Optical image-guided cancer surgery is a promising technique to adequately determine tumor margins by tumor-specific targeting, potentially resulting in complete resection of tumor tissue with ...improved survival. However, identification of the photons coming from the fluorescent contrast agent is complicated by autofluorescence, optical tissue properties, and accurate fluorescent targeting agents and imaging systems. All these factors have an important influence on the image that is presented to the surgeon. Considering the clinical consequences at stake, it is a prerequisite to answer the questions that are essential for the surgeon. What is optical image-guided surgery and how can it improve patient care? What should the oncologic surgeon know about the fundamental principles of optical imaging to understand which conclusions can be drawn from the images? And how do the limitations influence clinical decision making? This article discusses these questions and provides a clear overview of the basic principles and practical applications. Although there are limitations to the intrinsic capacity of the technique, when practical and technical surgical possibilities are considered, optical imaging can be a very powerful intraoperative tool in guiding the future oncologic surgeon toward radical resection and optimal clinical results.
Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, daratumumab is administered IV. The ...phase 1b PAVO (MMY1004) study evaluated subcutaneously administered daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous daratumumab according to the approved IV monotherapy dosing schedule at 1200 mg (n = 8) or 1800 mg (n = 45). Primary end points were safety and pharmacokinetic (PK) variables. The most common treatment-emergent adverse events with DARA-MD 1200 mg were thrombocytopenia, upper respiratory tract infection, insomnia, and decreased appetite (37.5% each). Anemia (33.3%), upper respiratory tract infection, pyrexia, and diarrhea (26.7% each) were the most common treatment-emergent adverse events with DARA-MD 1800 mg. One patient in the 1200-mg dose group (12.5%) and 11 patients in the 1800-mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1/2 and typically occurred at the first infusion. The 1800 mg dose achieved similar or greater serum concentrations compared with the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1200-mg and 1800-mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with relapsed or refractory MM, with the 1800-mg dose exhibiting PK concentrations and responses consistent with IV daratumumab in a similar patient population. This study was registered at www.clinicaltrials.gov as #NCT02519452.
•Subcutaneously administered daratumumab had similar safety and PK profile, and lower infusion-related reactions, compared with the IV formulation.•The 1800-mg subcutaneous dose of daratumumab induced deep, durable responses in patients with heavily pretreated MM.
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Observations of heavy metal pollution in white dwarf stars indicate that metal-rich planetesimals are frequently scattered into star-grazing orbits, tidally disrupted, and accreted onto the white ...dwarf surface, offering direct insight into the dynamical evolution of post-main-sequence exoplanetary systems. Emission lines from the gaseous debris in the accretion disks of some of these systems show variations on timescales of decades, and have been interpreted as the general relativistic precession of a recently formed, elliptical disk. Here we present a comprehensive spectroscopic monitoring campaign of the calcium infrared triplet emission in one system, HE 1349-2305, which shows morphological emission profile variations suggestive of a precessing, asymmetric intensity pattern. The emission profiles are shown to vary on a timescale of one to two years, which is an order of magnitude shorter than what has been observed in other similar systems. We demonstrate that this timescale is likely incompatible with general relativistic precession, and consider alternative explanations for the rapid evolution, including the propagation of density waves within the gaseous debris. We conclude with recommendations for follow-up observations, and discuss how the rapid evolution of the gaseous debris in HE 1349-2305 could be leveraged to test theories of exoplanetary debris disk evolution around white dwarf stars.
Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ...ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI.
We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 μm (500-615) versus 684 μm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls.
Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life.
ClinicalTrials.gov Identifier: NCT02616510.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tidal disruption and subsequent accretion of planetesimals by white dwarfs can reveal the elemental abundances of rocky bodies in exoplanetary systems. Those abundances provide information on the ...composition of the nebula from which the systems formed, which is analogous to how meteorite abundances inform our understanding of the early Solar System. We report the detection of lithium, sodium, potassium, and calcium in the atmosphere of the white dwarf Gaia DR2 4353607450860305024, which we ascribe to the accretion of a planetesimal. Using model atmospheres, we determine abundance ratios of these elements, and, with the exception of lithium, they are consistent with meteoritic values in the Solar System. We compare the measured lithium abundance with measurements in old stars and with expectations from Big Bang nucleosynthesis.
We present photometry and spectroscopy for 27 pulsating hydrogen-atmosphere white dwarfs (DAVs; a.k.a. ZZ Ceti stars) observed by the Kepler space telescope up to K2 Campaign 8, an extensive ...compilation of observations with unprecedented duration (>75 days) and duty cycle (>90%). The space-based photometry reveals pulsation properties previously inaccessible to ground-based observations. We observe a sharp dichotomy in oscillation mode line widths at roughly 800 s, such that white dwarf pulsations with periods exceeding 800 s have substantially broader mode line widths, more reminiscent of a damped harmonic oscillator than a heat-driven pulsator. Extended Kepler coverage also permits extensive mode identification: we identify the spherical degree of 87 out of 201 unique radial orders, providing direct constraints of the rotation period for 20 of these 27 DAVs, more than doubling the number of white dwarfs with rotation periods determined via asteroseismology. We also obtain spectroscopy from 4 m-class telescopes for all DAVs with Kepler photometry. Using these homogeneously analyzed spectra, we estimate the overall mass of all 27 DAVs, which allows us to measure white dwarf rotation as a function of mass, constraining the endpoints of angular momentum in low- and intermediate-mass stars. We find that 0.51-0.73 M white dwarfs, which evolved from 1.7-3.0 M ZAMS progenitors, have a mean rotation period of 35 hr with a standard deviation of 28 hr, with notable exceptions for higher-mass white dwarfs. Finally, we announce an online repository for our Kepler data and follow-up spectroscopy, which we collect at http://k2wd.org.
We report the discovery of short-period photometric variability and modulated Zeeman-split hydrogen emission in SDSSJ125230.93−023417.72 (EPIC 228939929), a variable white dwarf star observed at long ...cadence in K2 Campaign 10. The behavior is associated with a magnetic (B = 5.0 MG) spot on the stellar surface, making the 317.278 s period a direct measurement of the stellar rotation rate. This object is therefore the fastest-rotating, apparently isolated (without a stellar companion) white dwarf yet discovered and the second found to exhibit chromospheric Balmer emission after GD 356, in which the emission has been attributed to a unipolar inductor mechanism driven by a possible rocky planet. We explore the properties and behavior of this object, and consider whether its evolution may hold implications for white dwarf mergers and their remnants.
ABSTRACT
We report the discovery of two apparently isolated stellar remnants that exhibit rotationally modulated magnetic Balmer emission, adding to the emerging DAHe class of white dwarf stars. ...While the previously discovered members of this class show Zeeman-split triplet emission features corresponding to single magnetic field strengths, these two new objects exhibit significant fluctuations in their apparent magnetic field strengths with variability phase. The Zeeman-split hydrogen emission lines in LP 705−64 broaden from 9.4 to 22.2 MG over an apparent spin period of 72.629 min. Similarly, WD J143019.29−562358.33 varies from 5.8 to 8.9 MG over its apparent 86.394 min rotation period. This brings the DAHe class of white dwarfs to at least five objects, all with effective temperatures within 500 K of 8000 K and masses ranging from $0.65\,\,{\text{to}}\,\,0.83\, {\rm M}_{\odot }$.
How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain ...poorly understood. Using mouse melanoma models, we report that CD8+ TILs enhance peroxisome proliferator-activated receptor (PPAR)-α signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8+ TILs' effector functions, although co-inhibitor expression increases during tumor progression regardless of CD8+ TILs' antigen specificity. Further promoting FA catabolism improves the CD8+ TILs' ability to slow tumor progression. PD-1 blockade delays tumor growth without changing TIL metabolism or functions. It synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and even complete cures.
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•Metabolic stress causes CD8+ TIL exhaustion regardless of their antigen specificity•Low O2 and glucose induce CD8+ TILs to enhance FA catabolism to preserve functions•Promoting FA catabolism of CD8+ TILs improves their ability to combat tumors•A PPAR-α agonist enhances the therapeutic effect of PD-1 blockade in melanoma
Zhang et al. show that CD8+ T cells enhance PPAR-α signaling and fatty acid catabolism under the hypoglycemic and hypoxic condition to partially preserve effector functions. Metabolic reprogramming of T cells using a PPAR-α agonist improves tumor growth control, which is enhanced in combination with PD-1 blockade.
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