-17.53); BRCA2 (1.9% of cases and 0.3% of controls; OR, 6.20; 95% CI, 4.62-8.17); ATM (2.3% of cases and 0.37% of controls; OR, 5.71; 95% CI, 4.38-7.33); and BRCA1 (0.6% of cases and 0.2% of controls; OR, 2.58; 95% CI, 1.54-4.05).
In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5% of all pancreatic cancer patients, including 7.9% of patients with a family history of pancreatic cancer and 5.2% of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.
We use fast transient transmission and emission spectroscopies in the pulse laser heated diamond anvil cell to probe the energy-dependent optical properties of hydrogen at pressures of 10-150 GPa and ...temperatures up to 6000 K. Hydrogen is absorptive at visible to near-infrared wavelengths above a threshold temperature that decreases from 3000 K at 18 GPa to 1700 K at 110 GPa. Transmission spectra at 2400 K and 141 GPa indicate that the absorptive hydrogen is semiconducting or semimetallic in character, definitively ruling out a first-order insulator-metal transition in the studied pressure range.
Summary Patients with cholangiocarcinoma often present with locally advanced or metastatic disease. There is a need for effective therapeutic strategies for advanced stage cholangiocarcinoma. ...Recently, FGFR2 translocations have been identified as a potential target for tyrosine kinase inhibitor therapies. This study evaluated 152 cholangiocarcinomas and 4 intraductal papillary biliary neoplasms of the bile duct for presence of FGFR2 translocations by fluorescence in situ hybridization and characterized the clinicopathologic features of cases with FGFR2 translocations. Thirteen (10 women, 3 men; 8%) of 156 biliary tumors harbored FGFR2 translocations, including 12 intrahepatic cholangiocarcinomas (12/96; 13%) and 1 intraductal papillary neoplasm of the bile duct. Histologically, cholangiocarcinomas with FGFR2 translocations displayed prominent intraductal growth (62%) or anastomosing tubular glands with desmoplasia (38%). Immunohistochemically, the tumors with FGFR2 translocations frequently showed weak and patchy expression of CK19 (77%). Markers of the stem cell phenotype in cholangiocarcinoma, HepPar1 and CK20, were negative in all cases. The median cancer-specific survival for patients whose tumors harbored FGFR2 translocations was 123 months compared to 37 months for cases without FGFR2 translocations ( P = .039). This study also assessed 100 cholangiocarcinomas for ERBB2 amplification and ROS1 translocations. Of the cases tested, 3% and 1% were positive for ERBB2 amplification and ROS1 translocation, respectively. These results confirm that FGFR2 , ERRB2 , and ROS1 alterations are potential therapeutic targets for intrahepatic cholangiocarcinoma.
Objective Despite technical advances of fenestrated and branched endografts, endovascular exclusion of aneurysms involving renal, visceral, and/or supra-aortic branches remains a challenge. In situ ...fenestration (ISF) of standard endografts represents another endovascular means to maintain perfusion to such branches. This study aimed to review current indications, technical descriptions, and results of ISF. Method A review of the English language literature was performed in Medline databases, Cochrane Database, Web of Science, and Scopus using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Sixty-seven relevant papers were selected. Thirty-three papers were excluded, leaving 34 articles as the basis of the present review. Results Most experimental papers evaluated ISF feasibility and assessed the consequences of ISF on graft fabric. Regarding clinical papers, 73 ISF procedures have been attempted in 58 patients, including 26 (45%) emergent and three (5%) bailout cases. Sixty-five (89%) ISF were located at the level of the arch, and eight (11%) in the abdominal aorta. Graft perforation was performed by physical, mechanical, or unspecified means in 33 (45%), 38 (52%), and two vessels (3%), respectively. ISF was technically successful in 68/73 (93%) arteries. At 30 days, two (3.4%) patients died in the setting of an aorto-bronchial fistula and an aorto-oesophageal fistula, respectively. No post-operative death, major complication, or endoleak was described as secondary to the ISF procedure. With follow-up between 0 and 72 months, four (6.9%) late deaths were noted, unrelated to the aorta. One (1.7%) LSA stent was stenosed without symptoms. Conclusions Although there may be publication bias, multiple techniques were described to perform ISF with satisfactory short-term results. Long-term data remain scarce. Aortic endograft ISF is an off-label procedure that should not be used outside emergent bailout techniques or investigational studies. A comparison with alternative techniques of preserving aortic side branches is needed.
Ultrafast x-ray diffraction at the LCLS x-ray free electron laser has been used to resolve the structural behavior of antimony under shock compression to 59 GPa. Antimony is seen to transform to the ...incommensurate, host-guest phase Sb-II at ∼11 GPa, which forms on nanosecond timescales with ordered guest-atom chains. The high-pressure bcc phase Sb-III is observed above ∼15 GPa, some 8 GPa lower than in static compression studies, and mixed Sb-III/liquid diffraction are obtained between 38 and 59 GPa. An additional phase which does not exist under static compression, Sb-I^{'}, is also observed between 8 and 12 GPa, beyond the normal stability field of Sb-I, and resembles Sb-I with a resolved Peierls distortion. The incommensurate Sb-II high-pressure phase can be recovered metastably on release to ambient pressure, where it is stable for more than 10 ns.
PDF
