Evaluating the impact of Relative Total Dose Intensity (RTDI) on patients' short and long-term outcome in taxane- and anthracycline-based chemotherapy of metastatic breast cancer- a pooled analysis

Background: Chemotherapy dose delay and/or reduction lower relative total dose intensity (RTDI) and may affect short- and long-term outcome of metastatic breast cancer (MBC) patients. Methods: Based on 933 individual patients' data of from 3 randomized MBC trials using an anthracycline and taxane we examined the impact of RTDI on efficacy and determined the lowest optimal RTDI for MBC patients. Results: Median time to disease progression (TTDP) and overall survival (OS) of all patients were 39 and 98 weeks. Overall higher RTDI was correlated with a shorter TTDP (log-rank p = 0.0525 for 85% RTDI cut-off). Proportional hazards assumption was violated, there was an early drop in the TTDP-curve for the high RTDI group. It was explained by the fact that patients with primary disease progression (PDP) do have a high RTDI per definition. Excluding those 114 patients with PDP the negative correlation between RTDI and TTDP vanished. However, non-PDP patients with RTDI-cut-off levels <85% showed a shorter OS than patients with higher RTDI levels (p = 0.0086). Conclusions: Optimizing RTDI above 85% appears to improve long-term outcome of MBC patients receiving first-line chemotherapy. Lowering RTDI had no negative influence on short term outcome like OR and TTDP

A water cycle for the Anthropocene

International audienceHumor us for a minute and do an online image search of the water cycle. How many diagrams do you have to scroll through before seeing any sign of humans? What about water pollution or climate change—two of the main drivers of the global water crisis? In a recent analysis of more than 450 water cycle diagrams, we found that 85% showed no human interaction with the water cycle and 98% omitted any sign of climate change or waterpollution (Abbott et al., 2019). Additionally, 92% of diagrams depicted verdant, temperate ecosystems with abundant freshwater and 95% showed only a single river basin. It did not matter if the diagrams came from textbooks, scientific articles, or the internet, nor if they were old or new; most showed an undisturbed water cycle, free from human interference. These depictions contrast starkly with the state of the water cycle in the Anthropocene, when land conversion, human water use, and climate change affect nearly every water pool and flux (Wurtsbaugh et al., 2017; Falkenmark et al., 2019; Wine and Davison, 2019). The dimensions and scale of human interference with water are manifest in failing fossil aquifersin the world’s great agricultural regions (Famiglietti, 2014), accelerating ice discharge from the Arctic (Box et al., 2018), and instability in atmospheric rivers that support continental rainfall (Paul et al., 2016).We believe that incorrect water cycle diagrams are a symptom of a much deeper and widespread problem about how humanity relates to water on Earth. Society does not understand how the water cycle works nor how humans fit into it (Attari, 2014; Linton, 2014; Abbott et al., 2019). In response to this crisis of understanding, we call on researchers, educators, journalists, lawyers, and policy makers to change how we conceptualize and present the global water cycle. Specifically, we must teach where water comes from, what determines its availability, and how many individuals and ecosystems are in crisis because of water mismanagement, climate change, and land conversion. Because the drivers of the global water crisis are truly global, ensuring adequate water for humans and ecosystems will require coordinated efforts that extend beyond geopolitical borders and outlast the tenure of individual administrations (Keys et al., 2017; Adler, 2019). This level of coordination and holistic thinking requires widespread understanding of the water cycle and the global water crisis. Making the causes and consequences of the water crisis visible in our diagrams is atractable and important step towards the goal of a sustainable relationship with water that includes ecosystems and society

Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure

The methotrexate (MTX) rescue agent carboxypeptidase G2 (CPDG2) rapidly hydrolyses MTX to the inactive metabolite DAMPA (4-[[2,4-diamino-6-(pteridinyl)methyl]-methylamino]-benzoic acid) and glutamate in patients with MTX-induced renal failure and delayed MTX excretion. DAMPA is thought to be an inactive metabolite of MTX because it is not an effective inhibitor of the MTX target enzyme dihydrofolate reductase. DAMPA is eliminated more rapidly than MTX in these patients, which suggests a nonrenal route of elimination. In a phase II study (May 1997–March 2002), CPDG2 was administered intravenously to 82 patients at a median dose of 50 U kg−1 (range 33–60 U kg−1). Eligible patients for this study had serum MTX concentrations of >10 μM at 36 h or >5 μM at 42 h after start of MTX infusion and documented renal failure (serum creatinine ⩾1.5 times the upper limit of normal). Immediately before CPDG2 administration, a median MTX serum level of 11.93 μM (range 0.52–901 μM) was documented. Carboxypeptidase G2 was given at a median of 52 h (range 25–178 h) following the start of an MTX infusion of 1–12 g m−2 4–36 h−1 and resulted in a rapid 97% (range 73–99%) reduction of the MTX serum level. Toxicity related to CPDG2 was not observed. Toxicity related to MTX was documented in about half the patients; four patients died despite CPDG2 administration due to severe myelosuppression and septic complications. In conclusion, administration of CPDG2 is a well-tolerated, safe and a very effective way of MTX elimination in delayed excretion due to renal failure

An extraterrestrial trigger for the Early Cretaceous massive volcanism? Evidence from the paleo-Tethys Ocean

The Early Cretaceous Greater Ontong Java Event in the Pacific Ocean may have covered ca. 1% of the Earth's surface with volcanism. It has puzzled scientists trying to explain its origin by several mechanisms possible on Earth, leading others to propose an extraterrestrial trigger to explain this event. A large oceanic extraterrestrial impact causing such voluminous volcanism may have traces of its distal ejecta in sedimentary rocks around the basin, including the paleo-Tethys Ocean which was then contiguous with the Pacific Ocean. The contemporaneous marine sequence at central Italy, containing the sedimentary expression of a global oceanic anoxic event (OAE1a), may have recorded such ocurrence as indicated by two stratigraphic intervals with 187Os/188Os indicative of meteoritic influence. Here we show, for the first time, that platinum group element abundances and inter-element ratios in this paleo-Tethyan marine sequence provide no evidence for an extraterrestrial trigger for the Early Cretaceous massive volcanism

Minocycline Synergizes with N-Acetylcysteine and Improves Cognition and Memory Following Traumatic Brain Injury in Rats

Background: There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models. Methodology/Principal Findings: Drugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Coadministration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels. This effect on interleukin-1 was not observed when th

The role of deoxycytidine-metabolizing enzymes in the cytotoxicity induced by 3′-amino-2′,3′-dideoxycytidine and cytosine arabinoside

The cellular metabolism of 3′-amino-2′,3′-dideoxycytidine (3′-NH 2 -dCyd), a cytotoxic agent previously reported to be a poor substrate for purified Cyd/dCyd deaminase (dCydD), was compared with that of cytosine arabinoside (ara-C) in cells that displayed dCydD activity (HeLa) and in cells that did not (L1210). Growth inhibition induced by 3′-NH 2 -dCyd was dependent on the levels of anabolic enzymes, particularly dCyd kinase (dCydK), whereas cytotoxicity induced by ara-C was dependent on the expression of both anabolic and catabolic enzyme activities. Competition kinetics using purified enzyme revealed that the binding affinity of ara-C to dCydK was 5-fold that of the amino analog. However, this binding advantage is apparently offset in cells that contain high levels of dCydD, since the K i values for this enzyme were 0.2 and 23 mm for ara-C and 3′-NH 2 -dCyd, respectively. This was reflected in the decrease in analog sensitivity observed between the two cell lines, whereby the concentrations of ara-C and 3′-NH 2 -dCyd required to inhibit growth by 50% were 200 and 7 times higher, respectively, in the dCydD-containing HeLa cells as compared with the dCydD-deficient L1210 cells. The metabolic stability and cytotoxicity of 3′-NH 2 -dCyd was independent of cell number. An unexpected finding was the extent to which the effectiveness of ara-C could be mitigated by the number of dCydD-containing cells. A completely cytotoxic concentration of ara-C was rendered nontoxic by a 10-fold increase in cell number. This observation was supported by an increase in I-β- d -arabinofuranosyluracil (ara-U) formation, a decrease in ara-C 5′-triphosphate (ara-CTP) accumulation, and a rise in cell viability with increasing cell number. These findings indicate that unlike ara-C, the effectiveness of 3′-NH 2 -dCyd is independent of the level of deaminase, which suggests its possible utility in situations in which high levels of deaminase are manifest.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46922/1/280_2004_Article_BF00686406.pd

Traditional plant functional groups explain variation in economic but not size-related traits across the tundra biome

Aim Plant functional groups are widely used in community ecology and earth system modelling to describe trait variation within and across plant communities. However, this approach rests on the assumption that functional groups explain a large proportion of trait variation among species. We test whether four commonly used plant functional groups represent variation in six ecologically important plant traits. Location Tundra biome. Time period Data collected between 1964 and 2016. Major taxa studied 295 tundra vascular plant species. Methods We compiled a database of six plant traits (plant height, leaf area, specific leaf area, leaf dry matter content, leaf nitrogen, seed mass) for tundra species. We examined the variation in species-level trait expression explained by four traditional functional groups (evergreen shrubs, deciduous shrubs, graminoids, forbs), and whether variation explained was dependent upon the traits included in analysis. We further compared the explanatory power and species composition of functional groups to alternative classifications generated using post hoc clustering of species-level traits. Results Traditional functional groups explained significant differences in trait expression, particularly amongst traits associated with resource economics, which were consistent across sites and at the biome scale. However, functional groups explained 19% of overall trait variation and poorly represented differences in traits associated with plant size. Post hoc classification of species did not correspond well with traditional functional groups, and explained twice as much variation in species-level trait expression. Main conclusions Traditional functional groups only coarsely represent variation in well-measured traits within tundra plant communities, and better explain resource economic traits than size-related traits. We recommend caution when using functional group approaches to predict tundra vegetation change, or ecosystem functions relating to plant size, such as albedo or carbon storage. We argue that alternative classifications or direct use of specific plant traits could provide new insights for ecological prediction and modelling.Peer reviewe

Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious?

Neoadjuvant chemotherapy (NACT) is a term originally used to describe the administration of chemotherapy preoperatively before surgery. The original rationale for administering NACT or so-called induction chemotherapy to shrink or downstage a locally advanced tumour, and thereby facilitate more effective local treatment with surgery or radiotherapy, has been extended with the introduction of more effective combinations of chemotherapy to include reducing the risks of metastatic disease. It seems logical that survival could be lengthened, or organ preservation rates increased in resectable tumours by NACT. In rectal cancer NACT is being increasingly used in locally advanced and nonmetastatic unresectable tumours. Randomised studies in advanced colorectal cancer show high response rates to combination cytotoxic therapy. This evidence of efficacy coupled with the introduction of novel molecular targeted therapies (such as Bevacizumab and Cetuximab), and long waiting times for radiotherapy have rekindled an interest in delivering NACT in locally advanced rectal cancer. In contrast, this enthusiasm is currently waning in other sites such as head and neck and nasopharynx cancer where traditionally NACT has been used. So, is NACT in rectal cancer a real advance or just history repeating itself? In this review, we aimed to explore the advantages and disadvantages of the separate approaches of neoadjuvant, concurrent and consolidation chemotherapy in locally advanced rectal cancer, drawing on theoretical principles, preclinical studies and clinical experience both in rectal cancer and other disease sites. Neoadjuvant chemotherapy may improve outcome in terms of disease-free or overall survival in selected groups in some disease sites, but this strategy has not been shown to be associated with better outcomes than postoperative adjuvant chemotherapy. In particular, there is insufficient data in rectal cancer. The evidence for benefit is strongest when NACT is administered before surgical resection. In contrast, the data in favour of NACT before radiation or chemoradiation (CRT) is inconclusive, despite the suggestion that response to induction chemotherapy can predict response to subsequent radiotherapy. The observation that spectacular responses to chemotherapy before radical radiotherapy did not result in improved survival, was noted 25 years ago. However, multiple trials in head and neck cancer, nasopharyngeal cancer, non-small-cell lung cancer, small-cell lung cancer and cervical cancer do not support the routine use of NACT either as an alternative, or as additional benefit to CRT. The addition of NACT does not appear to enhance local control over concurrent CRT or radiotherapy alone. Neoadjuvant chemotherapy before CRT or radiation should be used with caution, and only in the context of clinical trials. The evidence base suggests that concurrent CRT with early positioning of radiotherapy appears the best option for patients with locally advanced rectal cancer and in all disease sites where radiation is the primary local therapy

Search for anisotropic gravitational-wave backgrounds using data from Advanced LIGO and Advanced Virgo's first three observing runs

We report results from searches for anisotropic stochastic gravitational-wave backgrounds using data from the first three observing runs of the Advanced LIGO and Advanced Virgo detectors. For the first time, we include Virgo data in our analysis and run our search with a new efficient pipeline called {\tt PyStoch} on data folded over one sidereal day. We use gravitational-wave radiometry (broadband and narrow band) to produce sky maps of stochastic gravitational-wave backgrounds and to search for gravitational waves from point sources. A spherical harmonic decomposition method is employed to look for gravitational-wave emission from spatially-extended sources. Neither technique found evidence of gravitational-wave signals. Hence we derive 95\% confidence-level upper limit sky maps on the gravitational-wave energy flux from broadband point sources, ranging from $F_{\alpha, \Theta} < {\rm (0.013 - 7.6)} \times 10^{-8} {\rm erg \, cm^{-2} \, s^{-1} \, Hz^{-1}},$ and on the (normalized) gravitational-wave energy density spectrum from extended sources, ranging from $\Omega_{\alpha, \Theta} < {\rm (0.57 - 9.3)} \times 10^{-9} \, {\rm sr^{-1}}$, depending on direction ($\Theta$) and spectral index ($\alpha$). These limits improve upon previous limits by factors of $2.9 - 3.5$. We also set 95\% confidence level upper limits on the frequency-dependent strain amplitudes of quasimonochromatic gravitational waves coming from three interesting targets, Scorpius X-1, SN 1987A and the Galactic Center, with best upper limits range from $h_0 < {\rm (1.7-2.1)} \times 10^{-25},$ a factor of $\geq 2.0$ improvement compared to previous stochastic radiometer searches.Comment: 23 Pages, 9 Figure