Metastatic colorectal cancer (mCRC) remains incurable in most cases, but survival has improved with advances in cytotoxic chemotherapy and targeted agents. However, the optimal use and sequencing of ...these agents across multiple lines of treatment is unclear. Here, we review current treatment approaches and optimal treatment sequencing across the first-, second- and third-line settings in mCRC, including biological aspects affecting sequencing and rechallenge. Effective first-line therapy is a key determinant of treatment outcomes and should be selected after considering both clinical factors and biological markers, notably RAS and BRAF. The second-line regimen choice depends on the systemic therapies given in first-line. Anti-angiogenic agents (e.g. bevacizumab, ramucirumab and aflibercept) are indicated for most patients, whereas epidermal growth factor receptor (EGFR) inhibitors do not improve survival in the second-line setting. Molecular profiling is important in third-line treatment, with options in RAS wild-type patients including EGFR inhibitors (cetuximab or panitumumab), regorafenib and trifluridine/tipiracil. Immunotherapy with pembrolizumab or nivolumab ± ipilimumab may be considered for patients with high microsatellite instability disease. Targeting HER2/neu amplification shows promise for the subset of CRC tumours displaying this abnormality. Sequencing decisions are complicated by the potential for any treatment break or de-escalation to evoke a distinct clinical progression type. Ongoing trials are investigating the optimal sequencing and timing of therapies for mCRC. Molecular profiling has established new targets, and increasing knowledge of tumour evolution under drug pressure will possibly impact on sequencing.
•Optimal sequencing of cytotoxic/targeted agents in metastatic colorectal cancer remains unclear.•First-line choice of therapy is critical as it affects treatment decisions in later lines.•Molecular profiling has established new targets that may impact sequencing.•Recent knowledge of tumour evolution also has clinical implications for sequencing.
The tropomyosin receptor kinase (TRK) family of receptor tyrosine kinases are encoded by NTRK genes and have a role in the development and normal functioning of the nervous system. Since the ...discovery of an oncogenic NTRK gene fusion in colorectal cancer in 1986, over 80 different fusion partner genes have been identified in a wide array of adult and paediatric tumours, providing actionable targets for targeted therapy. This review describes the normal function and physiology of TRK receptors and the biology behind NTRK gene fusions and how they act as oncogenic drivers in cancer. Finally, an overview of the incidence and prevalence of NTRK gene fusions in various types of cancers is discussed.
Colorectal cancer (CRC) represents a major cause of cancer deaths worldwide. Although significant progress has been made by molecular and immune therapeutic approaches, prognosis of advanced stage ...disease is still dismal. Alterations in the DNA damage response (DDR) pathways are emerging as novel targets for treatment across different cancer types. However, even though preclinical studies have shown the potential exploitation of DDR alterations in CRC, systematic and comprehensive testing is lagging and clinical development is based on analogies with other solid tumors according to a tissue-agnostic paradigm. Recently, functional evidence from patient-derived xenografts and organoids have suggested that maintenance with PARP inhibitors might represent a therapeutic opportunity in CRC patients previously responsive to platinum-based treatment.
In this review, we highlight the most promising preclinical data and systematically summarize published clinical trials in which DDR inhibitors have been used for CRC and provide evidence that disappointing results have been mainly due to a lack of clinical and molecular selection.
Future preclinical and translational research will help in better understanding the role of DDR alterations in CRC and pave the way to novel strategies that might have a transformative impact on treatment by identifying new therapeutic options including tailored use of standard chemotherapy.
•In CRC, the therapeutic application of DDR alterations has to be elucidated.•Results from clinical trials exploiting DDR alterations as a target are disappointing and hampered by several limitations.•A subset of CRC is vulnerable to PARP inhibition as suggested by recent preclinical evidence.•Currently, there is no consensus on methods to assess the functional role of DDR alterations in CRC.•A better understanding of DDR alterations based on functional testing might have a transformative impact on CRC treatment.
Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of ...patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors is driven by amplification or mutation of HER2. This paper reviews the role of HER2 amplification as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type. While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients.
The subthalamic nucleus (STN) has a key role in the pathophysiology of Parkinson's disease and is the primary target for high-frequency deep brain stimulation (DBS). The STN rest electrical activity ...in Parkinson's disease, however, is still unclear. Here we tested the hypothesis that pharmacological modulation of STN activity has rhythm-specific effects in the classical range of EEG frequencies, below 50 Hz. We recorded local field potentials (LFPs) through electrodes implanted in the STN of patients with Parkinson's disease (20 nuclei from 13 patients). After overnight withdrawal of antiparkinsonian therapy, LFPs were recorded at rest both before (off) and after (on) acute administration of different antiparkinsonian drugs: levodopa, apomorphine, or orphenadrine. In the off-state, STN LFPs showed clearly defined peaks of oscillatory activity below 50 Hz: at low frequencies (2–7 Hz), in the alpha (7–13 Hz), low-beta (13–20 Hz), and high-beta range (20–30 Hz). In the on-state after levodopa and apomorphine administration, low-beta activity significantly decreased and low-frequency activity increased. In contrast, orphenadrine increased beta activity. Power changes elicited by levodopa and apomorphine at low frequencies and in the beta range were not correlated, whereas changes in the alpha band, which were globally not significant, correlated with the beta rhythm (namely, low beta: 13–20 Hz). In conclusion, in the human STN, there are at least two rhythms below 50 Hz that are separately modulated by antiparkinsonian medication: one at low frequencies and one in the beta range. Multiple rhythms are consistent with the hypothesis of multiple oscillating systems, each possibly correlating with specific aspects of human STN function and dysfunction.
The article presents preliminary findings from a family survey about children's experiences during the COVID-19 lockdown, which was administered through the pediatric network SICuPP (Italian Society ...of Primary Care Pediatricians - Lombardy) in Northern Italy. The study involved 3443 parents with children aged from 1 to 5 years and from 6 to 10 years living in Lombardy region, the earliest and most severely affected by the COVID-19 emergency. All participants completed an online questionnaire and provided informed consent. Respondents generally displayed confidence and a sense of self-efficacy in relation to how they had coped with the COVID-19 emergency, despite the many difficulties encountered during the lockdown. They reported having observed some unexpected improvements and resources (e.g. parent/child and sibling relationships, adaptiveness and autonomy on the part of children). Parent-to-parent solidarity was commonly reported, although a small percentage of parents had experienced a greater sense of isolation and anxiety. Finally, the study indicated 'key areas of vulnerability' (concerning, for example, eating, rules, sleeping, use of technological devices, fears ...) that should be monitored in future by strengthening the territorial network linking families, educational services, and health services.
We assess future flood hazard in view of climate change at pan‐European scale using a large ensemble of climate projections. The ensemble consists of simulations from 12 climate experiments conducted ...within the ENSEMBLES project, forced by the SRES A1B emission scenario for the period 1961–2100. Prior to driving the hydrological model LISFLOOD, climate simulations are corrected for bias in precipitation and temperature using a Quantile Mapping (QM) method. For time slices of 30 years, a Gumbel distribution is fitted by the maximum likelihood method through the simulated annual maximum discharges. Changes in extreme river flows, here exemplified by the 100‐year discharge (Q100), are then analyzed with respect to a control period (1961–1990). We assess the uncertainty arising from using alternative climate experiments to force LISFLOOD and from the fitting of extreme value distributions. Results show large discrepancies in the magnitude of change in Q100among the hydrological simulations for different climate experiments, with some regions even showing an opposite signal of change. Due to the low signal‐to‐noise ratio in some areas the projected changes showed not all to be statistically significant. Despite this, western Europe, the British Isles and northern Italy show a robust increase in future flood hazard, mainly due to a pronounced increase in extreme rainfall. A decrease inQ100, on the other hand, is projected in eastern Germany, Poland, southern Sweden and, to a lesser extent, the Baltic countries. In these areas, the signal is dominated by the strong reduction in snowmelt induced floods, which offsets the increase in average and extreme precipitation.
Key Points
Future flood hazard using high‐resolution bias‐corrected climate simulations
Large uncertainties bound to projected changes of future flood hazard
Increasing trend in future flood hazard, shifting to rainfall‐dominated floods
Herbivore-induced plant volatiles (HIPVs) are an important cue used in herbivore location by carnivorous arthropods such as parasitoids. The effects of plant volatiles on parasitoids have been well ...characterised at small spatial scales, but little research has been done on their effects at larger spatial scales. The spatial matrix of volatiles (‘volatile mosaic’) within which parasitoids locate their hosts is dynamic and heterogeneous. It is shaped by the spatial pattern of HIPV-emitting plants, the concentration, chemical composition and breakdown of the emitted HIPV blends, and by environmental factors such as wind, turbulence and vegetation that affect transport and mixing of odour plumes. The volatile mosaic may be exploited differentially by different parasitoid species, in relation to species traits such as sensory ability to perceive volatiles and the physical ability to move towards the source. Understanding how HIPVs influence parasitoids at larger spatial scales is crucial for our understanding of tritrophic interactions and sustainable pest management in agriculture. However, there is a large gap in our knowledge on how volatiles influence the process of host location by parasitoids at the landscape scale. Future studies should bridge the gap between the chemical and behavioural ecology of tritrophic interactions and landscape ecology.
Coupled Superconducting and Magnetic Order in CeCoIn5 KENZELMANN, M; STRÄSSLE, Th; THOMPSON, J. D ...
Science (American Association for the Advancement of Science),
09/2008, Volume:
321, Issue:
5896
Journal Article
Peer reviewed
Strong magnetic fluctuations can provide a coupling mechanism for electrons that leads to unconventional superconductivity. Magnetic order and superconductivity have been found to coexist in a number ...of magnetically mediated superconductors, but these order parameters generally compete. We report that close to the upper critical field, CeCoIn5 adopts a multicomponent ground state that simultaneously carries cooperating magnetic and superconducting orders. Suppressing superconductivity in a first-order transition at the upper critical field leads to the simultaneous collapse of the magnetic order, showing that superconductivity is necessary for the magnetic order. A symmetry analysis of the coupling between the magnetic order and the superconducting gap function suggests a form of superconductivity that is associated with a nonvanishing momentum.
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